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Bekaii-Saab T, Cho SK, Hocum B, Grossman J, Appukkuttan S, Babajanyan S, Marian M, Lee W, Barzi A, Yang M. Cost-effectiveness analysis of regorafenib dose optimization for refractory metastatic colorectal cancer. J Med Econ 2025; 28:655-663. [PMID: 40265856 DOI: 10.1080/13696998.2025.2496068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND New regimens have emerged as third-line or later therapies for metastatic colorectal cancer (mCRC), including regorafenib dose optimization (ReDO), trifluridine/tipiracil and bevacizumab (TAS-BEV) combination therapy, and fruquintinib. We evaluated relative cost-effectiveness of these therapies in patients with mCRC from a US payer's perspective. MATERIALS AND METHODS A partitioned survival model (PSM) was constructed to estimate total costs and quality-adjusted life years (QALYs). Clinical parameters were obtained from pivotal trials of the respective therapies and incremental cost-effectiveness ratios (ICERs) were estimated to assess relative cost-effectiveness of these treatments. Model robustness was assessed using deterministic (DSA) and probabilistic sensitivity analysis (PSA). Three scenario analyses were conducted: (1) assuming equal efficacy across treatments, (2) with prior exposure to anti-vascular endothelial growth factor (VEGF) therapy, and (3) alternative clinical inputs for fruquintinib from a different clinical trial. RESULTS Under the conventional willingness-to-pay (WTP) threshold in US ($150,000 per QALY gained), ReDO was cost-effective when compared with TAS-BEV and was dominant over fruquintinib. TAS-BEV was associated with an incremental QALY of 0.197 over ReDO, resulting in an ICER at $554,567 per QALY gained. The base case results were robust in DSA and PSA. Most influential parameters were treatment cost and effectiveness. In patients with prior anti-VEGF therapy, ReDO remained cost-effective compared to TAS-BEV and fruquintinib under the conventional WTP threshold. LIMITATION Differences in trial populations may affect the comparability of the outcomes. Sensitivity and scenario analyses were conducted to address these limitations. CONCLUSION ReDO was cost-effective compared with TAS-BEV from the US payer's perspective despite a higher QALY gain associated with TAS-BEV. ReDO was dominant over fruquintinib, consistently having a higher QALY gain and lower cost.
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Affiliation(s)
| | | | - Brian Hocum
- Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA
| | | | | | | | | | | | - Afsaneh Barzi
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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Albassam H, Almutairi O, Alnasser M, Altowairqi F, Almutairi F, Alobid S. Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy. J Enzyme Inhib Med Chem 2025; 40:2468852. [PMID: 39992303 PMCID: PMC11852364 DOI: 10.1080/14756366.2025.2468852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 01/31/2025] [Accepted: 02/08/2025] [Indexed: 02/25/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.
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Affiliation(s)
- Hussam Albassam
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Omar Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Majed Alnasser
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Faisal Altowairqi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Faris Almutairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saad Alobid
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Lyu M, Zhang T, Bao Z, Li P, Chen M, Quan H, Wang C, Xia L, Li Y, Tang B. In situ forming AIEgen-alginate hydrogel for remodeling tumor microenvironment to boost FLASH immunoradiotherapy. Biomaterials 2025; 320:123281. [PMID: 40138965 DOI: 10.1016/j.biomaterials.2025.123281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/16/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Abstract
FLASH radiotherapy, which involves the delivery of an ultra-high radiation dose rate exceeding 40 Gy/s, has emerged as a promising tumor ablation strategy. While this approach generally spares normal tissues, the incomplete killing of tumors may sometimes lead to recurrence due to the immunosuppressive tumor microenvironment (TME). Herein, an aggregation-induced-emission luminogen (AIEgen)-alginate hydrogel was used to sensitize colon cancer via photodynamic therapy (PDT). Flower-like calcium carbonate nanoparticles, doped with an AIEgen termed CQu, were designed and applied as a cocktail with sodium alginate. When exposed to the acidic TME, Ca2+ is released from this structure, resulting in sodium alginate termed FA forming a hydrogel in situ within the TME. This hydrogel also captures high concentrations of CQu in the local TME. Under laser irradiation, the CQu can generate sustained reactive oxygen species (ROS) production, thereby facilitating Ca2+ influx and causing mitochondrial damage. Through a single injection of established FA hydrogel, followed by PDT and FLASH radiotherapy, immunogenic tumor cell death was induced which promoted antitumor immunity, thereby protecting against tumor recurrence while realizing abscopal effect. The results highlight the potential to improve the sensitivity of tumor cells to FLASH radiotherapy through sustained ROS production and Ca2+ overload, thereby yielding optimal immunotherapy outcomes.
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Affiliation(s)
- Meng Lyu
- Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
| | - Tianfu Zhang
- School of Biomedical Engineering, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhirong Bao
- Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Pei Li
- Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
| | - Mingzhu Chen
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei, 430072, China
| | - Hong Quan
- Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei, 430072, China
| | - Cunchuan Wang
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510630, China.
| | - Ligang Xia
- Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
| | - Yang Li
- Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
| | - Benzhong Tang
- School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, (CUHK-Shenzhen), Guangdong, 518172, China
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4
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Li S, Liu T, Li C, Zhang Z, Zhang J, Sun D. Overcoming immunotherapy resistance in colorectal cancer through nano-selenium probiotic complexes and IL-32 modulation. Biomaterials 2025; 320:123233. [PMID: 40081224 DOI: 10.1016/j.biomaterials.2025.123233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/11/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND AND OBJECTIVE Colorectal cancer (CRC) is a major global health burden, with immunotherapy often limited by immune tolerance and resistance. This study introduces an innovative approach using Selenium Nanoparticles-Loaded Extracellular Vesicles combined with Interleukin-32 and Engineered Probiotic Escherichia coli Nissle 1917 (SeNVs@NE-IL32-EcN) to enhance CD8+ T cell-mediated immune responses and overcome immunotherapy resistance. METHODS Single-cell RNA sequencing (scRNA-seq) and transcriptomic analyses were performed to identify key immune cells and regulators involved in CRC immunotherapy resistance, focusing on CD8+ T cells and the regulatory factor IL32. A humanized xenograft mouse model was used to evaluate the impact of IL32 and SeNVs@NE-IL32-EcN on tumor growth and immune responses. The SeNVs@NE-IL32-EcN complex was synthesized through a reverse micelle method and functionalized using extracellular vesicles. Its morphology, size, antioxidant activity, and safety were characterized using electron microscopy, dynamic light scattering (DLS), and in vitro co-culture assays. RESULTS Single-cell analyses revealed a significant reduction in CD8+ T cell infiltration in immunotherapy-resistant CRC patients. IL32 was identified as a key regulator enhancing CD8+ T cell cytotoxic activity through granzyme B and IFN-γ secretion. Treatment with SeNVs@NE-IL32-EcN significantly improved the proliferation and activity of CD8+ T cells and reduced tumor progression in humanized mouse models. In vitro and in vivo results demonstrated the complex's biocompatibility, antioxidant properties, and ability to enhance CRC immunotherapy while mitigating immune tolerance. CONCLUSION SeNVs@NE-IL32-EcN offers a novel nano-biomaterial strategy that integrates nanotechnology and probiotic therapy to enhance CD8+ T cell-mediated immunity and overcome CRC immunotherapy resistance. This study lays the foundation for future therapeutic applications in cancer treatment by advancing immune-modulating biomaterials.
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Affiliation(s)
- Shiquan Li
- Department of Colorectal & Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Tao Liu
- Department of Colorectal & Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Chenyao Li
- Department of Colorectal & Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Zhiyuan Zhang
- Department of Colorectal & Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Jiantao Zhang
- Department of Colorectal & Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Di Sun
- Department of Colorectal & Anal Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, 130021, China.
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Bahrami P, Al Zein M, Eid AH, Sahebkar A. Liver Transplantation for Non-hepatocellular Carcinoma: The Role of Immune Checkpoint Inhibitors. J Clin Exp Hepatol 2025; 15:102558. [PMID: 40303874 PMCID: PMC12036051 DOI: 10.1016/j.jceh.2025.102558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 03/22/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC), gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), and cholangiocarcinoma (CCA) exhibit high rates of morbidity and mortality once metastasized to the liver. Liver transplantation (LT) is a viable therapeutic approach for these cancers in highly selected patients; however, their invasive nature at late stages causes many patients to be delisted from transplantation or to require further downstaging. Immunotherapy with immune checkpoint modulators has revolutionized cancer research. Immune checkpoint inhibitors (ICI) leverage the chronic inflammatory state and the overexpression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) by malignant cells and regulatory T cells, to block immune checkpoints and counteract tumor's ability to evade the immune system. However, the interaction between allograft PD-L1 and PD-1 on infiltrating T cells functions as a means of graft tolerance in cases of LT. Therefore, the application of ICIs might block this protective effect and induce graft rejection, a phenomenon particularly observed in PD-1/PD-L1 inhibiting ICIs. The risk of post-LT graft rejection can be mitigated by applying advanced biomarkers and specifying certain mutations that enhance patient selection criteria for pre-LT ICI use. Furthermore, the determination of optimal intervals of ICI administration pre- and post-LT, identification of ICI indications in de novo malignancies occurring after LT, and investigation of biomarkers for early rejection detection, pave the way for more promising LT outcomes in patients with CRC, GEP-NEN, or CCA. Therefore, this review aims to illustrate a comprehensive overview of the role of ICI therapy in the management of non-hepatocellular carcinoma transplant oncology cancers by demonstrating the potential for its application in both pre-and post-LT states, and pathways to reduce or timely detect ICI-associated graft rejection.
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Affiliation(s)
- Pegah Bahrami
- Applied Biomedical Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Al Zein
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Sun W, Fan B, Qin X, Zhang X, Zhang P, Zhang Y. Synergistic ROS/enzyme dual-responsive oral drug delivery system: A novel multi-mechanistic platform for spatiotemporal control and overcoming drug resistance in colorectal cancer therapy. Mater Today Bio 2025; 33:101920. [PMID: 40528838 PMCID: PMC12173668 DOI: 10.1016/j.mtbio.2025.101920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 05/27/2025] [Accepted: 05/28/2025] [Indexed: 06/20/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, driven by complex interactions between inflammatory pathways, gut microbiota dysbiosis, and tumor microenvironment remodeling. Conventional therapies, particularly single-target oral chemotherapeutics, are hindered by poor bioavailability, systemic toxicity, and drug resistance. To address these limitations, we engineered KGM-PTX/CSM microspheres, a dual-responsive drug delivery system leveraging the elevated reactive oxygen species (ROS) in CRC and β-mannanase overexpression in the colorectum. The system comprises ROS-sensitive prodrug micelles (PSM) encapsulated within konjac glucomannan (KGM). PSM micelles were synthesized by conjugating hydrophilic chitosan oligosaccharides (COS) with the hydrophobic anti-inflammatory agent mesalazine (MSL) via ROS-labile thioether bonds, followed by paclitaxel (PTX) encapsulation. Upon oral administration, KGM undergoes β-mannanase-triggered degradation in the colon, releasing PSM micelles that subsequently disintegrate in the ROS-rich tumor microenvironment, enabling spatiotemporally controlled drug release. In vitro studies demonstrated ROS-responsive drug liberation (91.2 % cumulative release within 48 h) and enhanced cytotoxicity against PTX-resistant SW480/PTX cells (IC50: 9.33 μg/mL vs. 45.68 μg/mL for free PTX). Mechanistic investigations revealed synergistic interactions among the system's components: PTX stabilized microtubules to induce apoptosis, while MSL counteracted COX-2/P-gp-mediated drug resistance and alleviated PTX-associated intestinal inflammation. In the AOM/DSS-induced orthotopic CRC model, KGM-PTX/CSM significantly inhibited colorectal tumor growth, improved survival rates, and suppressed inflammatory cytokine expression (TNF-α, IL-1β, IL-6, and IL-10) in serum and colorectal tissues. Immunomodulatory effects included enhanced CD8+ T-cell activity, suppression of Treg-mediated immune evasion, and macrophage polarization toward the tumor-suppressive M1 phenotype. Gut microbiota analysis demonstrated restored operational taxonomic unit (OTU) counts, increased beneficial bacterial populations, elevated alpha and beta diversity, reduced pro-inflammatory bacteria, and increased short-chain fatty acid (acetate, propionate, and butyrate) concentrations, collectively improving intestinal microecology and inhibiting tumor progression. This study synergistically enhanced the anti-CRC effect through multiple mechanisms of action such as chemotherapy, reversal of chemotherapy resistance, regulation of intestinal flora, anti-inflammation, activation of immune cells, etc., which will provide a certain reference for the research of synergistic drug therapy for CRC.
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Affiliation(s)
- Weitong Sun
- College of Pharmacy, Jiamusi University, Jiamusi City, Heilongjiang Province, 154007, China
- Heilongjiang Pharmaceutical Research Institute, Jiamusi City, Heilongjiang Province, 154007, China
| | - Bingbing Fan
- College of Pharmacy, Jiamusi University, Jiamusi City, Heilongjiang Province, 154007, China
| | - Xiaohan Qin
- College of Pharmacy, Jiamusi University, Jiamusi City, Heilongjiang Province, 154007, China
| | - Xin Zhang
- College of Pharmacy, Jiamusi University, Jiamusi City, Heilongjiang Province, 154007, China
| | - Pengxia Zhang
- College of Pharmacy, Jiamusi University, Jiamusi City, Heilongjiang Province, 154007, China
| | - Yu Zhang
- College of Pharmacy, Jiamusi University, Jiamusi City, Heilongjiang Province, 154007, China
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7
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Han HJ, Han J, Choi Y, Hwang GJ, Kim S, Ryoo IJ, Kim BY, Soung NK. A novel tubulin inhibitor, No.07, shows anti-cancer and anti-metastatic effects in colon cancer and tumoroids. Life Sci 2025; 372:123644. [PMID: 40252756 DOI: 10.1016/j.lfs.2025.123644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 04/08/2025] [Accepted: 04/12/2025] [Indexed: 04/21/2025]
Abstract
Colorectal cancer is a highly metastatic disease and the second leading cause of cancer-related death worldwide. Despite the use of various treatment strategies, including chemotherapy and targeted therapy, challenges such as toxicity, drug resistance, and poor response indicate the critical need for new therapeutic agents. Microtubule target agents are one of the major treatment options for chemotherapy in various cancer patients. However, most of these agents are substrates of the MDR1 protein, which leads to the development of multidrug resistance, significantly limiting their effectiveness. Therefore, the development of new drugs is being actively pursued. In this study, we synthesized a novel compound, No.07, which demonstrates significant anti-cancer activity in 3D spheroid models, patient-derived colon cancer organoid models, and mice xenograft models. No.07 directly binds to tubulin dimers, interfering with microtubule polymerization and thereby disrupting tubulin dynamics, ultimately inducing mitotic arrest. Furthermore, No.07 increases mitochondria reactive oxygen species level, leading to the inactivation of the RAF-MEK-ERK signaling cascade, which consequently inhibits metastasis. Notably, Swiss ADME predictions suggest that No.07 is not a substrate of MDR1 and can cross the blood-brain barrier, unlike other microtubule target agents that are limited by MDR1-mediated drug resistance and poor brain penetration. Additionally, experiments using multidrug-resistant cell lines confirmed that No.07 effectively overcomes multidrug resistance, providing a significant improvement over traditionally used chemotherapy agents. In conclusion, No.07 has the potential to address the limitations of existing treatments as a novel therapeutic option.
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Affiliation(s)
- Ho Jin Han
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Junyeol Han
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Biomolecular Science, Korea National University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Yerim Choi
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Biomolecular Science, Korea National University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Gwi-Ja Hwang
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Sumin Kim
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Biomolecular Science, Korea National University of Science and Technology, Daejeon 34113, Republic of Korea
| | - In-Ja Ryoo
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Bo Yeon Kim
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Biomolecular Science, Korea National University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Nak-Kyun Soung
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea; Department of Biomolecular Science, Korea National University of Science and Technology, Daejeon 34113, Republic of Korea.
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Yao L, Yin H, Yang C, Han S, Ma J, Graff JC, Wang CY, Jiao Y, Ji J, Gu W, Wang G. Generating research hypotheses to overcome key challenges in the early diagnosis of colorectal cancer - Future application of AI. Cancer Lett 2025; 620:217632. [PMID: 40097064 DOI: 10.1016/j.canlet.2025.217632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 03/08/2025] [Accepted: 03/10/2025] [Indexed: 03/19/2025]
Abstract
We intend to explore the capability of ChatGPT 4.0 in generating innovative research hypotheses to address key challenges in the early diagnosis of colorectal cancer (CRC). We asked ChatGPT to generate hypotheses focusing on three main challenges: improving screening accuracy, overcoming technological limitations, and identifying reliable biomarkers. The hypotheses were evaluated for novelty. The experimental plans provided by ChatGPT for selected hypotheses were assessed for completion and feasibility. As a result, ChatGPT generated a total of 65 hypotheses. ChatGPT rated all 65 hypotheses, with 25 hypotheses receiving the highest rating (5) and 40 hypotheses receiving a rating of 4 or lower. The research team evaluated a total of 65 hypotheses, assigning them the following grades: hypotheses were rated as excellent (Grade 5), 16 were deemed suitable (Grade 4), 31 were classified as satisfactory (Grade 3), 12 were identified as needing Improvement (Grade 2), and one was considered poor (Grade 1). Additionally, the study determined that 17 of the generated hypotheses had corresponding publications. Out of the three experimental plans assessed, one was rated excellent (5) for feasibility, while the others received good (4) and moderate (3) ratings. Predicted outcomes and alternative approaches were rated as good, with some areas requiring further improvement. Our data demonstrate that AI has the potential to revolutionize hypothesis generation in medical research, though further validation through experimental and clinical studies is needed. This study suggests that while AI can generate novel hypotheses, human expertise is essential for evaluating their practicality and relevance in scientific research.
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Affiliation(s)
- Lan Yao
- College of Health Management, Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang, 150081, China; Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Centre, Memphis, TN, 38163, USA.
| | - Heliang Yin
- Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Centre, Memphis, TN, 38163, USA; Centre of Integrative Research, The First Hospital of Qiqihar City, Qiqihar, Heilongjiang, 161005, China.
| | - Chengyuan Yang
- Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Centre, Memphis, TN, 38163, USA.
| | - Shuyan Han
- Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Jiamin Ma
- Department of Breast Surgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, China.
| | - J Carolyn Graff
- College of Nursing, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| | - Cong-Yi Wang
- The Center for Biomedical Research, Dept of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yan Jiao
- Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Centre, Memphis, TN, 38163, USA
| | - Jiafu Ji
- State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Center of Peking University Cancer Hospital, Beijing, 100142, China.
| | - Weikuan Gu
- Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Centre, Memphis, TN, 38163, USA; Lt. Col. Luke Weathers, Jr. VA Medical Center, 116 N Pauline St. Memphis, TN, 38105, USA; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
| | - Gang Wang
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Nakano K, Oki E, Yamazaki M, Suzuki M, Kawai S, Fujita T, Kato A, Zaitsu Y, Jogo T, Kato C, Watanabe T, Hashimoto E, Nishime C, Fujii E, Ando K, Nagae G, Harimoto N, Ota M, Saeki H, Aburatani H, Maehara Y, Yamazaki T. Colorectal cancer cell line-derived organoid model with stem cell properties captures the regrowing state of residual cancer cells after neoadjuvant chemotherapy. Cell Death Discov 2025; 11:282. [PMID: 40537472 DOI: 10.1038/s41420-025-02567-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 05/16/2025] [Accepted: 06/11/2025] [Indexed: 06/22/2025] Open
Abstract
The effectiveness of colorectal cancer (CRC) therapy is limited owing to the absence of treatments targeting drug-tolerant residual cancer cells. Although neoadjuvant therapy is effective, pathological examination of residual tumors has revealed the presence of small clusters of LGR5-positive cancer cells in the fibrous tissue. Here, we established a colorectal cancer cell line-derived organoid (CCD-organoid) regrowth model using a patient-derived cell line with cancer stem cell properties and demonstrated that it displayed the morphological characteristics of small clusters in clinical tissues. Time course analysis of single-cell RNA sequencing of the CCD-organoid regrowth model revealed various states and dynamic alterations within non-cycling cells. We identified subpopulations highly expressing protein translation-related genes RPL17 and EEF1G. To identify key signals for the transition of residual cancer cells to regrowth, we evaluated inhibitors targeting pathways such as the Wnt pathway, reactive oxygen species pathway, and RNA polymerase I pathway, highlighted in the single-cell RNA sequencing analysis. Only the polymerase I-inhibitor BMH-21 significantly reduced tumor growth both in vitro and in vivo, indicating the critical cell subpopulation driving recurrence. Our results demonstrate the possibility of a unique therapeutic target for CRC treatment targeting drug-tolerant residual cancer cells.
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Affiliation(s)
- Kiyotaka Nakano
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan.
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Masaki Yamazaki
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Masami Suzuki
- Central Institute for Experimental Medicine and Life Science, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
| | - Shigeto Kawai
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Takanori Fujita
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan
| | - Atsuhiko Kato
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Yoko Zaitsu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Tomoko Jogo
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Chie Kato
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Takeshi Watanabe
- Chugai Research Institute for Medical Science, Inc., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Eri Hashimoto
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Chiyoko Nishime
- Central Institute for Experimental Medicine and Life Science, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
| | - Etsuko Fujii
- Translational Research Division, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Genta Nagae
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Mitsuhiko Ota
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka, 812-8582, Japan
- Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, 3-23-1 Shiobaru, Minami-ku, Fukuoka-shi, Fukuoka, 815-8588, Japan
| | - Tatsumi Yamazaki
- Central Institute for Experimental Medicine and Life Science, 3-25-12 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
- Chugai Pharmaceutical Co., Ltd., 1-1 Nihonbashi-Muromachi 2-chome, Chuo-ku, Tokyo, 103-8324, Japan
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10
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Pail O, Lin MJ, Anagnostou T, Brown BD, Brody JD. Cancer vaccines and the future of immunotherapy. Lancet 2025:S0140-6736(25)00553-7. [PMID: 40541217 DOI: 10.1016/s0140-6736(25)00553-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 02/04/2025] [Accepted: 03/17/2025] [Indexed: 06/22/2025]
Abstract
Vaccines have had a major impact on the control of infectious disease, most recently by helping to combat the COVID-19 pandemic. Prophylactic cancer vaccines have prevented several malignancies by protecting against cancer-causing pathogens. By contrast, therapeutic vaccines training the immune system to eliminate established tumours are now showing real promise in clinical settings. In the adjuvant setting, vaccines against melanoma and pancreatic cancer appear to be reducing minimal residual disease and relapse. In the macrometastatic setting, in-situ vaccines have induced systemic regressions in advanced-stage lung and breast cancers and lymphomas. More effective cancer vaccines are being developed through having a deeper understanding of crucial cellular factors in tumour immunology, the incorporation of newer vaccine components to effectively mobilise and activate cells, the use of omics and artificial intelligence in vaccine design, and addition of immune checkpoint blockade. In this Viewpoint, we analyse cancer vaccine trials, the strengths and limitations of different vaccine approaches, and we discuss how the next generation of cancer vaccines can help improve patient outcomes and quality of life.
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Affiliation(s)
- Orrin Pail
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
| | - Matthew J Lin
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Theodora Anagnostou
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brian D Brown
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joshua D Brody
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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11
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Dai YH, Zhuo-Ma SL, Luo YH. Effect of gastrointestinal endoscopy center care on the psychological state and pain level of colorectal cancer patients. World J Gastrointest Oncol 2025; 17:106154. [DOI: 10.4251/wjgo.v17.i6.106154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/01/2025] [Accepted: 04/21/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has become the third leading cancer with the third highest occurrence rate and the second highest death ratio globally. Its incidence and mortality rates have been increasing annually in recent years, posing a serious threat to global public health. Digestive endoscopy technology can not only be used for the diagnosis of CRC, but it can also be used in determining the depth of infiltration in early CRC. There are significant deficiencies in care measures in this area.
AIM To investigate the effect of digestive endoscopy center nursing on the psychological state and pain level of CRC patients.
METHODS A total of 120 CRC patients were randomly and equally divided into a control group and an observation group. The patients in the control group received basic routine nursing care, and the patients in the observation group received systematic digestive endoscopy center nursing care. The patients' compliance and nursing satisfaction were observed and recorded, as well as the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) and Visual Analogue Scale (VAS) scores.
RESULTS After care, the SAS and SDS scale scores of patients in both groups significantly decreased compared to before care (P < 0.05). The VAS scale scores significantly increased for each group compared to before examination (P < 0.05). The SAS, SDS and VAS scale scores of the observation group were significantly lower than those of the control group after nursing care (P < 0.05), and compliance and satisfaction of nursing care were significantly higher than those of the control group (P < 0.05).
CONCLUSION Digestive endoscopy center nursing can effectively intervene in and improve the psychological state and pain level of CRC patients, suggesting it is a valuable approach to adopt in the clinic.
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Affiliation(s)
- Yu-Hong Dai
- Gastroenterology Endoscopy Center, Ganzi Tibetan Autonomous Prefecture People's Hospital, Ganzi Tibetan Autonomous 626000, Sichuan Province, China
| | - Shi Lang Zhuo-Ma
- Department of Obstetrics and Gynecology, People's Hospital of Luding County, Ganzi Tibetan Autonomous 626100, Sichuan Province, China
| | - Yu-Hua Luo
- Department of Nursing, Ganzi Tibetan Autonomous Prefecture People's Hospital, Ganzi Tibetan Autonomous 626000, Sichuan Province, China
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12
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Liao X, Hu T. METTL14-mediated m6A modification of ETV4 inhibits tumor development in colorectal cancer. Mutat Res 2025; 831:111910. [PMID: 40541038 DOI: 10.1016/j.mrfmmm.2025.111910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 06/09/2025] [Accepted: 06/10/2025] [Indexed: 06/22/2025]
Abstract
BACKGROUND Many m6A methyltransferases have been identified to regulate colorectal cancer (CRC) progression. METTL14 has been confirmed to play a negative role in CRC process, but the molecular mechanism of METTL14 in regulating CRC progression needs to be further elucidated. METHODS The levels of METTL14, YTHDF2 and ETS translocation variant 4 (ETV4) were examined by qRT-PCR and western blot. Cell proliferation and apoptosis were determined by colony formation assay and flow cytometry. Cell glycolysis was assessed by detecting corresponding indicators. Cell ferroptosis was evaluated via measuring SOD, MDA, GSH, ROS and Fe2 + levels. The interaction between ETV4 and METTL14 or m6A readers was confirmed by RIP assay and RNA pull-down assay. Animal experiments were performed to confirm METTL14 roles in vivo. RESULTS METTL14 was downregulated in CRC tissues and cells, which overexpression inhibited proliferation and glycolysis, as well as promoted apoptosis and ferroptosis in CRC cells. METTL14 reduced the mRNA stability of ETV4 and inhibited ETV4 protein expression through m6A modification. m6A reader YTHDF2 could recognize m6A-methylated ETV4. The downregulation of ETV4 by METTL14 leads to increased apoptosis and ferroptosis in CRC cells, suggesting a critical role in tumor suppression. Moreover, METTL14 inhibited CRC tumorigenesis in vivo via reducing ETV4 expression. CONCLUSION METTL14 accelerated CRC cell apoptosis and ferroptosis via downregulating ETV4 in m6A-dependent manner, providing a molecular target for CRC treatment.
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Affiliation(s)
- Xiaofeng Liao
- Department of Gastroentero-pancreatic Surgery, Nanjing Jiangning Hospital, Nanjing, China.
| | - Tao Hu
- Department of Gastroentero-pancreatic Surgery, Nanjing Jiangning Hospital, Nanjing, China
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13
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Huang Q, Jing Y, Xiong L, Li L, Feng J, Cheng J. The interplay between driver mutation and oxidative stress in colorectal cancer: from pathogenesis to therapeutics. J Transl Med 2025; 23:635. [PMID: 40490762 DOI: 10.1186/s12967-025-06640-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 05/23/2025] [Indexed: 06/11/2025] Open
Abstract
Colorectal cancer (CRC) is a multifaceted disease influenced by genetic mutations and environmental factors, especially oxidative stress. Driver mutations are pivotal in CRC initiation and progression and alter key signaling pathways involved in cell proliferation, apoptosis, and genomic stability. Concurrently, oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a crucial role in CRC development by promoting DNA damage, lipid peroxidation, and redox signaling dysregulation. The molecular mechanisms linking driver mutations and oxidative stress pathways underscore their collective or antagonistic impact on CRC heterogeneity, therapeutic responses, and clinical outcomes. Insights into mutation-specific vulnerabilities and redox modulation offer promising avenues for targeted therapies and personalized medicine approaches in CRC treatment. Here, we discuss the intricate interplay between driver mutations and oxidative stress, highlight emerging trends, and propose future research directions to advance our understanding of CRC pathogenesis and optimize therapeutic interventions.
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Affiliation(s)
- Qi Huang
- Department of Anorectal Surgery, The People's Hospital of Leshan, Leshan, 614000, China
| | - Yuan Jing
- Department of Medical Records, The People's Hospital of Leshan, Leshan, 614000, China
| | - Lihua Xiong
- Department of Dermatology, Cheng Du Xinjin District Hospital of Traditional Chinese Medicine, Chengdu, 610500, China
| | - Lei Li
- Department of Anorectal Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Jingjuan Feng
- Department of Traditional Chinese Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Jian Cheng
- Department of Traditional Chinese Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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14
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Wang Y, An H, Zhang Y, Lyu QR, Zhang Z. SNORA13 antisense oligonucleotides enhances the therapeutical effects of 5-fluorouracil in colon adenocarcinoma. Front Pharmacol 2025; 16:1564682. [PMID: 40529507 PMCID: PMC12171199 DOI: 10.3389/fphar.2025.1564682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Accepted: 05/16/2025] [Indexed: 06/20/2025] Open
Abstract
Indroduction Colorectal cancer (CRC) is a prevalent malignancy and is the second leading cause of cancer-related mortality worldwide. 5-Fluorouracil (5-FU) is widely used in clinical intervention, however, drug resistance to 5-FU poses a significant challenge to treatment efficacy. Small nucleolar RNAs (snoRNAs) are a class of nuclear non-coding RNAs that mainly play roles in post-transcriptional RNA processing and modification in ribosomal RNA, which is crucial for sustaining protein synthesis. This study aimed to identify differentially expressed snoRNAs in CRC and pinpoint a specific snoRNA that may exert a synergistic effect with 5-FU administration. Methods Combinatorial small RNA array of clinical samples and data analysis from The Cancer Genome Atlas (TCGA) database were used to identify the differentially expressed snoRNAs in colorectal cancer (CRC). To investigate the role of SNORA13 in CRC, loss-of-function (LoF) study was conducted using transient antisense oligonucleotides (ASOs) transfection and SNORA13 knockout with CRISPR-Cas9 genome editing in HT29 colon adenocarcinoma cell line. A combined administration of SNORA13-ASO and 5-Fluorouracil (5-FU) was performed in nude mice xenograft model to verify the synergistic inhibitory effect. RNA-seq, Ribo-seq and proteomics were performed to identify the downstream target of SNORA13, and qRT-PCR and Western Blot were used to confirm the results of multi-omics analysis. Results The analysis of small RNA array data combined with the snoRNA expression profile in TCGA database determined that SNORA13 is commonly increased in CRC tissues. The LoF study revealed that the cell proliferation and colony formation are significantly suppressed upon SNORA13 deficiency. Next, the xenografted tumor model in nude mice demonstrated that the smaller tumorigenesis in SNORA13 knockout HT29 cell lines, and SNORA13 ASO enhances the anti-cancer efficacy of 5-FU. Finally, multi-omics analysis and molecular experimental validation revealed that nicotinamide N-methyltransferase (NNMT) is significantly suppressed in SNORA13 knockout HT29 cell lines. Conclusion Our study revealed SNORA13 is highly expressed in CRC and demonstrated knockdown of SNORA13, especially combined with 5-FU administration, may represent a promising therapeutic approach for CRC treatment.
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Affiliation(s)
- Yanzhi Wang
- Medical Research Center, Chongqing General Hospital, Chongqing University, Chongqing, China
| | - Huihui An
- Medical Research Center, Chongqing General Hospital, Chongqing University, Chongqing, China
| | - Yaou Zhang
- China State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, China
- Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, China
| | - Qing Rex Lyu
- Medical Research Center, Chongqing General Hospital, Chongqing University, Chongqing, China
| | - Zhe Zhang
- Department of Chinese Medical Gastroenterology, China-Japan Friendship Hospital, Beijing, China
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15
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Cooke TM, Sofocleous CT, Petre EN, Alexander ES, Ziv E, Solomon SB, Sotirchos VS. Microwave Ablation of Colorectal Pulmonary Metastases Offers Excellent Local Tumor Control and Can Prolong Time Off Chemotherapy. Cardiovasc Intervent Radiol 2025; 48:769-776. [PMID: 40295397 DOI: 10.1007/s00270-025-04036-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/25/2025] [Indexed: 04/30/2025]
Abstract
PURPOSE To evaluate oncologic outcomes after microwave ablation (MWA) of colorectal pulmonary metastases, with focus on disease control without chemotherapy. MATERIALS AND METHODS This institutional review board-approved retrospective study examined patients with oligometastatic or oligoprogressive colorectal pulmonary metastases undergoing MWA between January 2011 and December 2021. Imaging response was assessed with CT at 4-8 weeks post-MWA, with subsequent cross-sectional follow-up imaging every 2-4 months. Local tumor progression-free survival (LTPFS), chemotherapy-free survival (CFS) and overall survival (OS) were calculated using Kaplan-Meier methodology. Variables were evaluated for predictive significance using the log-rank test and Cox regression. RESULTS Two hundred twenty-five patients (127 male, 98 female; median age: 55 years) with 720 pulmonary metastases underwent 400 MWA sessions (mean number of treated metastases per session: 1.8; range 1-9). Mean treated tumor size was 0.9 cm. LTPFS at 1, 2 and 3-years was 91.9%, 85.9% and 81.5%, respectively. Tumors ≥ 1 cm in size, pleural-based tumors and pre-MWA carcinoembryonic antigen (CEA) levels ≥ 10 ng/mL were associated with shorter LTPFS (all P < 0.001). 74.7% (168/225) of patients did not receive chemotherapy for at least two months after the initial MWA. Median CFS was 12 months (95% CI 7.8-16.2) and was significantly prolonged in patients with lung-only disease compared to those with concurrent extrapulmonary disease (34.4 vs. 4.0 months, P < 0.001). Median OS was 47 months (95% CI 36.7-57.3). CONCLUSION MWA of colorectal pulmonary metastases is associated with high local tumor control rates and can offer prolonged CFS, particularly for patients without concurrent extrapulmonary disease.
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Affiliation(s)
- Timothy M Cooke
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA
| | - Constantinos T Sofocleous
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA
| | - Elena N Petre
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA
| | - Erica S Alexander
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA
| | - Etay Ziv
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA
| | - Stephen B Solomon
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA
| | - Vlasios S Sotirchos
- Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, H-112B, New York, NY, 10065, USA.
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16
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Dietz M, Gates TJ, Sikdar R, Subramanian S, Elias MH, Staley C. Impeding Quorum Sensing Among the Intestinal Microbiota Impacts the Metastatic Rate of Colorectal Cancer. Cancer Med 2025; 14:e71009. [PMID: 40536191 PMCID: PMC12177794 DOI: 10.1002/cam4.71009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 06/06/2025] [Accepted: 06/10/2025] [Indexed: 06/22/2025] Open
Abstract
BACKGROUND The gut microbiota is associated with colorectal cancer (CRC) risk and CRC metastatic potential. However, the role of bacteria in CRC progression and metastasis remains unclear. AIMS Here, we hypothesized that microbial communication, mediated through quorum sensing (QS), was a critical component regulating microbial functions related to cancer progression and metastasis. MATERIALS & METHODS To test this, male and female C57BL/6 mice were injected with organoids modeling aggressive colon cancer (CRC), carrying mutations in Apc, Kras, p53, and Smad4. Two groups of mice were treated with two different quorum quenching (QQ) lactonases (GcL or SsoPox) for 8 weeks (n = 10/group/sex). Fecal samples were collected weekly and characterized by Illumina next-generation sequencing, with tissues collected during necropsy. RESULTS Male mice treated with SsoPox had fewer metastases than control mice (χ2 = 3.206, p = 0.073), with no SsoPox-treated male developing a metastasis. In contrast, female mice treated with SsoPox had more metastases than control mice (χ2 = 2.554, p = 0.110), and every female, SsoPox-treated mouse that developed a primary tumor also developed metastasis by the experimental endpoint. However, QQ treatment was shown to minimally affect the gut microbiome composition. Similarly, no significant differences were observed in inflammatory response as assessed by immunofluorescent staining or fecal concentrations of immunoglobulin A, calprotectin, or lipocalin-2. Differences in fecal short-chain fatty acid concentrations also did not differ significantly. DISCUSSION These results suggest that QQ treatment has a sex-based effect on CRC metastatic rate. CONCLUSION Targeting communication among the gut microbiome may be a promising avenue for the development of CRC therapies that minimally impact microbial community composition and host immune response.
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Affiliation(s)
- Matthew Dietz
- Division of Basic and Translational Research, Department of SurgeryUniversity of MinnesotaMinneapolisMinnesotaUSA
- BioTechnology Institute, University of MinnesotaSt. PaulMinnesotaUSA
| | - Travis J. Gates
- Division of Basic and Translational Research, Department of SurgeryUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of PharmacologyUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
| | - Rakesh Sikdar
- BioTechnology Institute, University of MinnesotaSt. PaulMinnesotaUSA
- Department of Biochemistry, Molecular Biology, and BiophysicsUniversity of MinnesotaSt. PaulMinnesotaUSA
| | - Subbaya Subramanian
- Division of Basic and Translational Research, Department of SurgeryUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of PharmacologyUniversity of Minnesota Medical SchoolMinneapolisMinnesotaUSA
- Masonic Cancer Center, University of MinnesotaMinneapolisMinnesotaUSA
| | - Mikael H. Elias
- BioTechnology Institute, University of MinnesotaSt. PaulMinnesotaUSA
- Department of Biochemistry, Molecular Biology, and BiophysicsUniversity of MinnesotaSt. PaulMinnesotaUSA
| | - Christopher Staley
- Division of Basic and Translational Research, Department of SurgeryUniversity of MinnesotaMinneapolisMinnesotaUSA
- BioTechnology Institute, University of MinnesotaSt. PaulMinnesotaUSA
- Masonic Cancer Center, University of MinnesotaMinneapolisMinnesotaUSA
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17
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Richard M, Koch C, Trojan J. [Chemotherapy, targeted therapy and immunotherapy of metastatic colorectal cancer : What is new?]. RADIOLOGIE (HEIDELBERG, GERMANY) 2025; 65:443-449. [PMID: 40274654 DOI: 10.1007/s00117-025-01455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
In recent years the treatment options for metastatic colorectal cancer have significantly improved. This progress has particularly benefited specific subgroups of patients identified by certain biomarkers, such as those with a microsatellite instability, patients with B‑Raf (BRAF) V600E mutation, Kirsten rat sarcoma (KRAS) G12C mutation or v‑erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2) amplification. Additionally, targeted anti-epidermal growth factor (EGF) receptor therapy can be more effectively utilized through further patient selection. For patients who no longer respond to treatment, the new standard trifluridine/tipiracil in combination with bevacizumab has become established as the new third-line option. Furthermore, the selectively anti-angiogenic tyrosine kinase inhibitor fruquintinib has recently been approved as a last-line treatment. This article provides an overview of current standards and future developments in therapy.
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Affiliation(s)
- Mirjam Richard
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland
| | - Christine Koch
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland
| | - Jörg Trojan
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Deutschland.
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18
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Koo B, Kim YI, Lee M, Lim S, Shin Y. Enhanced Early Detection of Colorectal Cancer via Blood Biomarker Combinations Identified Through Extracellular Vesicle Isolation and Artificial Intelligence Analysis. J Extracell Vesicles 2025; 14:e70088. [PMID: 40511723 PMCID: PMC12163753 DOI: 10.1002/jev2.70088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 03/19/2025] [Accepted: 04/21/2025] [Indexed: 06/16/2025] Open
Abstract
Colorectal cancer (CRC) remains a major cause of cancer-related deaths worldwide, with early detection being crucial for improving survival rates. Despite the potential of extracellular vesicles (EVs) as blood biomarkers for CRC diagnosis, their clinical utility is limited due to complex and time-consuming isolation methods, unverified biomarkers and low diagnostic performance. Here, we introduce the ZAHV-AI system, which combines the zeolite-amine and homobifunctional hydrazide-based extracellular vesicle isolation (ZAHVIS) platform with AI-driven analysis for enhanced CRC diagnosis. The ZAHVIS platform enables simple, rapid and cost-effective EV isolation and one-step extraction of EV-derived proteins and nucleic acids (NAs), providing a streamlined approach. Using blood plasma samples from 80 CRC patients across all stages and 20 healthy individuals, we identified four EV-derived miRNA blood biomarkers (miR-23a-3p, miR-92a-3p, miR-125a-3p and miR-150-5p) by confirming statistical significance with relative quantification (RQ) values from real-time PCR and integrated these with carcinoembryonic antigen (CEA) levels into an AI-driven diagnostic model. Among 31 combinations used to identify optimal sets, optimal combination (miR-23a-3p, miR-92a-3p, miR-150-5p and CEA) for overall CRC achieved an area under the curve (AUC) of 0.9861, outperforming individual markers and conventional CEA tests. Notably, the system achieved perfect performance in detecting stages 0-1 (AUC: 1.0) and demonstrated high accuracy for stage 2 (AUC: 0.9722) and early-stage CRC (AUC: 0.9861), using stage-specific optimal combinations. Therefore, the ZAHV-AI system offers a reliable and clinically relevant tool for CRC diagnostics, significantly enhancing early detection and monitoring capabilities.
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Affiliation(s)
- Bonhan Koo
- Department of Biotechnology, College of Life Science and BiotechnologyYonsei UniversitySeodaemun‐guRepublic of Korea
| | - Young Il Kim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical CenterUniversity of Ulsan College of MedicineSongpa‐guRepublic of Korea
| | - Minju Lee
- Department of Biotechnology, College of Life Science and BiotechnologyYonsei UniversitySeodaemun‐guRepublic of Korea
| | - Seok‐Byung Lim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical CenterUniversity of Ulsan College of MedicineSongpa‐guRepublic of Korea
| | - Yong Shin
- Department of Biotechnology, College of Life Science and BiotechnologyYonsei UniversitySeodaemun‐guRepublic of Korea
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19
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Chen J, Cai Z, Huang S, Wang Y, Zhan S, Zheng W, Chi P. AQP9 weakens the cytotoxicity of CD8 + T cells in colon adenocarcinoma by boosting M2 polarization of macrophages under hypoxia conditions. Expert Rev Clin Immunol 2025; 21:803-814. [PMID: 40329438 DOI: 10.1080/1744666x.2025.2501718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 04/02/2025] [Accepted: 04/28/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is a leading cause of cancer mortality, with Aquaporin 9 (AQP9) implicated in its progression. M2 macrophages in the tumor microenvironment (TME) promote cancer metastasis, but the role of AQP9 on M2 macrophages remains unelucidated. RESEARCH DESIGN AND METHODS Using COAD cell lines, AQP9 expression was analyzed via RT-qPCR and Western blot (WB). Hypoxic conditions were simulated to assess HIF-1α and AQP9 interactions through ChIP and dual-luciferase assays. AQP9 knockdown effects on proliferation/migration were tested via colony formation and wound healing. M2 macrophage polarization and CD8+ T cell cytotoxicity were evaluated using flow cytometry, ELISA, and IHC in co-culture systems. RESULTS AQP9 was upregulated in COAD and correlated with poor prognosis. After AQP9 in COAD cells was knocked down, the abilities of tumor cells to migrate and proliferate were dampened. Hypoxia upregulated HIF-1α, which transcriptionally activated AQP9. Knocking down AQP9 repressed the M2 polarization of macrophages, thereby reinforcing the cytotoxicity of CD8+ T cells. No adverse events were reported in vitro. CONCLUSION AQP9 promotes COAD progression by driving HIF-1α-mediated M2 polarization, impairing CD8+ T cell function. Key limitations include the lack of in vivo validation and clinical cohort analysis.
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Affiliation(s)
- Jinping Chen
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Zongda Cai
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Shurong Huang
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Yangqiang Wang
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Shiyang Zhan
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Wei Zheng
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Pan Chi
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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20
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Burge ME, Espinoza D, Sjoquist KM, Siu DH, Mercieca-Bebber R, Chantrill LA, Karapetis CS, Steer CB, Yip S, Cuff J, Winata S, Tie J, Thaker DA, Srivastav R, Abdi E, Strickland A, Segelov E, Francesconi A, Price T, Ladwa R, Joubert W, Tebbutt NC. AGITG MONARCC: A Randomized Phase 2 Study of Panitumumab Monotherapy and Panitumumab Plus 5-Fluorouracil as First-Line Therapy for Older Patients With RAS and BRAF Wild Type Metastatic Colorectal Cancer. A Study by the Australasian Gastro-Intestinal Trials Group (AGITG). Clin Colorectal Cancer 2025; 24:120-128. [PMID: 39779412 DOI: 10.1016/j.clcc.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/21/2024] [Accepted: 11/24/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Panitumumab (pan) plus chemotherapy is a preferred first-line therapy for unresectable RAS and BRAF wild type metastatic colorectal cancer (mCRC). Older patients may not be suitable for combination regimens. We investigated 2 lower intensity pan-containing regimens. METHODS Prospective, noncomparative, randomized (1:1) phase 2 study of pan alone (Arm A) or pan plus FU (Arm B). Previously untreated mCRC were ≥70 years; RAS/BRAF wild type. PRIMARY ENDPOINT 6-month progression-free survival (PFS). Secondary endpoints included: overall survival (OS), response rate (RR), feasibility of geriatric assessments and overall treatment utility (OTU)-a composite measure based on radiological response, clinical progress, toxicity and patient-reported treatment worth. Planned sample size was 40 patients per arm. RESULTS 36 patients (Arm A n = 19, Arm B n = 17) were randomized between June 2018 and June 2021. Median age was 79 and 80 years respectively. 6-month PFS 63% (95% CI 38%-80%) arm A 82% (95%CI 55%-94%) Arm B. Median OS 21 months Arm A (95%CI 13-31) 28 (95%CI 14-39) months Arm B. RR 47% and 65% Arms A and B respectively. Baseline comprehensive geriatric assessments were completed in >80% of patients. At week 16, OTU was categorized as good in 92% (Arm A) and 90% (Arm B). No unexpected adverse events were seen. CONCLUSIONS Six-month PFS in both arms was consistent with that achieved with FU/bev, whilst the rate was numerically higher for Arm B. Baseline comprehensive geriatric assessments were feasible and OTU was high. Both treatment arms might be suitable in appropriately selected patients.
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Affiliation(s)
- Matthew E Burge
- Royal Brisbane and Women's Hospital, Brisbane, Australia; The University of Queensland, Brisbane, Australia.
| | - David Espinoza
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | | | - Derrick Ho Siu
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | | | | | | | - Christopher B Steer
- Border Medical Oncology, Albury Wodonga Regional Cancer Centre, Victoria, Australia
| | - Sonia Yip
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | - Jeff Cuff
- Australasian Gastro-Intestinal Trials Group-Community Advisory Panel. Level 6, Camperdown, New South Wales, Australia
| | - Stephanie Winata
- NHMRC Clinical Trials Centre, The University of Sydney, New South Wales, Australia
| | | | | | | | - Ehtesham Abdi
- The Tweed Hospital, Tweed Heads, New South Wales, Australia; Griffith University, Southport, Queensland, Australia
| | - Andrew Strickland
- Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia; Monash University, Clayton, Australia
| | - Eva Segelov
- Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia
| | | | - Timothy Price
- The Queen Elizabeth Hospital, Woodville South, South Australia
| | - Rahul Ladwa
- Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
| | - Warren Joubert
- Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
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21
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Ma J, Zhao J, Zhang C, Tan J, Cheng A, Niu Z, Lin Z, Pan G, Chen C, Ding Y, Zhong M, Zhuang Y, Xiong Y, Zhou H, Zhou S, Xu M, Ye W, Li F, Song Y, Wang Z, Hong X. Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy. Nat Commun 2025; 16:5006. [PMID: 40442064 PMCID: PMC12123037 DOI: 10.1038/s41467-025-60144-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 05/16/2025] [Indexed: 06/02/2025] Open
Abstract
Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1371 residue, before its degradation. Overexpressing CAD or mutating Asp1371 to block caspase-3 cleavage confers chemoresistance in xenograft and Cldn18-ATK gastric cancer models. Importantly, mutations related to Asp1371 of CAD are found in tumor samples that failed neoadjuvant chemotherapy and pharmacological targeting of CAD-Asp1371 mutations using RMY-186 ameliorates chemotherapy efficacy. Our work reveals the vulnerability of de novo pyrimidine synthesis during chemotherapy, highlighting CAD as a promising therapeutic target and biomarker.
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Affiliation(s)
- Jingsong Ma
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Jiabao Zhao
- State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Chensong Zhang
- State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Jinshui Tan
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Ao Cheng
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhuo Niu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zeyang Lin
- Department of Pathology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Guangchao Pan
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Chao Chen
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yang Ding
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Mengya Zhong
- Department of Radiology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yifan Zhuang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yubo Xiong
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Huiwen Zhou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Shengyi Zhou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Meijuan Xu
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Wenjie Ye
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China
| | - Funan Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China.
| | - Xuehui Hong
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China.
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22
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Zhu R, Gu S, Tao Y, Zhang Y. Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation. Discov Oncol 2025; 16:935. [PMID: 40423770 PMCID: PMC12116955 DOI: 10.1007/s12672-025-02686-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 05/12/2025] [Indexed: 05/28/2025] Open
Abstract
Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell resistance to anti-PD-1 therapy. We aimed to investigate whether butyrate promotes resistance to anti-PD-1 therapy in CRC and underlying metabolic and immunologic mechanisms. CRC murine models were established by subcutaneously inoculating MC38 cells or butyrate/anti-PD-1-administered tumor cells of mice, followed by treatment with butyrate, anti-PD-1, or a combination. Therapeutic efficacy was assessed by tumor growth and survival outcomes. In vitro, HCT116 cells were exposed to monotherapy or co-therapy regimens. Carnitine Palmitoyltransferase 1A (CPT1A) knockdown was conducted by shRNA transfection both in vivo and in vitro. Fatty acid oxidation (FAO) was determined by oxygen consumption rate and CPT1A expression. CD8+ T cell cytotoxicity assays and CD8 expression in tumors were performed to evaluate immune cell infiltration. The addition of butyrate into anti-PD-1 treatment combination did not improve survival or reduce tumor volume compared to anti-PD-1 alone, with a marked activation of CPT1A observed in treated tumor tissues. Butyrate significantly elevated FAO, contributing to elevated oxygen consumption rate and reduced CD8+ T cell cytotoxicity. However, in sh-CPT1A models, the combination therapy significantly improved antitumor efficacy and restored CD8+ T cell infiltration. Furthermore, CRC patient samples resistant to anti-PD-1 therapy exhibited elevated CPT1A levels. Butyrate-induced CPT1A-mediated FAO promotes resistance to anti-PD-1 therapy in CRC, suggesting that targeting CPT1A might enhance the efficacy of immunotherapy.
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Affiliation(s)
- Ran Zhu
- Department of Pathology, Changping Hospital of Integrated Chinese and Western Medicine, Beijing, 102208, China
| | - Shujiang Gu
- Department of Laboratory Medicine, Beijing Changping Traditional Chinese Medicine Hospital, Beijing, 102200, China
| | - Yuan Tao
- Department of Gastroenterology, Beijing Changping Traditional Chinese Medicine Hospital, Beijing, 102200, China
| | - Yan Zhang
- Department of Pathology, Beijing Changping Traditional Chinese Medicine Hospital, South Section of Donghuan Road, Changping District, Beijing, 102200, China.
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23
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Lunca S, Morarasu S, Zaharia R, Ivanov AA, Clancy C, O’Brien L, Ong WL, Dimofte GM. Can We Achieve More with Less? Parenchymal Sparing Surgery Versus Major Liver Resection for Colorectal Liver Metastases: An Observational Single-Center Study with Propensity Score Analysis. Diagnostics (Basel) 2025; 15:1334. [PMID: 40506905 PMCID: PMC12154166 DOI: 10.3390/diagnostics15111334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/15/2025] [Accepted: 05/23/2025] [Indexed: 06/16/2025] Open
Abstract
Background/Objectives: Colorectal liver metastases (CRLMs) occur in 25-30% of colorectal cancer (CRC) patients, significantly impacting survival. While major liver resection (MLR) was traditionally preferred for oncologic clearance, parenchymal-sparing surgery (PSS) has emerged as a less invasive alternative. This study compares perioperative and long-term outcomes of PSS versus MLR in CRLM patients. Methods: We conducted a retrospective cohort study at the Regional Oncology Institute, Iasi, Romania, analyzing patients who underwent hepatic resection for CRLM between August 2013 and June 2024. Patients were categorized into PSS (n = 58) and MLR (n = 28) groups. Outcomes assessed included perioperative parameters, postoperative morbidity, overall survival (OS), and disease-free survival (DFS). Results: PSS was associated with a shorter operative time (235.2 vs. 302.6 min, p = 0.003), lower morbidity (18.9% vs. 57.1%, p = 0.001), and fewer major complications (Clavien-Dindo ≥ III, p = 0.005). ICU stay was significantly longer in MLR patients (p = 0.04). After propensity score matching (PSM), PSS was found to have lower morbidity compared to MLR (p = 0.023) with similar major morbidity (p = 0.473) and LOS (p = 0.579). Overall survival (31 vs. 37.1 months, p = 0.884) and disease-free survival (25.2 vs. 22.2 months, p = 0.519) were comparable between the groups before and after propensity score matching PSM (40.9 vs. 21.2 months, p = 0.741 and 24.3 vs. 13.8 months, p = 0.653). Conclusions: PSS achieves comparable oncologic outcomes to MLR while reducing postoperative morbidity and ICU stay. These findings support PSS as the preferred approach for CRLM, reserving MLR for select cases requiring extensive resection.
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Affiliation(s)
- Sorinel Lunca
- Department of Surgery, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iași, Romania; (S.L.); (R.Z.); (A.-A.I.); (W.L.O.); (G.-M.D.)
- 2nd Department of Surgical Oncology, Regional Institute of Oncology (IRO), 700483 Iasi, Romania
| | - Stefan Morarasu
- Department of Surgery, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iași, Romania; (S.L.); (R.Z.); (A.-A.I.); (W.L.O.); (G.-M.D.)
- 2nd Department of Surgical Oncology, Regional Institute of Oncology (IRO), 700483 Iasi, Romania
| | - Raluca Zaharia
- Department of Surgery, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iași, Romania; (S.L.); (R.Z.); (A.-A.I.); (W.L.O.); (G.-M.D.)
- 2nd Department of Surgical Oncology, Regional Institute of Oncology (IRO), 700483 Iasi, Romania
| | - Andreea-Antonina Ivanov
- Department of Surgery, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iași, Romania; (S.L.); (R.Z.); (A.-A.I.); (W.L.O.); (G.-M.D.)
- 2nd Department of Surgical Oncology, Regional Institute of Oncology (IRO), 700483 Iasi, Romania
| | - Cillian Clancy
- Department of Colorectal Surgery, Tallaght University Hospital, D24 YN77 Dublin, Ireland; (C.C.); (L.O.)
- Trinity College, University of Dublin, D02 PN40 Dublin, Ireland
| | - Luke O’Brien
- Department of Colorectal Surgery, Tallaght University Hospital, D24 YN77 Dublin, Ireland; (C.C.); (L.O.)
- Trinity College, University of Dublin, D02 PN40 Dublin, Ireland
| | - Wee Liam Ong
- Department of Surgery, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iași, Romania; (S.L.); (R.Z.); (A.-A.I.); (W.L.O.); (G.-M.D.)
- 2nd Department of Surgical Oncology, Regional Institute of Oncology (IRO), 700483 Iasi, Romania
| | - Gabriel-Mihail Dimofte
- Department of Surgery, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iași, Romania; (S.L.); (R.Z.); (A.-A.I.); (W.L.O.); (G.-M.D.)
- 2nd Department of Surgical Oncology, Regional Institute of Oncology (IRO), 700483 Iasi, Romania
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24
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Liu X, Liu W, Wu Y, Wang Y, Jiang Q, Li Y, Li H, Hao L. Investigation of the cytotoxic effects and mechanisms of the SLC39A6-targeting ADC drug BRY812 in CRC. Sci Rep 2025; 15:18275. [PMID: 40414981 DOI: 10.1038/s41598-025-03713-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 05/22/2025] [Indexed: 05/27/2025] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, necessitating the development of novel therapeutic strategies. We explore the expression characteristics of SLC39A6 in CRC by combining multiple cohorts and multi-omics. The therapeutic effect and potential mechanism of BRY812 on CRC were explored through in vitro experiments. Our research results show that the expression of SLC39A6 in CRC tissues is higher than that in normal tissues, and it is closely related to tumor pathways, making it a good therapeutic target. BRY812 has an inhibitory effect on the growth, migration and stemness of CRC cells, and may exert its killing effect by downregulating the AKT pathway. This study has identified SLC39A6 as a potential therapeutic target in CRC. BRY812 is expected to become a highly promising therapeutic drug, bringing new hope to patients with CRC.
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Affiliation(s)
- Xianglin Liu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Wenqiang Liu
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai, China
| | - Yuting Wu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yichuan Wang
- Clinical Cancer Institute, Center for Translational Medicine, Naval Military Medical University, Shanghai, 200433, China
| | - Qingliang Jiang
- Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, 200433, China
| | - Yangyang Li
- Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, 200433, China
| | - Hengyu Li
- Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, 200433, China.
| | - Liqiang Hao
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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25
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Le Roux AB, Fung EK, Lee SG, Monette S, Xu H, Guo HF, Yang G, Ouerfelli O, Jungbluth A, Schöder H, Larson SM, Cheung NKV, Cheal SM, Veach DR. GPA33-pretargeted radioimmunotherapy with mono- and bivalent DOTA-based Lu-177-labeled radiohaptens in a mouse orthotopic liver xenograft model of metastatic human colorectal cancer. Theranostics 2025; 15:6274-6289. [PMID: 40521192 PMCID: PMC12159840 DOI: 10.7150/thno.107209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/04/2025] [Indexed: 06/18/2025] Open
Abstract
Rationale: Pretargeted radioimmunotherapy (PRIT), which combines systemic antibody-based targeting with ionizing radiation, is promising for treating liver metastases in patients with colorectal cancer (CRC). Previously, we established a three-step DOTA-PRIT regimen to deliver DOTA radiometal payloads to CRC using an anti-tumor/anti-DOTA bispecific antibody (BsAb) targeting cell surface glycoprotein A33 (GPA33), a tumor antigen target expressed on over 95% of primary and metastatic CRC; a clearing agent; and a monovalent 177Lu radiohapten called [177Lu]Lu-ABD. More recently, we developed a bivalent 177Lu radiohapten called [177Lu]Lu-Gemini to enhance tumor uptake and radiohapten retention. Here, we aimed to compare the efficacy and safety of bivalent vs. monovalent three-step DOTA-PRIT regimens in orthotopic CRC liver metastasis models, to mimic a clinical path forward. Methods: We established two orthotopic CRC liver metastasis models by inoculating either SW1222-luc (GPA33high) or LoVo (GPA33low) human CRC cells in athymic nude mice under ultrasonographic guidance. Tumor targeting efficacy and dosimetry of the radiohaptens were compared using ex vivo biodistribution studies, SPECT/CT, and quantitative autoradiography. We also performed a DOTA-PRIT experiment to compare the efficacy and safety profiles of bivalent (single-cycle [177Lu]Lu-Gemini, 48 h pretargeting interval) vs. monovalent (multicycle [177Lu]Lu-ABD, 24 h pretargeting interval) three-step DOTA-PRIT regimens, each designed to deliver comparable total radiation doses to tumors (around 50 Gy). Results: Both radiohaptens demonstrated efficient SW1222-luc tumor targeting, with [177Lu]Lu-Gemini showing superior targeting and tumor activity retention compared with [177Lu]Lu-ABD. In LoVo tumors, [177Lu]Lu-Gemini showed superior targeting, while [177Lu]Lu-ABD showed negligible targeting. Dosimetry estimates revealed higher SW1222-luc tumor mean absorbed doses for [177Lu]Lu-Gemini (119.88 cGy/MBq, 48 h pretargeting interval) compared with [177Lu]Lu-ABD (32.88 cGy/MBq, 24 h pretargeting interval), with more favorable blood and kidney therapeutic indices (50 and 9 for [177Lu]Lu-Gemini, and 15 and 5 for [177Lu]Lu-ABD, respectively). In the DOTA-PRIT experiment, both monovalent (injected activity: 3 × 44.4 MBq, 133.2 MBq total) and bivalent (injected activity: 44.4 MBq total) radiohapten regimens increased the median survival of treated mice compared with controls: 71 days for [177Lu]Lu-ABD-treated mice, 81 days for [177Lu]Lu-Gemini-treated mice, and 18 days for controls, without a statistical difference between treatment groups. Treatments were well tolerated, without significant weight loss or hematologic changes. Radiation-induced injuries were not identified histologically in the kidneys or bone marrow of mice submitted for necropsy. Conclusions: Our study demonstrates the exceptional benefit of a multivalent radiohapten strategy when treating an advanced model of CRC liver metastasis. Three-step GPA33 DOTA-PRIT with 177Lu-Gemini demonstrated that multivalency 1) improves PRIT therapeutic indices for blood and kidney and 2) has the potential to greatly reduce the administered activity without compromising the efficiency of the PRIT platform in clinically relevant models of target-rich and target-poor metastatic CRC.
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Affiliation(s)
| | - Edward K. Fung
- Department of Radiology, Weill Cornell Medicine, New York, NY
| | - Sang Gyu Lee
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sebastien Monette
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and Rockefeller University, New York, NY
| | - Hong Xu
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hong-Fen Guo
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Guangbin Yang
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ouathek Ouerfelli
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Achim Jungbluth
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Radiology, Weill Cornell Medicine, New York, NY
| | - Steven M. Larson
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Radiology, Weill Cornell Medicine, New York, NY
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nai-Kong V. Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sarah M. Cheal
- Department of Radiology, Weill Cornell Medicine, New York, NY
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Darren R. Veach
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Radiology, Weill Cornell Medicine, New York, NY
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26
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Ning XJ, Li JF, Guo HL, Chen JY. Causal association between body mass index and risk of colon polyps: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e42022. [PMID: 40419904 DOI: 10.1097/md.0000000000042022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/28/2025] Open
Abstract
The relationship between obesity and colorectal polyps remains inconclusive. This study aimed to examine whether body mass index (BMI) is causally associated with colon polyps. A two-sample Mendelian randomization (MR) analysis using the inverse variance weighted, weighted median and MR-Egger regression methods was performed. We used the publicly available summary statistics data sets of genome-wide association studies (GWAS) meta-analyses for BMI in individuals of European descent (n = 322,154; GIANT consortium) as the exposure and a GWAS for colon polyps included in the UK Biobank (total n = 463,010; case = 4779, control = 458,231) as the outcome. We selected 76 single nucleotide polymorphisms at genome-wide significance from GWASs on BMI as the instrumental variables. The inverse variance weighted method showed evidence to support a causal association between BMI and colon polyps (beta = 0.002, SE = 0.001, P = .012). MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = -9.3e-06;P = .889), but it showed no causal association between BMI and colon polyps (beta = 0.002, SE = 0.002, P = .09). However, the weighted median approach yielded evidence of a causal association between BMI and colon polyps (beta = 0.001, SE = 0.001, P = .01). Cochran Q test and the funnel plot indicated no evidence of heterogeneity and asymmetry, indicating no directional pleiotropy. The results of MR analysis support that BMI may be causally associated with an increased risk of colon polyps.
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Affiliation(s)
- Xin-Jie Ning
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian-Feng Li
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Hui-Long Guo
- Emergency and Disaster Medicine Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China
| | - Jing-Yao Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Wu D, Xia Q, Su X, Mao Y, Mao J, Ding Q, Liu J, Zhong W, Zhang X, Li H, Duan S. Long non-coding RNA TMEM51-AS1 inhibits colorectal cancer progression. Discov Oncol 2025; 16:878. [PMID: 40407985 PMCID: PMC12102048 DOI: 10.1007/s12672-025-02676-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 05/12/2025] [Indexed: 05/26/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cause of death worldwide and has high mortality and a poor prognosis. Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides that play roles in cancer through multiple mechanisms. TMEM51-AS1 is a newly discovered 40,650 bp lncRNA. Our results showed that TMEM51-AS1 expression was significantly downregulated in CRC tissues (fold change = 0.74, P < 0.0001). This finding was confirmed in 20 pairs of CRC carcinoma and paracancerous tissues (fold change = 0.5, P < 0.001). Additionally, TMEM51-AS1 expression was found to be significantly reduced in CRC cell lines compared to normal human intestinal epithelial cells (P < 0.001). Bioinformatic analysis revealed that TMEM51-AS1 expression was associated with immune escape, RNA methylation, and DNA damage and repair. TMEM51-AS1 may also activate energy metabolism pathways to participate in cancer development. Drug sensitivity analysis confirmed that several drugs are more effective in CRC patients with high expression of TMEM51-AS1. In conclusion, our study demonstrates that TMEM51-AS1 can suppress the progression of CRC.
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Affiliation(s)
- Dongping Wu
- Department of Radiation Oncology, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Qing Xia
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310014, Zhejiang, China
| | - Xinming Su
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310014, Zhejiang, China
- Department of Clinical Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Yunan Mao
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310014, Zhejiang, China
| | - Jiwei Mao
- Department of Radiation Oncology, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Qiannan Ding
- Medical Research Center, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Jianjiang Liu
- Department of Radiation Oncology, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Wangyan Zhong
- Department of Radiation Oncology, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Xiaoyu Zhang
- Department of Radiation Oncology, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China
| | - Hanbing Li
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China.
| | - Shiwei Duan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310014, Zhejiang, China.
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Qiao Q, Li J, Tao C, Yang M, Chen W, Qiu L, Tu H. Camptothecin-loaded chondroitin sulfate-celecoxib reduction-sensitive micelles for enhanced colon cancer treatment. Int J Biol Macromol 2025; 315:144489. [PMID: 40409631 DOI: 10.1016/j.ijbiomac.2025.144489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 05/07/2025] [Accepted: 05/20/2025] [Indexed: 05/25/2025]
Abstract
Studies have shown that inflammation is closely linked to the cancer development, and the patients with inflammatory bowel disease (IBD) have a higher risk of colon cancer. Celecoxib (CXB) and camptothecin (CPT) showed potential treatment for IBD and colon cancers, respectively. However, their applications are limited by synchronous delivery, water insolubility, and off-target side effects. Herein, a glutathione (GSH) responsive chondroitin sulfate A (CSA)-SS-CXB micelle loaded with CPT (CSA-SS-CXB@CPT) was prepared as a targeted system to treat colon cancer by anti-inflammatory and antitumor synergistic effect. Specifically, CSA had tumor tumor-targeting effect due to colon cancer lesion-high expression of CD44 receptors. In vitro results verified that CSA-SS-CXB@CPT selectively internalized into colon cancer HT-29 cells and had strong reactive oxygen species (ROS) elimination ability. The CSA-SS-CXB@CPT could rapidly release CXB and CPT in the tumor microenvironment for playing an anti-tumor role. In vivo experiments illustrated that CSA-SS-CXB@CPT significantly targeted tumor tissues and suppressed tumor growth without producing serious side effects in tumor-bearing nude mice. Therefore, this work provides an opportunity for targeted co-delivery of anti-inflammatory and chemotherapy drugs to treat colon cancer.
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Affiliation(s)
- Qiao Qiao
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jie Li
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Chunying Tao
- Department of Oncology, Heze Municipal Hospital, Heze 274000, China
| | - Meiyang Yang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
| | - Weijun Chen
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Lipeng Qiu
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
| | - Huiming Tu
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China.
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Liu T, Yao Y, Liu B, Teng X, Zhang X, Dong M. Cost-effectiveness analysis of FOLFOXIRI plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment of metastatic colorectal cancer. Expert Rev Pharmacoecon Outcomes Res 2025. [PMID: 40395124 DOI: 10.1080/14737167.2025.2509706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/28/2025] [Accepted: 05/15/2025] [Indexed: 05/22/2025]
Abstract
OBJECTIVES We first evaluated thecost-effectiveness of the FOLFOXIRI plus bevacizumab versus mFOLFOX6 plusbevacizumab as the first-line treatment of metastatic colorectal cancer fromhealthcare system perspective. METHODS A partitioned survivalmodel was developed to assess the costs and effects of FOLFOXIRI plusbevacizumab versus mFOLFOX6 plus bevacizumab. Health outcomes weremeasured in quality-adjusted life years (QALYs), and incrementalcost-effectiveness ratios (ICERs). The evaluation of the Chinese healthcarepayer perspective was performed across a lifetime horizon, encompassing directmedical expenses. RESULTS The estimated cost for FOLFOXIRI plus bevacizumab treatment was 9306.364USD, which was higher than 8218.436 USD estimated for mFOLFOX6 plusbevacizumab, leading to an ICER of 1961.857 USD per QALY. One-way sensitivityanalysis suggested the body surface area (BSA), the cost of irinotecan,and the cost of fluorouracilhad the largest impact on the ICER. The cost-effectiveness acceptability curvesshowed the probability of FOLFOXIRI plus bevacizumab being cost-effective was100% at a threshold of 12 300 USD per QALY. CONCLUSION FOLFOXIRI plus bevacizumab hadan economic advantage compared to mFOLFOX6 plus bevacizumab as the first-line treatment ofmetastatic CRC in China.
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Affiliation(s)
- Tong Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yao Yao
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bingjie Liu
- School of Health Management, Harbin Medical University, Harbin, China
| | - Xue Teng
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Zhang
- School of Health Management, Harbin Medical University, Harbin, China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
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Wang J, Liu C, Wang P, Liu Z, Hu W, Lv Z, Huang C, Yao X. Bioengineered Tumor-Derived Extracellular Vehicles Suppressed Colorectal Cancer Liver Metastasis and Bevacizumab Resistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2417714. [PMID: 40397411 DOI: 10.1002/advs.202417714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 04/08/2025] [Indexed: 05/22/2025]
Abstract
Antiangiogenic therapies, such as bevacizumab, are among the causes of cancer-related death in patients with colorectal cancer (CRC) with liver metastasis. Delivering siRNAs via primary cell originating from primary cells is a promising method for targeting CRC liver metastasis and drug resistance. Here, it is found that the expression of CCL24 is significantly upregulated in tumor tissues at the CRC liver metastasis site. In addition, CCL24 is significantly upregulated in tumor tissues from bevacizumab-resistant patients. CCL24 promotes the formation of inflammatory tumor-associated fibroblast subsets in the CRC liver metastasis microenvironment and induces resistance to bevacizumab therapy. Based on these results, a primary cell-derived extracellular vehicle delivery system is designed for the simultaneous delivery of siRNAs targeting CCL24 in the tumor microenvironment (TME). Downregulation of CCL24 in the TME by delivering bioengineered extracellular vehicles significantly increased sensitivity to antiangiogenic therapy in a CRC mouse model. A novel therapeutic target is identified for patients with CRC with liver metastasis and suggested a possible therapeutic alternative for patients with CRC with resistance to antiangiogenic therapy and distant metastasis.
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Affiliation(s)
- Junjiang Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Chunsheng Liu
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Ping Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Zhiyuan Liu
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Weixian Hu
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Zejian Lv
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Chengzhi Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
| | - Xueqing Yao
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510000, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Department of General Surgery, Guangdong Provincial People's Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou, 341000, China
- Department of General Surgery, Guangdong Provincial People's Hospital Heyuan Hospital, Heyuan, 517000, China
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Meng J, Zuo J, Li L, Zhang Y, Zhao M, Xiong P. Sonodynamic Therapy Induces Pyroptosis and Recruits CAR-NK Cells to Enhance the Treatment of Oral Squamous Cell Carcinoma. ACS APPLIED MATERIALS & INTERFACES 2025; 17:29352-29363. [PMID: 40338058 PMCID: PMC12100594 DOI: 10.1021/acsami.5c03584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/09/2025]
Abstract
Background: Immunotherapy strategies have demonstrated promising efficacy in treating various cancers. However, cancer cells often evade immune surveillance by reducing their immunogenicity, which limits immune cell infiltration into the tumor microenvironment. Pyroptosis, a proinflammatory form of programmed cell death, is characterized by the formation of plasma membrane pores that lead to the release of intracellular contents and stimulate a robust immune response. Results: To exploit this mechanism, we developed hematoporphyrin monomethyl ether (HMME)-loaded nanoliposomes capable of efficiently accumulating at the tumor site. Upon ultrasound irradiation, these nanomedicines generate reactive oxygen species (ROS) that activate Caspase-3, which cleaves Gasdermin E (GSDME) and induces tumor cell pyroptosis. Notably, this sonodynamic therapy (SDT) based on nanosonosensitizers enhanced the targeted enrichment of chimeric antigen receptor (CAR)-engineered natural killer (NK) cells at the ultrasound-irradiated tumor site, significantly improved the tumor immune response, and effectively inhibited the growth and proliferation of oral squamous cell carcinoma (OSCC) cells both in vivo and in vitro. Conclusions: Given that NK cell immunotherapy has an excellent safety profile with minimal risks of cytokine release syndrome and neurotoxicity, this approach holds promise as an adjunct to various NK cell-based immunotherapies through SDT-induced pyroptosis.
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Affiliation(s)
- Jing Meng
- Department
of Ultrasound, Ninth People’s Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai200001, P.R. China
| | - Jiaxin Zuo
- Department
of Ultrasound, Ninth People’s Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai200001, P.R. China
| | - Luyu Li
- Shanghai
Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University
School of Medicine, Shanghai200240, China
| | - Yunxuan Zhang
- School
of Pharmacy, Shanghai Jiao Tong University, Shanghai200240, P.R. China
| | - Minghao Zhao
- School
of Pharmacy, Shanghai Jiao Tong University, Shanghai200240, P.R. China
| | - Ping Xiong
- Department
of Ultrasound, Ninth People’s Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai200001, P.R. China
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Lin Z, Rasinski P, Nilsson T, Holstensson M, Song Y, Blomgren A, Jutidamrongphan W, Pandya K, Hong J, Rominger A, Shi K, Axelsson R, Lan X, Seifert R. FAPI PET Versus FDG PET/CT in Gastrointestinal Cancers: An Overview. Semin Nucl Med 2025:S0001-2998(25)00056-X. [PMID: 40399164 DOI: 10.1053/j.semnuclmed.2025.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 05/23/2025]
Abstract
Fibroblast activation protein (FAP) is a type II transmembrane serine protease that is highly expressed in cancer-associated fibroblasts (CAFs) but absent in quiescent fibroblasts. Its overexpression is associated with poor prognosis in various cancers and contributes to treatment resistance. In recent years, radiolabeled FAP inhibitors (FAPI) for PET imaging have shown promising clinical value across a range of cancers. Gastrointestinal (GI) malignancies, which often exhibit a desmoplastic reaction with a high density of FAP-expressing CAFs, are particularly well-suited for FAPI PET. Given the limitations of [18F]FDG PET in GI cancers, such as low sensitivity in certain histological subtypes and high physiological background uptake, FAPI PET is expected to serve as a complementary method, potentially enhancing both diagnostic accuracy and treatment guidance. This review provides a comprehensive comparison of the clinical applications of FAPI PET and [18F]FDG PET in various GI cancers, including their value in diagnosis, staging, and treatment guidance. Additionally, this review summarizes studies on the expanding role of FAPI PET, including its use in assessing treatment response and predicting prognosis, aiming to provide insights into its potential contribution to the improved management of GI malignancies.
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Affiliation(s)
- Zhaoguo Lin
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Pawel Rasinski
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Ted Nilsson
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Maria Holstensson
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Yangmeihui Song
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Hubei Key Laboratory of Molecular Imaging, Wuhan, China; Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, China
| | - August Blomgren
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Warissara Jutidamrongphan
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Kalyani Pandya
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Jimin Hong
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Axel Rominger
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Kuangyu Shi
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Rimma Axelsson
- Department of Nuclear Medicine and Medical Physics, Karolinska University Hospital, Huddinge, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; Hubei Key Laboratory of Molecular Imaging, Wuhan, China; Key Laboratory of Biological Targeted Therapy, The Ministry of Education, Wuhan, China
| | - Robert Seifert
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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Zhang J, Liu Z, Ma X, Shi Z, Zhao J, Xie Y, Shang X, Zhang X. Deciphering the interaction between the expression of LRP2 served as a mitochondrial metabolism-related gene and prognosis in colon cancer integrating multi-omics analysis. Discov Oncol 2025; 16:782. [PMID: 40377809 PMCID: PMC12084449 DOI: 10.1007/s12672-025-02568-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 05/05/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is increasingly prevalent among patients under 50 years old, and the 5-year survival rate for patients with metastasis is less than 20%. Identifying significant biomarkers and therapeutic targets is crucial. We investigated the expression of LRP2 in COAD and its prognostic value utilizing single-cell sequencing and transcriptomics datasets, which was conducted preliminary validation at the patient samples and cellular levels as well. METHODS Based on differential gene expression of tumor samples and normal tissues in The Cancer Genome Atlas (TCGA), we performed consensus clustering, univariate and multivariate Cox regression analysis applying 1,234 mitochondrial metabolism-related genes (MMRGs) to identify some essential genes associated with poor prognosis in COAD patients. We validated survival outcome and biological function of the target gene leveraging single-cell sequencing and transcriptomics datasets from Gene Expression Omnibus (GEO), and evaluated the value of the target gene in the clinical pathology stage of COAD patients. Simultaneously, the expression levels of critical gene were detected in the diverse tissues of COAD by immunohistochemistry (IHC) staining. Transcriptomics data was continuously implemented to compare the discrepancy between the expression levels of the target gene and somatic mutation burden, inspecting the key pathways of the target gene by gene set enrichment analysis (GSEA) and examining its drug sensitivity synthetically in the CellMiner databases. The proliferative capacity augmented in LRP2-overexpressed colon cancer cells was determined employing cell counting kit-8 (CCK-8) and flow cytometry assays. RESULTS LRP2 served as a key mitochondrial metabolism-related gene was assessed clinical prognosis in COAD patients according to the TCGA database. High expression of LRP2 was prominently associated with poor prognosis in COAD patients (P < 0.05), which was validated by GEO databases, and the expression levels of LRP2 were positively related to clinical pathological stage simultaneously (P < 0.05). Some specific cell types were clustered and proliferation pathways were immensely enriched, which were correlated with LRP2 in two single-cell sequencing datasets. The mutation profiles displayed remarkable differences in two levels of LRP2, we also observed high expressions of LRP2 were immensely correlated with high tumor mutation burden (TMB) and unfavorable prognosis in these patients (P < 0.05). LRP2 was significantly enriched in multiple cancer proliferation-related pathways, and the noteworthy correlation between LRP2 and the sensitivity to various drugs was identified (P < 0.05). The expression levels of LRP2 were multifarious in different COAD patients based on IHC staining. LRP2-overpression could stimulate the proliferation capability of HCT116 and SW480 cell lines markedly (P < 0.05). CONCLUSION The expression levels of LRP2 were intimately correlated with gene mutations, prognosis, pathological stage and the sensitivity to anticancer drugs in COAD. Augmented levels of LRP2 would manifest poor prognosis, which furnished novel insights for clinical diagnosis and treatment in COAD. LRP2 could extensively facilitate the proliferation ability of colon cell lines.
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Affiliation(s)
- Jie Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, 300060, China
| | - Ziyun Liu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Xiaoqing Ma
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zhenyu Shi
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Jing Zhao
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yongjie Xie
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Xiaobin Shang
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Xia Zhang
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Wang N, Zhao TY, Ma X. Increased colorectal cancer risk in prediabetes: A meta-analysis. World J Diabetes 2025; 16. [DOI: 10.4239/wjd.v16.i5.103403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/21/2025] [Accepted: 02/21/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND
Previous research yielded conflicting results regarding the association between prediabetes and colorectal cancer (CRC).
AIM
To systematically assess the incidence of CRC in individuals with prediabetes compared with individuals with normoglycemia via a meta-analysis.
METHODS
Relevant cohort studies were acquired by searching MEDLINE, Web of Science, and EMBASE. A random-effects model was applied to combine the findings after accounting for heterogeneity. Several subgroup analyses were conducted to assess the impact of study characteristics on the results.
RESULTS
Eleven cohort studies involving 4996352 participants, including 383917 (7.7%) with prediabetes at baseline, were analyzed in this meta-analysis. Over a mean follow-up period of 6.5 years, the combined findings revealed that individuals with prediabetes at baseline had a higher likelihood of developing CRC than those with normoglycemia [risk ratio (RR) = 1.18, 95% confidence interval = 1.11 to 1.25, P < 0.001] with low statistical heterogeneity (I 2 = 27%). Subgroup analyses indicated that the association between prediabetes and an increased risk of CRC was mainly observed in studies defining prediabetes using impaired fasting glucose (RR = 1.24) and slightly elevated hemoglobin A1c levels (RR = 1.18) but not in those that defined prediabetes using impaired glucose tolerance (RR = 1.06). Other study characteristics such as design, country, participant age and sex, the duration of follow-up, or adjustment for body mass index did not significantly impact the results (all P > 0.05).
CONCLUSION
People with prediabetes might have a higher likelihood of developing CRC than individuals with normoglycemia.
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Affiliation(s)
- Na Wang
- Physical Examination Center, China-Japan Friendship Hospital, Beijing 100029, China
| | - Tian-Yi Zhao
- Physical Examination Center, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao Ma
- Physical Examination Center, China-Japan Friendship Hospital, Beijing 100029, China
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Liao JN, Ni WJ, Wu PH, Yang YD, Yang Y, Long W, Xie MZ, Zhu XZ, Xie FH, Leng XM. Switching from messenger RNAs to noncoding RNAs, METTL3 is a novel colorectal cancer diagnosis and treatment target. World J Gastrointest Oncol 2025; 17:104076. [DOI: 10.4251/wjgo.v17.i5.104076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/10/2025] [Accepted: 04/03/2025] [Indexed: 05/15/2025] Open
Abstract
N6-methyladenosine (m6A) modification, one of the most prevalent RNA epigenetic modifications in eukaryotes, constitutes over 60% of all RNA methylation modifications. This dynamic modification regulates RNA processing, maturation, nucleocytoplasmic transport, translation efficiency, phase separation, and stability, thereby linking its dysregulation to diverse physiological and pathological processes. METTL3, a core catalytic component of the methyltransferase complex responsible for m6A deposition, is frequently dysregulated in diseases, including colorectal cancer (CRC). Although METTL3’s involvement in CRC pathogenesis has been documented, its precise molecular mechanisms and functional roles remain incompletely understood. METTL3 mediates CRC progression-encompassing proliferation, invasion, drug resistance, and metabolic reprogramming-through m6A-dependent modulation of both coding RNAs and noncoding RNAs. Its regulatory effects are primarily attributed to interactions with key signaling pathways at multiple stages of CRC development. Emerging evidence highlights METTL3 as a promising biomarker for CRC diagnosis and prognosis, as well as a potential therapeutic target. By synthesizing recent advances in METTL3 research within CRC, this review provides critical insights into novel strategies for clinical diagnosis and targeted therapy.
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Affiliation(s)
- Jun-Nan Liao
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Wen-Juan Ni
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ping-Hui Wu
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ya-Dong Yang
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ying Yang
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Wen Long
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Mei-Zhen Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiu-Zhi Zhu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Fu-Hua Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiao-Min Leng
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
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Ilhan Y, Balcik OY, Guzel HG, Onder AH, Demir B, Baser MN, Karadag I, Ozbay MF, Genc TB, Uzuntas S, Poyrazoglu O, Beypinar I, Ergun Y, Ozturk B. Novel tumor marker index combining carcinoembryonic antigen and carbohydrate antigen 19-9: New prognostic factor for metastatic colorectal cancer. World J Gastrointest Oncol 2025; 17:104341. [DOI: 10.4251/wjgo.v17.i5.104341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/02/2025] [Accepted: 02/28/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is a global health challenge with a poor prognosis. Prognostic markers are critical for survival prediction.
AIM To evaluate a novel tumor marker index (TMI) combining carcinoembryonic antigen and carbohydrate antigen 19-9.
METHODS This multicenter, retrospective study measured baseline carcinoembryonic antigen and carbohydrate antigen 19-9 levels to calculate a TMI as the geometric mean of values normalized to their upper limits of normal. Receiver operating characteristic curve analysis assessed TMI’s prognostic accuracy, and patients were stratified into high-TMI (≥ 1.39) and low-TMI (< 1.39) groups. The primary endpoint was overall survival (OS), with progression-free survival and treatment response as secondary endpoints.
RESULTS The study included 305 mCRC patients with a median follow-up of 22.9 months. The median OS for high-TMI patients was 29.5 months, significantly lower than the 45.6 months observed in the low-TMI group (P = 0.02). The 2-year OS rates for the high- and low-TMI groups were 59.4% and 72.9%, respectively. Median progression-free survival was also shorter for the high-TMI group (14.0 vs 16.0 months, P = 0.84). High TMI is an independent prognostic factor for worse OS.
CONCLUSION TMI is a simple, cost-effective prognostic tool for mCRC, with high TMI associated with poorer survival outcomes.
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Affiliation(s)
- Yusuf Ilhan
- Department of Medical Oncology, Antalya City Hospital, Antalya 07080, Türkiye
| | - Onur Yazdan Balcik
- Department of Medical Oncology, Alanya Alaaddin Keykubat University, Antalya 07400, Türkiye
| | - Halil Goksel Guzel
- Department of Medical Oncology, Antalya Training and Research Hospital, Antalya 07100, Türkiye
| | - Arif Hakan Onder
- Department of Medical Oncology, Antalya Training and Research Hospital, Antalya 07100, Türkiye
| | - Bilgin Demir
- Department of Medical Oncology, Adnan Menderes University, Aydın 09100, Türkiye
| | - Mehmet Nuri Baser
- Department of Medical Oncology, Adnan Menderes University, Aydın 09100, Türkiye
| | - Ibrahim Karadag
- Department of Medical Oncology, Hitit University, Erol Olcok Education and Research Hospital, Corum 19169, Türkiye
| | - Mehmet Fatih Ozbay
- Department of Medical Oncology, Kırsehir Training and Research Hospital, Kırsehir 40200, Türkiye
| | - Tugrul Burak Genc
- Department of Medical Oncology, Mus State Hospital, Mus 49000, Türkiye
| | - Sahnura Uzuntas
- Department of Internal Medicine, Alanya Alaaddin Keykubat University, Antalya 07425, Türkiye
| | - Oguz Poyrazoglu
- Department of Internal Medicine, Hitit University, Erol Olcok Education and Research Hospital, Corum 19169, Türkiye
| | - Ismail Beypinar
- Department of Medical Oncology, Alanya Alaaddin Keykubat University, Antalya 07400, Türkiye
| | - Yakup Ergun
- Department of Medical Oncology, Bower Hospital, Diyarbakir 21100, Türkiye
| | - Banu Ozturk
- Department of Medical Oncology, Antalya Training and Research Hospital, Antalya 07100, Türkiye
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Shi J, Zheng P, Ouyang L, Cui F. Single-Cell RNA-Seq Recognized Key Genes for Metastasis and Macrophage Infiltration in Colorectal Cancer. Hum Mutat 2025; 2025:9488531. [PMID: 40406545 PMCID: PMC12097859 DOI: 10.1155/humu/9488531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Accepted: 04/25/2025] [Indexed: 05/26/2025]
Abstract
Colorectal cancer (CRC) is one of the most common malignancies in the world. However, the main causes of metastasis and immune cell infiltration in CRC are still unclear. This experiment was conducted to identify the key genes of metastasis and macrophage infiltration in CRC according to single-cell sequencing (scRNA-seq) data. By analyzing the data of GSE261012 and GSE234804 in the Gene Expression Omnibus (GEO) database, the key node genes for the stages of tumorigenesis, epithelial-mesenchymal transition, and metastasis of CRC were found. These genes were modeled by lasso regression by The Cancer Genome Atlas (TCGA) database, and ZFAND2A was identified as a key gene for metastasis and macrophage infiltration in CRC. Finally, the specific function of ZFAND2A in cancer cell activity was explored in vitro by qRT-PCR, WB analysis, CCK-8, and transwell assay. The specific function of ZFAND2A in macrophage polarization was explored in vitro by qRT-PCR, ELISA, and flow cytometry. We identified crucial gene expression in the entire process of CRC tumor progression, including tumorigenesis, epithelial-mesenchymal transition, and metastasis. Ten thousand six hundred and thirty-seven genes were determined as genes associated with tumor progression and metastasis. Among them, six genes were identified to be related to CRC prognosis. The results of TCGA data indicated that ZFAND2A showed lower expression in tumors and was related to a good prognosis of CRC. Overexpression of ZFAND2A inhibits the proliferation and migration of CRC cells. Additionally, there was a correlation between ZFAND2A expression and macrophage infiltration. Increasing ZFAND2A promotes M1 polarization in macrophages. Our findings provide new potential biomarkers for the metastatic mechanisms and prognosis of CRC. In addition, ZFAND2A is expected to become a potential therapeutic target for CRC.
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Affiliation(s)
- Juan Shi
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, China
| | - Peiming Zheng
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, China
| | - Libo Ouyang
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, China
| | - Facai Cui
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, China
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Feng H, Zhao LY, Xu Z, Xie QF, Deng HJ, Yu J, Liu H. Homologous recombination deficiency and immunotherapy response in microsatellite-stable colorectal cancer: Evidence from a cohort study in China. World J Gastrointest Oncol 2025; 17:102767. [DOI: 10.4251/wjgo.v17.i5.102767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/14/2025] [Accepted: 03/07/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Patients with colorectal cancer (CRC) exhibiting microsatellite instability (MSI)-high generally demonstrate a favorable response to immunotherapy. In contrast, the efficacy of immunotherapy in microsatellite-stable (MSS) CRC patients is considerably restricted. This study sought to evaluate the effectiveness of immunotherapy in MSS patients characterized by homologous recombination deficiency (HRD) as opposed to those with homologous recombination proficiency (HRP).
AIM To investigate and compare the clinicopathological characteristics, treatment modalities, and outcomes between the HRD and HRP groups in CRC.
METHODS Next-generation sequencing was performed on 268 CRC patients to identify tumor-associated genetic alterations and assess their HRD scores and MSI status. Patients with HRD-related gene alterations or an HRD score ≥ 30 were classified into the HRD group, while the remaining patients were assigned to the HRP group. Clinical data, including staging and treatment regimens, were collected for analysis. Cox regression and Kaplan-Meier survival curves were employed to evaluate whether the HRD group demonstrated improved survival outcomes following immunotherapy treatment.
RESULTS Among the 268 patients, 64 were classified into the HRD group, which had a higher proportion of early-stage CRC diagnoses compared to the HRP group. Kaplan-Meier survival curves indicated significantly better survival rates in the HRD group compared to the HRP group across all cohorts, as well as among MSS patients treated with immunotherapy (P < 0.05).
CONCLUSION This study demonstrates that CRC patients with HRD have a more favorable prognosis and suggests that HRD status could serve as a predictive marker for immunotherapy response in MSS patients.
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Affiliation(s)
- Hao Feng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Ying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhou Xu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Qing-Feng Xie
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hai-Jun Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Ma JX, Li XJ, Li YL, Liu MC, Du RH, Cheng Y, Li LJ, Ai ZY, Jiang JT, Yan SY. Chaperonin-containing tailless complex polypeptide 1 subunit 6A negatively regulates autophagy and protects colorectal cancer cells from cisplatin-induced cytotoxicity. World J Gastroenterol 2025; 31:105729. [DOI: 10.3748/wjg.v31.i18.105729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/27/2025] [Accepted: 04/14/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1 (TCP1) complex, which plays a pivotal role in ensuring the accurate folding of numerous proteins, chaperonin-containing TCP1 subunit 6A (CCT6A) participates in various physiological and pathological processes. However, its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer (CRC) cells.
AIM To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.
METHODS Cell proliferation was evaluated using the MTS assay, EdU staining, and colony growth assays. The expression of CCT6A was monitored by immunoblotting and quantitative PCR. CCT6A was knocked out by CRISPR-Cas9, and overexpressed by transfecting plasmids. Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay. To monitor apoptosis and necroptosis, immunoblotting, co-immunoprecipitation, and flow cytometry were employed.
RESULTS Cisplatin (DDP) exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A. Depletion of CCT6A amplified the cytotoxic effects of DDP, whereas overexpression of CCT6A attenuated these adverse effects. CCT6A suppressed autophagy, apoptosis, and necroptosis under both basal and DDP-treated conditions. Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP, whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP. Furthermore, inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.
CONCLUSION CCT6A negatively modulates autophagy, apoptosis, and necroptosis, and CCT6A confers resistance to DDP therapy in CRC, suggesting its potential as a therapeutic target.
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Affiliation(s)
- Jian-Xing Ma
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Xiao-Jun Li
- Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ya-Long Li
- Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ming-Chan Liu
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Rui-Hang Du
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Yi Cheng
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Liang-Jie Li
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Zhi-Ying Ai
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Jian-Tao Jiang
- The Second Affiliated Hospital of Xi’an Jiaotong University, Xibei Hospital, Xi’an 710000, Shaanxi Province, China
| | - Si-Yuan Yan
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
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Zhang L, Zhang Y, Chen L, Wang X, Liu Y, Huang Y, Song Y, Zhang Y, Tai J. Research trends and hotspots of circulating tumor DNA in colorectal cancer: a bibliometric study. Front Oncol 2025; 15:1492880. [PMID: 40438683 PMCID: PMC12116327 DOI: 10.3389/fonc.2025.1492880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 04/23/2025] [Indexed: 06/01/2025] Open
Abstract
Introduction Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths. The current standard of care for patients with early-stage CRC includes surgical resection and, in selected patients, adjuvant chemotherapy. Circulating tumor DNA (ctDNA) testing is an important component of liquid biopsy, and with the development of testing technology, its value for clinical application has attracted widespread attention. The aim of this study was to help researchers review what has been achieved and better understand the direction of future research through bibliometric analysis. Methods We used the Web of Science Core Collection database to search for ctDNA in CRC-related articles published between 2014 - 2023. Bibliometric analyses of major keywords, authors, countries, institutions, literature and journals in the field were performed using CiteSpace and VOSviewer. Results The number of publications in the field has continued to increase over the last decade. The United States has the highest number of publications, and Italian research scholars have made outstanding contributions. Cancers is the journal with the highest number of publications. Conclusion This study systematically summarizes the research findings in the field of ctDNA in CRC from 2014 to 2023 and describes the research hotspots and trends worldwide that can guide future research.
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Affiliation(s)
- Lele Zhang
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Lei Chen
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Xu Wang
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Yulian Liu
- Department of Traditional Chinese Medicine, Chongqing Hospital of Jiangsu Province Hospital, Chongqing, China
| | - Yishan Huang
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Yu Song
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Jiandong Tai
- Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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Lin Q, Liu H, Xu Q. Identification of dysregulated competitive endogenous RNA network driven by copy number variation in colon adenocarcinoma. Comput Methods Biomech Biomed Engin 2025:1-12. [PMID: 40357733 DOI: 10.1080/10255842.2025.2498718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 04/01/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025]
Abstract
Competitive endogenous RNA (ceRNA) network modulation plays a crucial role in pathogenesis of colon adenocarcinoma (COAD). This study analyzed The Cancer Genome Atlas(TCGA) data to identify 151 copy number variation (CNV)-driven lncRNAs in COAD, constructing a ceRNA network (6 lncRNAs-14 miRNAs-68 mRNAs). Functional enrichment revealed their roles in muscle system processes , blood vessel development and extracellular matrix organization. Survival analysis linked LINC00941 amplification to poor prognosis. Two CNV-driven lncRNA-targeting drugs were identified, offering insights into COAD mechanisms and potential biomarkers.
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Affiliation(s)
- Qingliang Lin
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors, Fuzhou, China
- Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies), Fuzhou, China
| | - Haiyu Liu
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, China
| | - Qian Xu
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, China
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Wang W, Zhang Q, Fan S, Wang Y, Le X, Ai M, Du C, Feng J, Li C. Prediction of KRAS gene mutations in colorectal cancer using a CT-based radiomic model. Front Med (Lausanne) 2025; 12:1592497. [PMID: 40421293 PMCID: PMC12104245 DOI: 10.3389/fmed.2025.1592497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Accepted: 04/28/2025] [Indexed: 05/28/2025] Open
Abstract
Background Determining the KRAS gene mutation status in colorectal cancer (CRC) before surgery is highly important for an individualized clinical treatment. This study aimed to explore the clinical value of radiomics models based on CT images in predicting the KRAS mutation status in patients with CRC. Methods A total of 201 CRC patients who underwent surgery and pathology examinations from March 2022 to January 2025 were included. They were randomly allocated to a training group (160 patients) or a testing group (41 patients) at a ratio of 8:2. All patients underwent plain CT and contrast-enhanced examinations before surgery. The 3D segmentation of the tumour was manually delineated by two radiologists who were unaware of the pathological results and KRAS gene detection outcomes. The PyRadiomics package in Python was used to extract 2,264 radiomic features from each ROI. After dimensionality reduction, machine learning methods such as extremely randomized trees (ERT), random forest (RF), XGBoost, Bagging, and CatBoost were used for model construction. The performance of the models was compared using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. The Delong test was employed to assess the differences between the various models. Results After feature selection, the top 8 features with the highest mutual information scores were extracted to construct a prediction model. The Delong test revealed that the XGBoost model, which is based on CT images from the vein phase, performed the best, with AUC values of 0.90 and 0.81 in the training and test sets, respectively. The calibration curve indicated a high consistency between the actual and predicted probabilities of the samples. The decision curve analysis results revealed that the XGBoost model exhibited the highest net clinical benefit among all the models. Conclusion In this study, a highly accurate radiomics model was developed for KRAS gene mutation status prediction in patients with CRC before surgery. This technique avoids the potential risks of tumour rupture and dissemination during biopsy and can serve as a powerful tool to assist doctors in developing personalized and precise targeted treatments for colorectal cancer, which highly important in clinical work.
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Affiliation(s)
- Wenjing Wang
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Qingbiao Zhang
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Shimei Fan
- Physical Examination Center, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yuyin Wang
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Xingyan Le
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Min Ai
- Department of Anesthesiology, Nanan District People's Hospital of Chongqing, Chongqing, China
| | - Chunqi Du
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Junbang Feng
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Chuanming Li
- Medical Imaging Department, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
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Zhang L, Gao S, Lin X, Hu J, Zhang G, Tang W, Hu Y, Wang Y, Chu L. Development of a cancer-specific survival assessment for lymph node-positive colorectal cancer patients treated with adjuvant chemotherapy. Front Surg 2025; 12:1589875. [PMID: 40421275 PMCID: PMC12104235 DOI: 10.3389/fsurg.2025.1589875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Accepted: 04/23/2025] [Indexed: 05/28/2025] Open
Abstract
Background To construct a prognostic model for predicting cancer-specific survival in lymph node-positive colorectal cancer patients treated with adjuvant chemotherapy after surgery. Methods Data were collected from the 2010-2015 SEER database and from CRC patients at the Second Affiliated Hospital of Bengbu Medical University (2017-2023). Lasso regression and random survival forest methods were used to screen ten clinicopathologic features. Cox regression analysis identified independent prognostic factors for CRC. Nomogram plot model was used to predict 1-, 3-, and 5-year survival rates, with its accuracy verified through ROC curves, calibration curves, and decision curve analysis (DCA). The X-tile software differentiated between high and low-risk groups and illustrated survival differences using Kaplan-Meier curves. Results Age, histologic grade, stage, CEA, nerve invasion, and LNR were independent prognostic risk factors for colorectal cancer (P < 0.001); and LNR were the five variables used to construct the Nomogram. The area under the curve (AUC) was 0.83, 0.85, and 0.84 at 1, 3, and 5 years for the training cohort; 0.83, 0.85, and 0.84 at 1, 3, and 5 years for the internal validation cohort; and 0.83, 0.85, and 0.84 at 1, 3, and 5 years for the external validation cohort, respectively. calibration curves, C-indexes, and DCA curves validated the accuracy of the model, respectively. The survival prognosis of the high-risk group was lower than that of the low-risk group in all three data sets. (HR = 6.37, CI:6.05-6.71, P < 0.05; HR = 7.05, CI:6.52-7.64, P < 0.05; HR = 2.69, CI:1.66-4.37, P < 0.05). Conclusions LNR represents a new independent prognostic factor for lymph node-positive CRC. The optimal threshold determined by the Nomogram method effectively categorizes subgroups of lymph node-positive CRC cases after surgical chemotherapy, crucial for guiding clinical treatment strategy selection.
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Affiliation(s)
- Lei Zhang
- Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Shuang Gao
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Xiaoyuan Lin
- Center for Medical Research and Innovation, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Junjie Hu
- Department of Radiotherapy, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Guolin Zhang
- Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Wei Tang
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Yubo Hu
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Yuanpeng Wang
- Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Liang Chu
- Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
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Kopyeva I, Bretherton RC, Ayers JL, Yu M, Grady WM, DeForest CA. Matrix Stiffness and Biochemistry Govern Colorectal Cancer Cell Growth and Signaling in User-Programmable Synthetic Hydrogels. ACS Biomater Sci Eng 2025; 11:2810-2823. [PMID: 40304602 DOI: 10.1021/acsbiomaterials.4c01632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
Colorectal cancer (CRC) studies in vitro have been conducted almost exclusively on 2D cell monolayers or suspension spheroid cultures. Though these platforms have shed light on many important aspects of CRC biology, they fail to recapitulate essential cell-matrix interactions that often define in vivo function. Toward filling this knowledge gap, synthetic hydrogel biomaterials with user-programmable matrix mechanics and biochemistry have gained popularity for culturing cells in a more physiologically relevant 3D context. Here, using a poly(ethylene glycol)-based hydrogel model, we systematically assess the role of matrix stiffness and fibronectin-derived RGDS adhesive peptide presentation on CRC colony morphology and proliferation. Highlighting platform generalizability, we demonstrate that these hydrogels can support the viability and promote spontaneous spheroid or multicellular aggregate formation of six CRC cell lines that are commonly utilized in biomedical research. These gels are engineered to be fully degradable via a "biologically invisible" sortase-mediated reaction, enabling the triggered recovery of single cells and spheroids for downstream analysis. Using these platforms, we establish that substrate mechanics play a significant role in colony growth: soft conditions (∼300 Pa) encourage robust colony formation, whereas stiffer (∼2 kPa) gels severely restrict growth. Tuning the RGDS concentration did not affect the colony morphology. Additionally, we observe that epidermal growth factor receptor (EGFR) signaling in Caco-2 cells is influenced by adhesion ligand identity─whether the adhesion peptide was derived from collagen type I (DGEA) or fibronectin (RGDS)─with DGEA yielding a marked decrease in the level of downstream protein kinase phosphorylation. Taken together, this study introduces a versatile method to culture and probe CRC cell-matrix interactions within engineered 3D biomaterials.
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Affiliation(s)
- Irina Kopyeva
- Department of Bioengineering, University of Washington, Seattle 98105, Washington, United States
- Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle 98105, Washington, United States
| | - Ross C Bretherton
- Department of Bioengineering, University of Washington, Seattle 98105, Washington, United States
- Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle 98105, Washington, United States
| | - Jessica L Ayers
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle 98109, Washington, United States
| | - Ming Yu
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle 98109, Washington, United States
| | - William M Grady
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle 98109, Washington, United States
- Department of Internal Medicine, University of Washington, Seattle 98105, Washington, United States
| | - Cole A DeForest
- Department of Bioengineering, University of Washington, Seattle 98105, Washington, United States
- Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle 98105, Washington, United States
- Department of Chemical Engineering, University of Washington, Seattle 98105, Washington, United States
- Molecular Engineering & Sciences Institute, University of Washington, Seattle 98105, Washington, United States
- Department of Chemistry, University of Washington, Seattle 98105, Washington, United States
- Institute for Protein Design, University of Washington, Seattle 98105, Washington, United States
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Yu K, Yu Y, Zhang C, Hao L. Mechanistic insights into PDZK1-interacting protein 1 on the malignant progression of colorectal carcinoma. Cytojournal 2025; 22:52. [PMID: 40539126 PMCID: PMC12178085 DOI: 10.25259/cytojournal_200_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 03/31/2025] [Indexed: 06/22/2025] Open
Abstract
Objective PDZ domain containing 1-interacting protein 1 (PDZK1IP1) is commonly overexpressed in a wide variety of cancer. Hence, the objective of the present study is to ascertain the influences of PDZK1IP1 on colorectal carcinoma (CRC) development. Material and Methods PDZK1IP1 expression was tested through reverse transcription-quantitative polymerase chain reaction and Western blot analysis, and its correlation with prognosis was analyzed using the GEPIA website. Small interfering RNA against PDZK1IP1 was adopted to downregulate PDZK1IP1 expression in CRC cells. The effects of PDZK1IP1 on cell growth were ascertained using colony formation and CCK-8 tests, and CRC cell apoptosis was analyzed through flow cytometry. Cell migration capability and invasiveness were measured using Matrigel Transwell and scratch-healing assays. Results PDZK1IP1 was highly expressed in the CRC tissues (P < 0.001) and cells (P < 0.05), and its knockdown restrained cell growth (P < 0.05), migratory potential (P < 0.01), and invasive capacities (P < 0.001) and accelerated cell apoptosis (P < 0.001). Mechanically, PDZK1IP1 silencing blocked CRC progression by inactivating the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of the rapamycin pathway. Conclusion PDZK1IP1 contributes to the oncogenesis of CRC. This finding provides a basis for the diagnosis, treatment, and prevention of CRC.
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Affiliation(s)
- Kuaiyun Yu
- Department of General Surgery, Yantaishan Hospital, Yantai, Shandong Province, China
| | - Yao Yu
- Department of General Pediatric Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - Chang Zhang
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
| | - Leilei Hao
- Department of Anorectal, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong Province, China
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Ma L, Huang G, Lin C, Li X, Liu C, Huang W, Zhang Q, Luo Y. LACTB promotes cell differentiation and inhibits cell proliferation in colorectal cancer. Biochim Biophys Acta Gen Subj 2025; 1869:130816. [PMID: 40354832 DOI: 10.1016/j.bbagen.2025.130816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 04/23/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
This study aims at exploring the role of LACTB on colorectal cancer (CRC) cell differentiation. In this study, 143 colorectal cancer tissue samples were collected for analyzing the correlation between LACTB level and clinical information. Another 24 recent cases and adjacent tissues underwent qPCR, Western blot, and immunohistochemistry (IHC) to detect LACTB expression. The differentiation and proliferation of CRC cells were evaluated by AKP levels, E-cadherin expression, cell viability, colony formation, EdU assay, and cell cycle. Subcutaneous models explored LACTB's pro-differentiation effects. The glandular-like structures of tumor were observed by HE staining, immunofluorescence detection of microvilli proteins, and transmission electron microscopy. Our results showed that LACTB expression in colorectal cancer tissues was lower than that in adjacent normal tissues. Higher LACTB expression was correlated with slower tumor progression, better prognosis and higher differentiation degree. Overexpressing LACTB in CRC cells enhanced differentiation markers level (AKP and E-cadherin), while inhibited cell proliferation and colony formation, induced cell cycle arrest. Conversely, LACTB knockdown had an opposite effect. Subcutaneous xenograft tumor model suggested that LACTB overexpression inhibited tumor growth, induced tissue differentiation and glandular-like structures formation. Collectively, our results show that LACTB overexpression promotes cell differentiation and inhibits cell proliferation in CRC cells, which may serve as a therapy target for CRC.
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Affiliation(s)
- Lili Ma
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Guan Huang
- Department of Pathology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, Guangdong, China
| | - Chun Lin
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Xiaoqing Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chao Liu
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Weiye Huang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Qingling Zhang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
| | - Yang Luo
- Department of Urology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China.
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Abdelrahim M, Esmail A, Al-Najjar E, Khasawneh B, Umoru G, Abdelrahim W, Abboud K, Ajewole VB. Safety and Efficacy of Regorafenib and 5-Fluorouracil Combination Therapy in Refractory Metastatic Colorectal Cancer After Third-Line Treatment: An Institutional Experience. Biomedicines 2025; 13:1151. [PMID: 40426978 PMCID: PMC12109328 DOI: 10.3390/biomedicines13051151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Colorectal carcinoma (CRC) is one of the most common cancer types along with breast, prostate, and lung cancer. Many patients with CRC present with metastatic disease despite receiving standard first- and second-line therapies; thus emerges the demand for implementing new therapies that could improve outcomes among CRC patients. This case series was conducted to assess the efficacy and safety of regorafenib plus 5-fluorouracil (5-FU) in patients with refractory metastatic CRC (mCRC). Methods: We conducted a retrospective analysis of data from adult patients aged 18 and above who were diagnosed with refractory mCRC and received regorafenib plus 5-FU combination therapy at Houston Methodist Hospital between November 2017 and October 2023. Our study focuses on assessing key outcomes, including Overall Survival [OS], Progression-Free Survival [PFS], and safety. Results: Among the 12 patients we included in this study who underwent regorafenib plus 5-FU combination therapy for refractory mCRC after receiving at least three prior lines of treatment, the best response for six patients (50%) was successfully achieved, with disease control within 7-12 weeks from therapy initiation. Patients had an overall good tolerance for this treatment regimen and reported only the most common adverse events, including Hand-Foot Syndrome (HFS), mucositis, and hypertension (HTN), which were mostly resolved with dose adjustment of medications. Conclusions: This study highlights that using a combination of regorafenib plus 5-FU can be a potential treatment option for patients with refractory mCRC. Additional research, including prospective clinical trials, is required to assess the effectiveness and safety of regorafenib and 5-FU combination therapy in comparison to other currently limited treatment options.
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Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
| | - Bayan Khasawneh
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
| | - Godsfavour Umoru
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
| | - Waseem Abdelrahim
- Michael E. DeBakey HS for Health Professions, Houston, TX 77030, USA
| | - Karen Abboud
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
| | - Veronica B. Ajewole
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA; (A.E.)
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Zhu J, Fu S, Zou X, Zeng H, Cui G, Peng Y, Tang D, Zhang F, Shen H, Zeng S, Han Y. PRMT5 Inhibitor Synergizes with Chemotherapy to Induce Resembling Mismatch Repair Deficiency and Enhance Anti-TIGIT Therapy in Microsatellite-Stable Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2500271. [PMID: 40344511 DOI: 10.1002/advs.202500271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 04/06/2025] [Indexed: 05/11/2025]
Abstract
Microsatellite stable (MSS) colorectal cancer (CRC) is considered an "immune-cold" tumor, accounting for ≈85% of all CRC cases. The overall response rate to chemotherapy combined with immune checkpoint inhibitors in MSS CRC is typically less than 10%. The specific mechanism that enhances chemotherapy sensitivity and mediated immunogenicity renders MSS CRC more responsive to immunotherapy remains elusive. Experiments in this study identify a DNA damage repair-related epigenetic gene, protein arginine methyltransferase 5 (PRMT5), whose inhibition enhances Irinotecan (CPT-11) sensitivity and synergistically induces a postmeiotic segregation increased 2 (PMS2)-deficient-like state, leading to the release of cytosolic double-stranded DNA. This activates the cyclic GMP-AMP synthase (cGAS)-stimulator of the IFN gene (STING) signaling pathway, thereby enhancing anti-tumor immunotherapy through dendritic cell-T cell-dependent functions. Importantly, combining the epigenetic anti-tumor drug GSK3326595 with CPT-11 significantly upregulates the immune receptor tyrosine-based inhibitory motif (TIGIT) level on CD8+ T cells and subsequently demonstrates impressive anti-tumor efficacy in vivo when additional anti-TIGIT is included. Collectively, this study reveals the crucial role of PRMT5 blockade combined with CPT-11 in inducing a mismatch repair deficiency-like state and provides a novel triple-drug combination therapy strategy as a potential treatment for patients with MSS CRC.
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Affiliation(s)
- Jiang Zhu
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Shenao Fu
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Xi Zou
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Hanjiang Zeng
- Department of Nephrology, Xingsha Campus, Hunan Provincial People's Hospital, Changsha, Hunan, 410100, P. R. China
| | - Guangzu Cui
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Yinghui Peng
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Diya Tang
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Fan Zhang
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- College of Life Science, Mudanjiang Medical University, Mudanjiang, 157011, P. R. China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Kaifu District, Central South University, Changsha, Hunan, 410008, P. R. China
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Li JJ, Xu PF, Nie YL. Partial response to posterior line immunotherapy for more than 15 months in a pMMR patient with cutaneous metastasis of rectal carcinoma: a case report. Therap Adv Gastroenterol 2025; 18:17562848251338673. [PMID: 40351380 PMCID: PMC12062587 DOI: 10.1177/17562848251338673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 04/12/2025] [Indexed: 05/14/2025] Open
Abstract
The vast majority of colorectal cancers (CRCs) are proficient mismatch repair (pMMR) and microsatellite stable, and their immune microenvironment appears as a "cold tumor," which is not sensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). The utilization of ICIs in pMMR advanced CRC is still in the exploratory phase. Cutaneous metastasis from colorectal carcinoma is extremely rare, presenting with diverse clinical manifestations, and there is a lack of standard treatment options for such cases. Patients with skin metastasis from CRC usually progress rapidly and are associated with a dismal prognosis. Herein, we report the case of a 66-year-old woman with extensive cutaneous metastasis of pMMR advanced rectal carcinoma. The patient presented to the abdominal oncology clinic with a complaint of erythema on the right lower limb, perineum, and abdominal skin. The patient underwent radical surgery for rectal carcinoma 3 years before the presentation. The histologic examination revealed low-grade squamous cell subepithelial adenocarcinoma. The patient was treated with sintilizumab in combination with fruquintinib, which exhibited remarkable efficacy and improved the patient's quality of life significantly. Previous cases of cutaneous metastasis of colorectal carcinoma were retrieved to characterize the clinicopathological features. For the rare subset of patients with skin metastasis from CRC, immunotherapy combined with anti-angiogenic targeted therapy may be considered.
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Affiliation(s)
- Jing-Jing Li
- Department of Abdominal Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong
- University of Science and Technology, Wuhan, Hubei Province, China
| | - Peng-Fei Xu
- Department of Abdominal Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong
- University of Science and Technology, Wuhan, Hubei Province, China
| | - Yan-Li Nie
- Department of Abdominal Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong
- University of Science and Technology, No. 116 Zhuodaoquan South Road, Wuhan, Hubei Province 430000, China
- Hubei Provincial Clinical Research Center for Colorectal Cancer, Wuhan, Hubei Province, China
- Wuhan Clinical Research Center for Colorectal Cancer, Wuhan, Hubei Province, China
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Oh S, Sim HB, Kim H, Mun SK, Ji M, Choi B, Kim DY, Kim JJ, Paik MJ. Cellular metabolomics study in colorectal cancer cells and media following treatment with 5-fluorouracil by gas chromatography-tandem mass spectrometry. Metabolomics 2025; 21:62. [PMID: 40335841 DOI: 10.1007/s11306-025-02263-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 04/18/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Metabolic reprogramming is a distinctive characteristic of colorectal cancer (CRC) which provides energy and nutrients for rapid proliferation. Although numerous studies have explored the rewired metabolism of CRC, the metabolic alterations occurring in CRC when the cell cycle is arrested by treatment with 5-fluorouracil (5-FU), an anticancer drug that arrests the S phase, remain unclear. METHODS A systematic profiling analysis was conducted as ethoxycarbonyl/methoxime/tert-butyldimethylsilyl derivatives using gas chromatography-tandem mass spectrometry in HT29 cells and media following 5-FU treatment in a concentration- and time-dependent manner. RESULTS In HT29 cells of 24 h after 5-FU treatment (3-100 μM) and 48 h after 5-FU treatment (1-10 μM), six amino acids, including valine, leucine, isoleucine, serine, glycine, and alanine and two organic acids, including pyruvic acid and lactic acid, were significantly increased compared to the DMSO-treated group. However, 48 h after 5-FU treatment (30-100 μM) in HT29 cells, the levels of these metabolites decreased along with an approximately 50% reduction in viability, an increase in the level of reactive oxygen species, induction of cycle arrest in the G1 phase, and the induction of apoptosis. On the other hand, the levels of fatty acids showed a continuous increase in HT29 cells 48 h after 5-FU treatment (1-100 μM). In the media, the decreased availabilities in the cellular uptake of nutrient metabolites, including valine, leucine, isoleucine, serine, and glutamine, were observed at 48 h after 5-FU treatment in a dose-dependent manner. CONCLUSION It is assumed that there is a possible shift in energy dependence from the tricarboxylic acid cycle to fatty acid metabolism. Thus, metabolic profiling analysis revealed altered energy metabolism in CRC cells following 5-FU treatment.
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Affiliation(s)
- Songjin Oh
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
| | - Hyun Bo Sim
- Department of Biomedical Science, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
| | - Hyeongyeong Kim
- Department of Biomedical Science, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
| | - Seul-Ki Mun
- Department of Biomedical Science, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
| | - Moongi Ji
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
| | - Byeongchan Choi
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
| | - Doo-Young Kim
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea
- New Drug Discovery Lab, Hyundai Pharm, Yongin, 17089, Republic of Korea
| | - Jong-Jin Kim
- Department of Biomedical Science, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea.
| | - Man-Jeong Paik
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, 255 Jungang-ro, Suncheon, 57922, Republic of Korea.
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