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Tian SC, Song XH, Feng KK, Li CL, Tu YF, Hu YS, Shao JW. Self-oxygenating nanoplatform integrating CRISPR/Cas9 gene editing and immune activation for highly efficient photodynamic therapy. J Colloid Interface Sci 2025; 693:137632. [PMID: 40262200 DOI: 10.1016/j.jcis.2025.137632] [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: 12/26/2024] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/24/2025]
Abstract
Photodynamic therapy (PDT) has arisen as a promising method due to its spatiotemporal precision and minimal invasiveness. It encounters significant obstacles in solid tumors due to hypoxia-induced therapeutic resistance and the self-protective mechanisms of cancer cells facilitated by MutT homolog 1 (MTH1), an enzyme involved in oxidative damage repair. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on hollow mesoporous manganese dioxide (H-MnO2) for PDT. This platform utilizes H-MnO2 to produce oxygen (O2) through the decomposition of hydrogen peroxide (H2O2) in TME, thereby mitigating hypoxia and enhancing reactive oxygen species (ROS) generation. The high concentration of glutathione (GSH) and hyaluronidase (HAase) in TME induces the release of CRISPR/Cas9 ribonucleoproteins (RNP) to target the MTH1 gene, thereby impairs oxidative damage repair pathways and amplifys ROS-mediated cytotoxicity. The released Mn2+ ions function as immunomodulatory agents, activate innate immune responses via stimulating STING signal pathway. In vitro, IHMRH NPs markedly increased intracellular O2 levels, ROS production, lipid peroxidation and DNA damage, leading to tumor cell death, immune activation, and effective gene editing. In vivo, the nanoplatform suppressed tumor growth, diminished MTH1 gene expression, stimulated dendritic cell (DC) maturation through immunogenic cell death (ICD). This multimodal nanosystem may amplifies oxidative stress, collaborates with innate and adaptive immune activation to surpass the constraints of traditional PDT. The research presents a novel framework for cancer combination therapy by systematically integrating nanotechnology with precision gene editing.
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Affiliation(s)
- Shi-Cheng Tian
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Xun-Huan Song
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China; Center for Preclinical Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ke-Ke Feng
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Cheng-Lei Li
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Yi-Fan Tu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Yong-Shan Hu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Jing-Wei Shao
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China.
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Liu Q, Yu M, Lin Z, Wu L, Xia P, Zhu M, Huang B, Wu W, Zhang R, Li K, Zhu L, Wang Q. COL1A1-positive endothelial cells promote gastric cancer progression via the ANGPTL4-SDC4 axis driven by endothelial-to-mesenchymal transition. Cancer Lett 2025; 623:217731. [PMID: 40254092 DOI: 10.1016/j.canlet.2025.217731] [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: 10/31/2024] [Revised: 03/19/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
Gastric cancer (GC) is an aggressive and heterogeneous disease with poor survival outcomes. The progression of GC involves complex, multi-step processes. Endothelial cells (ECs) play a crucial role in tumor angiogenesis, proliferation, invasion, and metastasis, particularly through the process of endothelial-to-mesenchymal transition (EndoMT). However, the specific role and mechanisms of EndoMT in gastric cancer remain unclear. Based on 6 GC single-cell RNA-sequencing (scRNA-seq) cohorts (samples = 97), we established an EndoMT-related gene signature, termed EdMTS. Leveraging this gene signature, ssGSEA was applied to calculate sample scores across multiple bulk RNA-seq datasets, which include information on immunotherapy, metastasis, GC progression, and survival. Moreover, we applied the Monocle2 method to calculate cell pseudotime and used CellChat to analyze interactions between malignant and EC cells. We verified the molecular mechanism by multiple immunofluorescence and cell function experiments. Findings In this study, we established a single-cell atlas of ECs in GC and identified a subpopulation of COL1A1+ ECs that play a critical role in tumor progression and metastasis. These COL1A1+ ECs were significantly associated with worse clinical outcomes in GC patients. Further analysis revealed that COL1A1+ ECs originated from lymphatic ECs and underwent EndoMT through the upregulation of CEBPB, driving tumor invasiveness. Moreover, COL1A1+ ECs interacted with malignant cells via ANGPTL4-SDC4 axis, enhancing invasion and migration. These findings provide a deeper understanding of the role of COL1A1+ ECs in GC progression and highlight potential therapeutic targets for disrupting the EndoMT process in these cells to provide a benefit for GC patients.
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Affiliation(s)
- Quanzhong Liu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China
| | - Miao Yu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
| | - Zihan Lin
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
| | - Lingxiang Wu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China
| | - Peng Xia
- School of Biological Science & Medical Engineering, Southeast University, Nanjing, China
| | - Mengyan Zhu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China
| | - Bin Huang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China
| | - Wei Wu
- School of Biological Science & Medical Engineering, Southeast University, Nanjing, China
| | - Ruohan Zhang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China
| | - Kening Li
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China
| | - Lingjun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Qianghu Wang
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China; The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 210002, Nanjing, China; School of Biological Science & Medical Engineering, Southeast University, Nanjing, China.
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Hou YJ, Yang XX, Meng HX. Mitochondrial metabolism in laryngeal cancer: therapeutic mechanisms and prospects. Biochim Biophys Acta Rev Cancer 2025; 1880:189335. [PMID: 40311711 DOI: 10.1016/j.bbcan.2025.189335] [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: 02/02/2025] [Revised: 04/23/2025] [Accepted: 04/23/2025] [Indexed: 05/03/2025]
Abstract
Tumours reprogram pathways that regulate nutrient uptake and metabolism to meet the biosynthetic, bioenergetic, and redox requirements of cancer cells. This phenomenon is known as metabolic reprogramming and is edited by the deletion of oncogenes and the activation of proto-oncogenes. This article highlights the pathological mechanisms associated with metabolic reprogramming in laryngeal cancer (LC), including enhanced glycolysis, tricarboxylic acid cycle, nucleotide synthesis, lipid synthesis and metabolism, and amino acid metabolism, with a special emphasis on glutamine, tryptophan, and arginine metabolism. All these changes are regulated by HPV infection, hypoxia, and metabolic mediators in the tumour microenvironment. We analyzed the function of metabolic reprogramming in the development of drug resistance during standard LC treatment, which is challenging. In addition, we revealed recent advances in targeting metabolic strategies, assessing the strengths and weaknesses of clinical trials and treatment programs to attack resistance. This review summarises some currently important biomarkers and lays the foundation for therapeutic pathways in LC.
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Affiliation(s)
- Yun-Jing Hou
- Harbin Medical University, Harbin, China; Harbin Medical University Cancer Hospital, Harbin, China; Department of Precision Medicine Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin-Xin Yang
- Harbin Medical University, Harbin, China; Harbin Medical University Cancer Hospital, Harbin, China; Department of Precision Medicine Center, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hong-Xue Meng
- Harbin Medical University, Harbin, China; Harbin Medical University Cancer Hospital, Harbin, China; Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China.
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Li L, Wei C, Xie Y, Su Y, Liu C, Qiu G, Liu W, Liang Y, Zhao X, Huang D, Wu D. Expanded insights into the mechanisms of RNA-binding protein regulation of circRNA generation and function in cancer biology and therapy. Genes Dis 2025; 12:101383. [PMID: 40290118 PMCID: PMC12022641 DOI: 10.1016/j.gendis.2024.101383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/06/2024] [Accepted: 06/22/2024] [Indexed: 04/30/2025] Open
Abstract
RNA-binding proteins (RBPs) regulate the generation of circular RNAs (circRNAs) by participating in the reverse splicing of circRNA and thereby influencing circRNA function in cells and diseases, including cancer. Increasing evidence has demonstrated that the circRNA-RBP network plays a complex and multifaceted role in tumor progression. Thus, a better understanding of this network may provide new insights for the discovery of cancer drugs. In this review, we discuss the characteristics of RBPs and circRNAs and how the circRNA-RBP network regulates tumor cell phenotypes such as proliferation, metastasis, apoptosis, metabolism, immunity, drug resistance, and the tumor environment. Moreover, we investigate the factors that influence circRNA-RBP interactions and the regulation of downstream pathways related to tumor development, such as the tumor microenvironment and N6-methyladenosine modification. Furthermore, we discuss new ideas for targeting circRNA-RBP interactions using various RNA technologies.
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Affiliation(s)
- Lixia Li
- Cancer Hospital, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Chunhui Wei
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Yu Xie
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Yanyu Su
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Caixia Liu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Guiqiang Qiu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Weiliang Liu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Yanmei Liang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Xuanna Zhao
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Dan Huang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
| | - Dong Wu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, China
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Zheng XD, Li HY, Gao SY, Wang Q, Liu JB. High hypoxia inducible factor-1α expression is associated with reduced survival in patients with breast cancer: A meta-analysis. World J Clin Oncol 2025; 16:105691. [DOI: 10.5306/wjco.v16.i6.105691] [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: 02/03/2025] [Revised: 04/06/2025] [Accepted: 05/13/2025] [Indexed: 06/20/2025] Open
Abstract
BACKGROUND Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in the prognosis of breast cancer, but the current evidence remains inconclusive.
AIM To provide comprehensive evidence about the correlation of altered HIF-1α expression with overall survival (OS) and disease-free survival (DFS) in breast cancer patients.
METHODS A systematic search was conducted in PubMed, Embase, and Web of Science databases to collect relevant articles that were published before April 8, 2024. A meta-analysis was used to assess the impact of altered HIF-1α expression on the OS and DFS of breast cancer patients. Subgroup and sensitivity analyses were also performed in this meta-analysis.
RESULTS This meta-analysis included 40 studies. The average percentage of breast cancer patients with high HIF-1α expression was 39.6%. The overall meta-analysis results demonstrated that high HIF-1α expression is strongly linked to poor outcomes in patients of breast cancer. Compared with low HIF-1α expression, the overall hazard ratio for OS in patients with high HIF-1α expression was 1.47 [95% confidence interval (CI): 1.29-1.69], and the overall hazard ratio for DFS was 1.82 (95%CI: 1.56-2.12). Furthermore, both OS [1.18 (95%CI: 1.01-1.38)] and DFS [1.79 (95%CI: 1.03-3.11)] were markedly shorter in triple-negative breast cancer cases with high HIF-1α expression. Subgroup analysis revealed that the antibody used to detect HIF-1α expression affected only the correlation linking HIF-1α expression to DFS in breast cancer patients (P = 0.0004). Furthermore, the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.
CONCLUSION Compared to patients with low HIF-1α expression, those with high expression level had shorter OS and DFS. However, the prognostic significance of high HIF-1α expression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.
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Affiliation(s)
- Xue-Di Zheng
- Department of Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Huan-Yu Li
- Department of Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Si-Yu Gao
- Department of Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Qi Wang
- Department of Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
| | - Jiang-Bo Liu
- Department of Breast Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan Province, China
- Department of Breast and Thyroid Surgery, The Third Affiliated Hospital, Zhengzhou University, Zhengzhou 450000, Henan Province, China
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Wang L, Wang MH, Yuan YH, Xu RZ, Bai L, Wang MZ. Identification and validation of extracellular matrix-related genes in the progression of gastric cancer with intestinal metaplasia. World J Gastrointest Oncol 2025; 17:105160. [DOI: 10.4251/wjgo.v17.i6.105160] [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: 01/13/2025] [Revised: 03/31/2025] [Accepted: 04/23/2025] [Indexed: 06/13/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is a highly lethal malignancy with a high incidence and mortality rate globally. Its development follows the Correa model, with intestinal metaplasia (IM) being a critical precursor to GC. However, the mechanisms underlying IM progression to GC remain unclear. This study explored extracellular matrix (ECM)-related gene changes during IM progression to GC, aiming to identify biomarkers that could improve early diagnosis and treatment strategies for GC, ultimately enhancing patient outcomes.
AIM To analyze transcriptome sequencing data, molecular biomarkers that can predict GC risk and monitor IM progression can be identified, providing new insights and strategies for preventing IM-GC transformation.
METHODS Weighted gene co-expression network analysis served for confirming gene modules. Upregulated ECM-related genes were further tested using univariate Cox regression and least absolute shrinkage and selection operator analysis to select hub genes and construct a survival analysis model. The intestinal cell model was established by stimulating GES-1 cells with chenodeoxycholic acid.
RESULTS Weighted gene co-expression network analysis identified 1709 differentially expressed genes from the GSE191275 dataset, while The Cancer Genome Atlas stomach adenocarcinoma revealed 4633 differentially expressed genes. The intersection of these datasets identified 71 upregulated and 171 downregulated genes, which were enriched in ECM-related pathways. Univariate Cox regression analysis identified six genes with prognostic significance, and least absolute shrinkage and selection operator regression pinpointed secreted protein acidic and rich in cysteine (SPARC) and SERPINE1 as non-zero coefficient genes. A prognostic model integrating clinical tumor node metastasis staging, age, SERPINE1, and SPARC was constructed. Immunohistochemistry analysis confirmed an increasing expression of SPARC protein from normal gastric mucosa (-), to IM (+- to +), and to GC (+ to ++), with significant differences (P < 0.05). Western blot analysis demonstrated significantly higher SPARC expression in induced intestinal cells compared to GES-1. Furthermore, after SPARC knockdown in the human GC cell line HGC27, cell counting kit-8 and colony formation assays showed a reduction in cell proliferative ability, while the wound healing assay revealed impaired cell migration capacity.
CONCLUSION Comprehensive analysis suggested that a model incorporating clinical tumor node metastasis staging, age, and SPARC/SERPINE1 expression served as a prognostic predictor for GC. Moreover, elevated SPARC expression in IM and GC suggests its potential as a proper biomarker to detect GC in early stage and as a novel therapeutic target, guiding clinical applications.
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Affiliation(s)
- Lu Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
| | - Meng-Han Wang
- Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
| | - Yao-Hong Yuan
- Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
| | - Rui-Ze Xu
- Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
| | - Lu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
| | - Mi-Zhu Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou 300000, Inner Mongolia Autonomous Region, China
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Ai Z, Liu B, Chen J, Zeng X, Wang K, Tao C, Chen J, Yang L, Ding Q, Zhou M. Advances in nano drug delivery systems for enhanced efficacy of emodin in cancer therapy. Int J Pharm X 2025; 9:100314. [PMID: 39834843 PMCID: PMC11743866 DOI: 10.1016/j.ijpx.2024.100314] [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: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/05/2025] Open
Abstract
Cancer remains one of the leading causes of death worldwide, highlighting the urgent need for novel antitumor drugs. Natural products have long been a crucial source of anticancer agents. Among these, emodin (EMO), a multifunctional anthraquinone compound, exhibits significant anticancer effects but is hindered in clinical applications by challenges such as low solubility, rapid metabolism, poor bioavailability, and off-target toxicity. Nano drug delivery systems offer effective strategies to overcome these limitations by enhancing the solubility, stability, bioavailability, and targeting ability of EMO. While substantial progress has been made in developing EMO-loaded nanoformulations, a comprehensive review on this topic is still lacking. This paper aims to fill this gap by providing an overview of recent advancements in nanocarriers for EMO delivery and their anticancer applications. These carriers include liposomes, nanoparticles, polymeric micelles, nanogels, and others, with nanoparticle-based formulations being the most extensively explored. Nanoformulations encapsulating EMO have demonstrated promising therapeutic results against various cancers, particularly breast cancer, followed by liver and lung cancers. We systematically summarize the preparation methods, materials, and physicochemical properties of EMO-loaded nanopreparations, underscoring key findings on how nanotechnology improves the anticancer efficacy of EMO. This review provides valuable insights for researchers engaged in developing nano delivery systems for anticancer drugs.
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Affiliation(s)
- Zhenghao Ai
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Bingyao Liu
- Department of Radiology, West China Hospital Sichuan University Jintang Hospital, Chengdu, China
| | - Junyan Chen
- Department of Cardiothoracic Surgery, Luzhou People's Hospital, Luzhou, China
| | - Xinhao Zeng
- Department of Pediatric Surgery, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou, China
| | - Ke Wang
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Chao Tao
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Jing Chen
- Department of Clinical Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, China
| | - Liuxuan Yang
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Qian Ding
- Department of Clinical Pharmacy, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, China
| | - Meiling Zhou
- Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China
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Capik O, Karatas OF. Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer. Cell Oncol (Dordr) 2025; 48:539-557. [PMID: 39928285 PMCID: PMC12119682 DOI: 10.1007/s13402-025-01042-z] [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] [Accepted: 01/30/2025] [Indexed: 02/11/2025] Open
Abstract
Hypoxia is a critical microenvironmental condition that plays a major role in driving tumorigenesis and cancer progression. Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells' interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.
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Affiliation(s)
- Ozel Capik
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey.
- Cancer Therapeutics Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey.
| | - Omer Faruk Karatas
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey
- Cancer Therapeutics Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
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Shi W, Dong J, Zhong B, Hu X, Zhao C. Predicting the Prognosis of Bladder Cancer Patients Through Integrated Multi-omics Exploration of Chemotherapy-Related Hypoxia Genes. Mol Biotechnol 2025; 67:2367-2381. [PMID: 38806990 PMCID: PMC12055635 DOI: 10.1007/s12033-024-01203-9] [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: 01/10/2024] [Accepted: 05/14/2024] [Indexed: 05/30/2024]
Abstract
Bladder cancer is a prevalent malignancy with high mortality rates worldwide. Hypoxia is a critical factor in the development and progression of cancers. However, whether and how hypoxia-related genes (HRGs) could affect the development and the chemotherapy response of bladder cancer is still largely unexplored. This study comprehensively explored the complex molecular landscape associated with hypoxia in bladder cancer by analyzing 260 hypoxia genes based on transcriptomic and genomic data in 411 samples. Employing the 109 dysregulated hypoxia genes for consensus clustering, we delineated two distinct bladder cancer clusters characterized by disparate survival outcomes and distinct oncogenic roles. We defined a HPscore that was correlated with a variety of clinical features, including TNM stages and pathologic grades. Tumor immune landscape analysis identified three immune clusters and close interactions between hypoxia genes and the various immune cells. Utilizing a network-based method, we defined 129 HRGs exerting influence on apoptotic processes and critical signaling pathways in cancer. Further analysis of chemotherapy drug sensitivity identified potential drug-target HRGs. We developed a Risk Score model that was related to the overall survival of bladder cancer patients based on doxorubicin-target HRGs: ACTG2, MYC, PDGFRB, DHRS2, and KLRD1. This study not only enhanced our understanding of bladder cancer at the molecular level but also provided promising avenues for the development of targeted therapies, representing a significant step toward the identification of effective treatments and addressing the urgent need for advancements in bladder cancer management.
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Affiliation(s)
- Wensheng Shi
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, Hunan, China
- Furong Laboratory, Changsha, 410008, Hunan, China
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jiaming Dong
- Department of Radiation, Cangzhou Central Hospital, Hebei, 061000, China
| | - Bowen Zhong
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, Hunan, China
- Furong Laboratory, Changsha, 410008, Hunan, China
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiheng Hu
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, 410008, Hunan, China
- Furong Laboratory, Changsha, 410008, Hunan, China
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Chunguang Zhao
- Department of Critical Care Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Luo W, Sun Y, Cao L. TSPAN31 Activates Fatty Acid Metabolism and PI3K/AKT Pathway to Promote Tumor Progression in Breast Cancer. Mol Carcinog 2025; 64:1078-1089. [PMID: 40135650 DOI: 10.1002/mc.23912] [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: 12/11/2024] [Revised: 03/04/2025] [Accepted: 03/13/2025] [Indexed: 03/27/2025]
Abstract
Breast cancer (BC) is one of the most common human malignancies, but the mechanisms of BC have not been fully elucidated. Recently, tetraspanin 31 (TSPAN31) is reported to be linked to cancer progression. However, the function of TSPAN31 remains unclear in BC. Investigation of the function and potential mechanism of TSPAN31 in BC was the purpose of this study. Immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were applied to measure TSPAN31 expression. Loss and gain functional experiments were utilized to survey the influences of TSPAN31 on BC biological process, including cell growth, invasion, migration, and fatty acid metabolism. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis based on DepMap database and Gene Set Enrichment Analysis based on The Cancer Genome Atlas database were executed to find TSPAN31-related pathway. Western blot was carried out to assess the changes of fatty acid synthase (FASN), sterol regulatory element binding protein 1 (SREBP1), acyl-CoA synthetase long-chain family member 1 (ACSL1), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K, protein kinase B (AKT), and p-AKT. In human non-triple negative breast cancer tissues and cells, TSPAN31 expression was upregulated. TSPAN31 knockdown induced BC cell apoptosis, inhibited cell proliferation, invasion, migration, and fatty acid metabolism, and reduced the protein levels of FASN, SREBP1, ACSL1, p-PI3K/PI3K, and p-AKT/AKT. In contrast, TSPAN31 overexpression led to the opposite results. Additionally, the activator of PI3K (740 Y-P) attenuated the inhibition of TSPAN31 knockdown on fatty acid metabolism, proliferation, and invasion in BC cells. Through activation of fatty acid metabolism and PI3K/AKT pathway, TSPAN31 played a carcinogenic role in BC. For the mechanism of BC tumorigenesis, our study provides an interesting insight.
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Affiliation(s)
- Wenquan Luo
- Breast and Thyroid Surgery Department, Feicheng People's Hospital, Feicheng, Shandong, China
| | - Yuxiang Sun
- Breast and Thyroid Surgery Department, Feicheng People's Hospital, Feicheng, Shandong, China
| | - Liang Cao
- Radiotherapy Department, Taian Tumor Prevention and Treatment Hospital, Taian, Shandong, China
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11
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Li Y, Zhang R, Dang Y, Liang Y, Wang L, Chen N, Zhuang L, Liu W, Gong T. Sieging tumor cells using an amorphous ferric coordination polymer. MATERIALS HORIZONS 2025; 12:3388-3398. [PMID: 40025991 DOI: 10.1039/d4mh01558d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
Metastasis is one of the main reasons for cancer treatment failure. Unfortunately, most treatment approaches inevitably damage the extracellular matrix (ECM) during tumor cell elimination, thereby augmenting the risk of metastasis. Herein, we proposed a "sieging tumor cells" strategy based on ferric coordination polymers (FeCPs), which involved anchoring tumor cells through ECM consolidation and selectively eliminating them in the tumor regions. Due to the weak coordination interactions and amorphous structure of FeCPs, the acidic tumor microenvironment facilitated their disintegration, releasing salicylic acid (SA), 2,5-dihydroxyterephthalic acid (DHTA) and Fe3+ ions. The released SA inhibited heparinase activity to consolidate the ECM, while Fe-mediated chemodynamic therapy (CDT) was enhanced by DHTA due to its fast electron transport behavior, ultimately inhibiting tumor growth and metastasis. The results from the orthotopic 4T1 breast tumor model indicated that lung metastasis was reduced by about 90%, and the survival rate improved by 70% after FeCP treatment. Overall, this "sieging tumor cells" strategy provides an emerging approach for the treatment of malignant tumors by consolidating the ECM in combination with self-enhanced CDT.
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Affiliation(s)
- Yanli Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Ruoqi Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Yuanye Dang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Yongyu Liang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Lulu Wang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Na Chen
- Soochow University Library, Soochow University, Suzhou 215006, China
| | - Luwen Zhuang
- Center for Water Resources and Environment, and Guangdong Key Laboratory of Marine Civil Engineering, School of Civil Engineering, Sun Yat-sen University, Guangzhou 510275, China.
| | - Wen Liu
- School of Public Health, Guangzhou Medical University, Guangzhou 511436, China.
| | - Teng Gong
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
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12
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Shah S, D'Souza GGM. Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis. Cells 2025; 14:732. [PMID: 40422235 DOI: 10.3390/cells14100732] [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: 04/18/2025] [Revised: 05/11/2025] [Accepted: 05/14/2025] [Indexed: 05/28/2025] Open
Abstract
Drug delivery to solid tumors is challenged by multiple physiological barriers arising from the tumor microenvironment, including dense extracellular matrix, cellular heterogeneity, hypoxic gradients, and elevated interstitial fluid pressure. These features hinder the uniform distribution and accumulation of therapeutics, reducing treatment efficacy. Despite their widespread use, conventional two-dimensional monolayer cultures fail to reproduce these complexities, contributing to the poor translational predictability of many preclinical candidates. Three-dimensional multicellular tumor spheroids have emerged as more representative in vitro models that capture essential features of tumor architecture, stromal interactions, and microenvironmental resistance mechanisms. Spheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia, and can incorporate non-tumor cells to mimic tumor-stroma crosstalk. Advances in spheroid analysis now enable detailed evaluation of drug penetration, cellular migration, cytotoxic response, and molecular gradients using techniques such as optical and confocal imaging, large-particle flow cytometry, biochemical viability assays, and microfluidic integration. By combining physiological relevance with analytical accessibility, spheroid models support mechanistic studies of drug transport and efficacy under tumor-like conditions. Their adoption into routine preclinical workflows has the potential to improve translational accuracy while reducing reliance on animal models.
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Affiliation(s)
- Shrey Shah
- Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
- Atom Bioworks Inc., Cary, NC 27513, USA
| | - Gerard G M D'Souza
- Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
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13
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Milella M, Rutigliano M, Pandolfo SD, Aveta A, Crocetto F, Ferro M, d'Amati A, Ditonno P, Lucarelli G, Lasorsa F. The Metabolic Landscape of Cancer Stem Cells: Insights and Implications for Therapy. Cells 2025; 14:717. [PMID: 40422220 DOI: 10.3390/cells14100717] [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: 04/05/2025] [Revised: 05/06/2025] [Accepted: 05/14/2025] [Indexed: 05/28/2025] Open
Abstract
Cancer stem cells (CSCs) are a subpopulation with self-renewal and differentiation capacities believed to be responsible for tumor initiation, progression, and recurrence. These cells exhibit unique metabolic features that contribute to their stemness and survival in hostile tumor microenvironments. Like non-stem cancer cells, CSCs primarily rely on glycolysis for ATP production, akin to the Warburg effect. However, CSCs also show increased dependence on alternative metabolic pathways, such as oxidative phosphorylation (OXPHOS) and fatty acid metabolism, which provide necessary energy and building blocks for self-renewal and therapy resistance. The metabolic plasticity of CSCs enables them to adapt to fluctuating nutrient availability and hypoxic conditions within the tumor. Recent studies highlight the importance of these metabolic shifts in maintaining the CSC phenotype and promoting cancer progression. The CSC model suggests that a small, metabolically adaptable subpopulation drives tumor growth and therapy resistance. CSCs can switch between glycolysis and mitochondrial metabolism, enhancing their survival under stress and dormant states. Targeting CSC metabolism offers a promising therapeutic strategy; however, their adaptability complicates eradication. A multi-targeted approach addressing various metabolic pathways is essential for effective CSC elimination, underscoring the need for further research into specific CSC markers and mechanisms that distinguish their metabolism from normal stem cells for successful therapeutic intervention.
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Affiliation(s)
- Martina Milella
- Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area-Urology, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Monica Rutigliano
- Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area-Urology, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Savio Domenico Pandolfo
- Department of Urology, University of L'Aquila, 67100 L'Aquila, Italy
- Department of Neurosciences, Science of Reproduction and Odontostomatology, Federico II University, 80138 Naples, Italy
| | - Achille Aveta
- Department of Urology, University of L'Aquila, 67100 L'Aquila, Italy
| | - Felice Crocetto
- Department of Urology, University of L'Aquila, 67100 L'Aquila, Italy
| | - Matteo Ferro
- Urology Unit, Department of Health Science, University of Milan, 20122 Milan, Italy
| | - Antonio d'Amati
- Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area-Urology, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Pasquale Ditonno
- Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area-Urology, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Giuseppe Lucarelli
- Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area-Urology, University of Bari "Aldo Moro", 70124 Bari, Italy
- SSD Urologia Clinicizzata, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Francesco Lasorsa
- Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area-Urology, University of Bari "Aldo Moro", 70124 Bari, Italy
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14
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Yang M, Meng Y, Li J, Bai L, Cheng Y, Liu Y, Cao M, Yang X, Wang Y, Liu Y. Nanofabricated Bacterial Cell Walls with Intrinsic Peroxidase-Mimicking and Sonodynamic Activities for Cancer Combination Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2505310. [PMID: 40365750 DOI: 10.1002/advs.202505310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Indexed: 05/15/2025]
Abstract
Bacterial cancer therapy recently has been attracting more and more attention because of its multiple functions to fight cancer. Porphyromonas gingivalis (Pg), a Gram-negative pathogenic bacterium, acquires protoporphyrin IX (PpIX) and iron from heme and synthesizes abundant µ-oxo bisheme on its cell walls (CWs). For the first time, it is found that the CWs extracted from Pg has intrinsic peroxidase (POD)-mimicking and sonodynamic activities owing to the presence of µ-oxo bisheme. In this study, the CWs of Pg are nanofabricated to form the CW vesicles (CWV) containing a large amount of lipopolysaccharide (LPS) and further encapsulated doxorubicin (DOX) to prepare DOX-loaded CWV (DOX@CWV), hoping to eradicate cancer by combining sonodynamic therapy (SDT), chemotherapy, and bacterial immunotherapy. The results confirmed that DOX@CWV can catalyze the conversion of H2O2 into O2 and consume the reduced glutathione (GSH), and thus greatly boost their own sonodynamic performance upon ultrasonic irradiation. Both in vitro and in vivo, DOX@CWV efficiently inhibited cancer growth by combining SDT and chemotherapy, and also exerted synergistic anticancer immune effects of bacterial immunotherapy and SDT. In summary, the findings not only contribute a promising bacterial therapeutic agent but also provide a combination strategy for clinical cancer treatment.
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Affiliation(s)
- Meng Yang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Yang Meng
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Junling Li
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Liya Bai
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Yuanyuan Cheng
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China
| | - Yuanyuan Liu
- Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Mingxin Cao
- Department of Orthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, and Institute of Stomatology, Tianjin, 300070, China
| | - Xiaoying Yang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Yinsong Wang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, International Joint Laboratory of Ocular Diseases (Ministry of Education), Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
- Department of Orthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, and Institute of Stomatology, Tianjin, 300070, China
| | - Yang Liu
- Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & 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 Hepatobiliary and Pancreatic Oncology, Tianjin Cancer Hospital Airport Hospital, National Clinical Research Center for Cancer, Tianjin, 300308, China
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15
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Yang J, Zeng Z, Liu Y, Li Y, Xu X. Developing bioinspired delivery systems for enhanced tumor penetration of macromolecular drugs. J Control Release 2025; 383:113845. [PMID: 40379215 DOI: 10.1016/j.jconrel.2025.113845] [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: 11/14/2024] [Revised: 05/12/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Macromolecular drugs, such as proteins and nucleic acids, play a pivotal role in treating refractory diseases and hold significant promise in the growing pharmaceutical market. However, without efficient delivery systems, macromolecular drugs are highly susceptible to rapid biodegradation or systemic clearance, underscoring the need for advanced delivery strategies for clinical translation. A major challenge lies in their limited tissue penetration due to large molecular weight and size, which has recently garnered significant attention as it often leads to therapeutic failure or the emergence of resistance. In this review, we first outline the biological barriers limiting macromolecular tissue penetration, then explore the inherent permeation mechanisms of biomacromolecules in biological systems. We then highlight delivery strategies aimed at enhancing the tissue penetration of macromolecular therapeutics, with a particular focus on tissue-adaptive and tissue-remodeling delivery platforms. Finally, we provide a concise perspective on future research directions in deep tissue penetration for biomacromolecules. This review offers a comprehensive summary of recent advancements and presents critical insights into optimizing the therapeutic efficacy of macromolecular drugs.
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Affiliation(s)
- Jin Yang
- Department of Pharmacy, College of Biology, Hunan University, Changsha, Hunan 410082, China; State Key Laboratory of Chemo and Biosensing, Hunan University, Changsha, Hunan 410082, China
| | - Zenan Zeng
- Department of Pharmacy, College of Biology, Hunan University, Changsha, Hunan 410082, China
| | - Yiming Liu
- Department of Pharmacy, College of Biology, Hunan University, Changsha, Hunan 410082, China
| | - Yachao Li
- Department of Pharmacy, College of Biology, Hunan University, Changsha, Hunan 410082, China; State Key Laboratory of Chemo and Biosensing, Hunan University, Changsha, Hunan 410082, China
| | - Xianghui Xu
- Department of Pharmacy, College of Biology, Hunan University, Changsha, Hunan 410082, China; State Key Laboratory of Chemo and Biosensing, Hunan University, Changsha, Hunan 410082, China.
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16
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Parodi I, Palamà MEF, Di Lisa D, Pastorino L, Lagazzo A, Falleroni F, Aiello M, Fato MM, Scaglione S. Core-Shell Hydrogels with Tunable Stiffness for Breast Cancer Tissue Modelling in an Organ-on-Chip System. Gels 2025; 11:356. [PMID: 40422376 DOI: 10.3390/gels11050356] [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: 03/28/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/28/2025] Open
Abstract
Breast cancer remains the most common malignancy in women, yet, many patients fail to achieve full remission despite significant advancements. This is largely due to tumour heterogeneity and the limitations of current experimental models in accurately replicating the complexity of in vivo tumour environment. In this study, we present a compartmentalised alginate hydrogel platform as an innovative in vitro tool for three-dimensional breast cancer cell culture. To mimic the heterogeneity of tumour tissues, we developed a core-shell structure (3.5% alginate core and 2% alginate shell) that mimic the stiffer, denser internal tumour matrix. The human triple-negative breast cancer cell line (MDA-MB-231) was embedded in core-shell alginate gels to assess viability, proliferation and hypoxic activity. Over one week, good cells proliferation and viability was observed, especially in the softer shell. Interestingly, cells within the stiffer core were more positive to hypoxic marker expression (HIF-1α) than those embedded in the shell, confirming the presence of a hypoxic niche, as observed in vivo. When cultured in the MIVO® milli fluidic organ-on-chip resembling the physiological fluid flow conditions, cancer cells viability became comparable between core and shell hydrogel area, emphasising the importance of the fluid flow in nutrients diffusion within three-dimensional matrixes. Cisplatin chemotherapy treatment further highlighted these differences: under static conditions, cancer cell death was prominent in the softer shell, whereas cells in the stiffer core remained resistant to cisplatin. Conversely, drug diffusion was more homogeneous in the core-shell structured treated in the organ-on-chip, leading to a uniform reduction in cell viability. These findings suggest that integrating a compartmentalised core-shell cell laden alginate model with the millifluidic organ on chip offers a more physiologically relevant experimental approach to deepening cancer cell behaviour and drug response.
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Affiliation(s)
- Ilaria Parodi
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
- National Research Council of Italy, Institute of Electronic, Computer and Telecommunications Engineering (CNR-IEIIT), 16149 Genoa, Italy
| | | | - Donatella Di Lisa
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16131 Genoa, Italy
| | - Laura Pastorino
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
| | - Alberto Lagazzo
- Department of Civil, Chemical and Environmental Engineering, University of Genoa, 16145 Genoa, Italy
| | | | - Maurizio Aiello
- National Research Council of Italy, Institute of Electronic, Computer and Telecommunications Engineering (CNR-IEIIT), 16149 Genoa, Italy
- React4life S.p.A., 16152 Genoa, Italy
| | - Marco Massimo Fato
- Department of Informatics, Bioengineering, Robotics, and System Engineering, University of Genoa, 16145 Genoa, Italy
| | - Silvia Scaglione
- National Research Council of Italy, Institute of Electronic, Computer and Telecommunications Engineering (CNR-IEIIT), 16149 Genoa, Italy
- React4life S.p.A., 16152 Genoa, Italy
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17
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Guo H, Zhao Z, Liu L. HIF-1α modulates pancreatic cancer ECM proteins via the TGF-β1/Smad signaling pathway introduction. Front Oncol 2025; 15:1564655. [PMID: 40406267 PMCID: PMC12094911 DOI: 10.3389/fonc.2025.1564655] [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: 01/21/2025] [Accepted: 04/14/2025] [Indexed: 05/26/2025] Open
Abstract
Introduction Pancreatic cancer is characterized by its aggressive nature and poor prognosis, ranking among the most lethal malignancies. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a crucial role in cancer progression. This study investigated the relationship between hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1) in regulating ECM protein expression in pancreatic cancer. Methods PANC-1 cells were cultured under both normoxic and hypoxic conditions. Pharmacological inhibition of HIF-1α and TGF-β1, as well as TGF-β1 stimulation, were employed to evaluate ECM protein expression. HIF-1α knockdown experiments and co-immunoprecipitation were performed to assess molecular interactions. Clinical specimens were analyzed for HIF-1α and TGF-β1 expression. Results HIF-1α was found to modulate ECM protein expression through the TGF-β1/Smad signaling pathway. Pharmacological inhibition of either HIF-1α or TGF-β1 significantly decreased the expression of ECM proteins, while TGF-β1 stimulation enhanced their production. HIF-1α knockdown abolished TGF-β1-induced ECM protein expression, indicating that HIF-1α is essential for TGF-β1-mediated ECM regulation. Co-immunoprecipitation experiments revealed a physical interaction between HIF-1α and TGF-β1. Clinical specimens showed significantly elevated expression of both HIF-1α and TGF-β1 in pancreatic cancer tissues compared to adjacent normal tissues, correlating with advanced disease stages. Discussion These findings elucidate a novel mechanism where HIF-1α and TGF-β1 cooperatively regulate ECM production in pancreatic cancer, providing potential therapeutic targets for intervention.
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Affiliation(s)
| | | | - Linxun Liu
- Qinghai Provincial People’s Hospital, Xining, Qinghai, China
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18
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Wang H, Zhu YN, Zhang S, Liu K, Huang R, Li Z, Mei L, Li Y. Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer. Mol Med 2025; 31:179. [PMID: 40340806 PMCID: PMC12063413 DOI: 10.1186/s10020-025-01237-y] [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: 12/02/2024] [Accepted: 04/28/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive. METHODS Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters. RESULTS Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy. CONCLUSION We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.
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Affiliation(s)
- Hongwei Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Yu-Nan Zhu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Sifan Zhang
- Department of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China
| | - Kexin Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Rong Huang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China
| | - Zhigao Li
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
| | - Lan Mei
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
| | - Yingpu Li
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, 150000, Heilongjiang Province, China.
- NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.
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19
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Xu Z, Zang M, Li H, Tian R, Zhang Z, Liu W, Xiao F, Yan X, Zhu Y, Zhu C, Xu J, Yu S, Wang T, Sun H, Liu J. Living Biotherapeutics Using Nanoparticles-Armed Cyanobacteria for Boosting Photodynamic-Immunotherapy of Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2502746. [PMID: 40344505 DOI: 10.1002/advs.202502746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/02/2025] [Indexed: 05/11/2025]
Abstract
The interdisciplinary development of synthetic biology and material sciences propels medicine into a new era. For cancer therapy, living biotherapeutics integrating functional living bacteria with nanomedicine are particularly interesting. The current study developed a living biotherapeutic platform integrating oxygen-self-supplying cyanobacteria with multifunctional prodrug nanoparticles to boost photodynamic immunotherapy. Generally, tetracarboxyl porphyrin is associated with cisplatin via a covalent self-assembly strategy into uniform prodrug-skeletal nanoparticles (ZnNCs). This helped encapsulate the antitumor drug dicumarol derivative (DicTBS). Later, these developed DicTBS-ZnNC nanoparticles helped arm the surface of cyanobacteria using electrostatic adsorption to yield living nanotherapeutics (Cyano@DicTBS-ZnNCs). Cyano@DicTBS-ZnNCs achieved a self-supply of nanoparticles and oxygen under 660 nm laser irradiation, producing PDT therapeutic effects. Furthermore, combining cisplatin and dicoumarol achieved synergistic anticancer effects. This approach also induced immunogenic cell death (ICD) and regulated the tumor microenvironment (TME). This promoted an immune-supportive environment to improve antitumor immune responses.
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Affiliation(s)
- Zhengwei Xu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Mingsong Zang
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Hui Li
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Ruizhen Tian
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Zherui Zhang
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Wang Liu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Fei Xiao
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Xuesha Yan
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Yan Zhu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Canhong Zhu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Jiayun Xu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Shuangjiang Yu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Tingting Wang
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Hongcheng Sun
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Junqiu Liu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 311121, P. R. China
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20
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Hu X, Chen Y, Ying H, He C, Ren Y, Tian Y, Tan Y. Metabolic-associated fatty liver disease (MAFLD) promotes the progression of hepatocellular carcinoma by enhancing KIF20A expression. Int Immunopharmacol 2025; 154:114589. [PMID: 40168801 DOI: 10.1016/j.intimp.2025.114589] [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: 02/13/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Compared to other HCC, those related to MAFLD exhibit distinct prognostic differences. This article aims to elucidate the impact of MAFLD on HCC prognosis through the lens of KIF20A, thereby providing a theoretical foundation for targeted therapies in MAFLD-related HCC. METHODS We employed the Weighted gene co-expression network analysis (WGCNA) method alongside the Mime package to identify key genes associated with MAFLD-related HCC. Subsequently, we utilized OCLR and CytoTRACE algorithms to evaluate the relationship between these genes and HCC stemness. The R package was employed to conduct immunological analyses on both mRNA sequencing and single-cell data. We validated the effects of core genes on HCC through experimental approaches, including cell culture, Transwell assays, Western Blot, and proliferation assays. Finally, we predicted potential therapeutic drugs using the OncoPredict software package. RESULTS WGCNA identified the cyan module associated with MAFLD in GSE135251 and the blue module linked to HCC in TCGA. Further analysis identified KIF20A as the core gene in MAFLD-related HCC. Utilizing the OCLR and CytoTRACE algorithms, KIF20A was found to correlate with mRNA stemness index (mRNAsi). Analysis of public databases revealed that KIF20A promotes immune tolerance through the SPP1-CD44 pathway and drives HCC progression via the G2M checkpoint. Experimental results demonstrated that lipotoxic damage in HCC cells and small extracellular vesicles (sEVs) derived from these cells upregulate KIF20A, thereby accelerating HCC progression. Finally, OncoPredict and AutoDock were employed to predict drugs targeting KIF20A. CONCLUSION MAFLD-related HCC can elevate KIF20A levels and promote tumor proliferation and migration.
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Affiliation(s)
- Xinsong Hu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yifei Chen
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China; Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, Jiangsu, China
| | - Hao Ying
- Department of Neurology, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Cong He
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yangyang Ren
- Clinical Laboratory, Xinyi People's Hospital, Xuzhou, Jiangsu, China.
| | - Yiqing Tian
- Clinical Laboratory, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu, China.
| | - Youwen Tan
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang, Jiangsu, China.
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21
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Gómez-Pastor S, Maugard A, Walker HR, Elies J, Børsum KE, Grimaldi G, Reina G, Ruiz A. CD-44 targeted nanoparticles for combination therapy in an in vitro model of triple-negative breast cancer: Targeting the tumour inside out. Colloids Surf B Biointerfaces 2025; 249:114504. [PMID: 39817967 DOI: 10.1016/j.colsurfb.2025.114504] [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: 06/14/2024] [Revised: 12/30/2024] [Accepted: 01/07/2025] [Indexed: 01/18/2025]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer defined by the lack of three key receptors: estrogen, progesterone, and HER2. This lack of receptors makes TNBC difficult to treat with hormone therapy or drugs, and so it is characterised by a poor prognosis compared to other kinds of breast cancer. This study explores photoactive Poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a potential therapeutic strategy for TNBC. The nanoparticles are functionalised with hyaluronic acid (HA) for targeted delivery to CD-44 receptors overexpressed in TNBC cells, especially under hypoxic conditions. Additionally, we co-loaded the nanoparticles with Doxorubicin (Dox) and Indocyanine Green (ICG) to enable combinatorial chemo-photothermal therapy. After carefully optimising the formulation, we propose an effortless and reproducible preparation of the nanodrugs. We demonstrate that HA-conjugated nanoparticles effectively target TNBC cells and inhibit their proliferation while the treatment efficiency is enhanced during near-infrared light irradiation. We also prove that our treatment is effective in a 3D cell culture model, highlighting the importance of tumour architecture and the metabolic stage of the cells in the tumour microenvironment. This approach is promising for a tumour-targeted theragnostic for TNBC with improved efficacy in hypoxic microenvironments.
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Affiliation(s)
- Silvia Gómez-Pastor
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom; Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - Auréane Maugard
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom
| | - Harriet R Walker
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom
| | - Jacobo Elies
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom
| | - Kaja E Børsum
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom
| | - Giulia Grimaldi
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom; School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom.
| | - Giacomo Reina
- Empa Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen 9014, Switzerland.
| | - Amalia Ruiz
- Institute of Cancer Therapeutics, University of Bradford, Bradford, Richmond Rd, Bradford BD7 1DP, United Kingdom.
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22
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Bai Y, Osmundson EC, Donahue MJ, De Vis JB. Magnetic resonance imaging to detect tumor hypoxia in brain malignant disease: A systematic review of validation studies. Clin Transl Radiat Oncol 2025; 52:100940. [PMID: 40093743 PMCID: PMC11908384 DOI: 10.1016/j.ctro.2025.100940] [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: 10/17/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025] Open
Abstract
Tumor hypoxia indicates a worse prognosis in brain malignancies; however, current gold-standard methods for assessing tumor hypoxia are invasive and often inaccessible. Magnetic Resonance Imaging (MRI) is widely available, but its validity for identifying tumor hypoxia or hypoxia-related neoangiogenesis is not well characterized. A systematic literature search was performed across PubMed and Embase Databases. The search query identified MRI studies that validated hypoxia-surrogate imaging sequences against gold-standard hypoxia or neoangiogenesis detection methods in patients with brain malignancies. Literature screen identified 23 manuscripts published between 2007 and 2022. Among conventional MRI sequences, peritumoral edema and signal change after contrast administration were associated with gold-standard oxygen-assessment methods. T2*- and T2'-derived measures were associated with gold-standard methods, while reports on quantitative measures of oxygen extraction fraction were conflicting. Fiber density, tissue cellularity, blood volume, vascular transit time, and permeability measurements were associated with gold-standard methods, whereas blood flow measurements yielded conflicting results. MRI measures are promising surrogates for tumor hypoxia or hypoxia-related neoangiogenesis. Additional studies are needed to reconcile disparate findings. Future sensitivity analyses are needed to establish the MRI methods most accurate at identifying tumor hypoxia.
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Affiliation(s)
- Y Bai
- Vanderbilt School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - E C Osmundson
- Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M J Donahue
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
| | - J B De Vis
- Department of Radiation Oncology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA
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23
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Liu J, Chen Z, Deng L, Yao C, Zhou Z, Zhou C, Bin Y, Liu M, Wang L, Wang L, Wang Z. Metal-phenolic networks specifically eliminate hypoxic tumors by instigating oxidative and proteotoxic stresses. Bioact Mater 2025; 47:361-377. [PMID: 40026824 PMCID: PMC11870026 DOI: 10.1016/j.bioactmat.2025.01.022] [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: 10/13/2024] [Revised: 01/04/2025] [Accepted: 01/18/2025] [Indexed: 03/05/2025] Open
Abstract
Hypoxia, a prevalent characteristic of solid tumors, substantially impairs the efficacy of cancer treatments. However, there are no feasible clinical approaches for treating hypoxic tumors. Here, we develop metal-phenolic networks (CuGI) utilizing the natural glycolysis inhibitor (epigallocatechin gallate) and the essential metal element in the human body (copper ions), specifically targeting and annihilating hypoxic cancer cells. CuGI redirects the metabolic pathway of hypoxic cancer cells from anaerobic glycolysis to oxidative phosphorylation, thereby enhancing reactive oxygen species production and promoting oligomerization of lipoylated proteins in the tricarboxylic acid cycle. Through targeted induction of oxidative and proteotoxic stresses, CuGI induces apoptosis and cuproptosis specifically in cancer cells under hypoxic conditions while sparing normal cells. Moreover, cancer cell membrane-coated CuGI (CuGI@CM) exhibits enhanced tumor penetration effect and demonstrates commendable biocompatibility, effectively suppressing colorectal tumor growth. Importantly, CuGI@CM, when combined with vascular disruptors or radiotherapy which aggravate tumor hypoxia, synergistically potentiates therapeutic efficacy. Thus, CuGI represents a specific and potent nanotherapeutic capable of selectively eliminating hypoxic tumors, offering promise in combination therapies to address tumor hypoxia.
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Affiliation(s)
- Jia Liu
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zuoyu Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lixue Deng
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chundong Yao
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhixin Zhou
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Cheng Zhou
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yawen Bin
- Hubei Key Laboratory of Precision Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Miaodeng Liu
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liping Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lin Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zheng Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Engineering Research Center of Clinical Laboratory and Active Health Smart Equipment, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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24
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Zhang WX, Chen J, Guo Q, Lv QY, Song X, Cui HF. Reversal of doxorubicin-resistance of MCF-7/Adr cells via multiple regulations by glucose oxidase loaded AuNRs@MnO 2@SiO 2 nanocarriers. Colloids Surf B Biointerfaces 2025; 253:114748. [PMID: 40334474 DOI: 10.1016/j.colsurfb.2025.114748] [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: 03/21/2025] [Revised: 04/23/2025] [Accepted: 04/27/2025] [Indexed: 05/09/2025]
Abstract
Targeting to multiple MDR mechanisms is a desired strategy for efficient reversal of multidrug resistance (MDR). Herein, a multi-functional and hierarchical-structured AuNRs@MnO2@SiO2 (AMS) nanocarrier is reported for multiple regulations of MDR. The glucose oxidase (GOx) loaded AMS (AMS/G) showed efficient capabilities of hypoxia-relieving, O2-generation enhanced cancer starvation therapy (CST), and near-infrared (NIR) laser photothermal therapy (PTT) to MCF-7/Adr, a doxorubicin (Dox)-resistant breast cancer cell line. It was revealed that hypoxia inducible factor-1α and heat shock protein 90, can be significantly down-regulated by AMS/G. The Dox resistance and the adenosine triphosphate (ATP)-binding cassette (ABC) transporters: P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), can be dramatically reversed by the AMS/G+NIR treatment. Specifically, the hypoxia-relieving function can down-regulate all the three ABC transporters. The enhanced CST decreases the expression of MRP1. The PTT diminishes the BCRP and MRP1. Assisted by the multiple and synergistic reversal mechanisms, the Dox co-loaded AMS/G (AMS/D/G) with NIR laser significantly inhibited the cell proliferation, migration, and drug efflux at both normoxia and hypoxia conditions. Cell apoptosis is greatly induced in a caspase-3 dependent manner. Tumor ATP depletion and Dox accumulation were confirmed in vivo. The tumor growth inhibition is greatly and synergistically enhanced, without inducing obvious side effects. Collectively, the nanostructured AMS/D/G can inhibit multiple ABC transporters and provide a promisingly platform for highly efficient reversal of tumor drug resistance.
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Affiliation(s)
- Wen-Xing Zhang
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Junyang Chen
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Qian Guo
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Qi-Yan Lv
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China
| | - Xiaojie Song
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China.
| | - Hui-Fang Cui
- School of Life Sciences, Zhengzhou University, Science Avenue 100#, Zhengzhou 450001, China.
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25
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George S, Saju H, Jaikumar T, Raj R, Nisarga R, Sontakke S, Sangshetti J, Paul MK, Arote RB. Deciphering a crosstalk between biological cues and multifunctional nanocarriers in lung cancer therapy. Int J Pharm 2025; 674:125395. [PMID: 40064384 DOI: 10.1016/j.ijpharm.2025.125395] [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: 02/08/2025] [Accepted: 02/21/2025] [Indexed: 03/17/2025]
Abstract
In recent years, the utilization of nanocarriers has significantly broadened across a diverse spectrum of biomedical applications. However, the clinical translation of these tiny carriers is limited and encounters hurdles, particularly in the intricate landscape of the tumor microenvironment. Lung cancer poses unique hurdles for nanocarrier design. Multiple physiological barriers hinder the efficient drug delivery to the lungs, such as the complex anatomy of the lung, the presence of mucus, immune responses, and rapid clearance mechanisms. Overcoming these obstacles necessitates a targeted approach that minimizes off-target effects while effectively penetrating nanoparticles/cargo into specific lung tissues or cells. Furthermore, understanding the cellular uptake mechanisms of these nano carriers is also essential. This knowledge aids in developing nanocarriers that efficiently enter cells and transfer their payload for the most effective therapeutic outcome. Hence, a thorough understanding of biological cues becomes crucial in designing multifunctional nanocarriers tailored for treating lung cancer. This review explores the essential biological cues critical for developing a flexible nanocarrier specifically intended to treat lung cancer. Additionally, it discusses advancements in nanotheranostics in lung cancer.
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Affiliation(s)
- Sharon George
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India
| | - Hendry Saju
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India
| | - Tharun Jaikumar
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India
| | - Reshma Raj
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India
| | - R Nisarga
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India
| | - Samruddhi Sontakke
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India
| | - Jaiprakash Sangshetti
- Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad 431001, India
| | - Manash K Paul
- Department of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India; Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), 90095 CA, USA.
| | - Rohidas B Arote
- Centre for Nano and Material Sciences, Jain (Deemed to be) University, Jain Global Campus, Bangalore, Karnataka 562112, India; Dental Research Institute, School of Dentistry, Seoul National University, Gwanak-ku, Seoul 08826, Republic of Korea.
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26
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Mierke CT. Softness or Stiffness What Contributes to Cancer and Cancer Metastasis? Cells 2025; 14:584. [PMID: 40277910 PMCID: PMC12026216 DOI: 10.3390/cells14080584] [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: 03/11/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
Beyond the genomic and proteomic analysis of bulk and single cancer cells, a new focus of cancer research is emerging that is based on the mechanical analysis of cancer cells. Therefore, several biophysical techniques have been developed and adapted. The characterization of cancer cells, like human cancer cell lines, started with their mechanical characterization at mostly a single timepoint. A universal hypothesis has been proposed that cancer cells need to be softer to migrate and invade tissues and subsequently metastasize in targeted organs. Thus, the softness of cancer cells has been suggested to serve as a universal physical marker for the malignancy of cancer types. However, it has turned out that there exists the opposite phenomenon, namely that stiffer cancer cells are more migratory and invasive and therefore lead to more metastases. These contradictory results question the universality of the role of softness of cancer cells in the malignant progression of cancers. Another problem is that the various biophysical techniques used can affect the mechanical properties of cancer cells, making it even more difficult to compare the results of different studies. Apart from the instrumentation, the culture and measurement conditions of the cancer cells can influence the mechanical measurements. The review highlights the main advances of the mechanical characterization of cancer cells, discusses the strength and weaknesses of the approaches, and questions whether the passive mechanical characterization of cancer cells is still state-of-the art. Besides the cell models, conditions and biophysical setups, the role of the microenvironment on the mechanical characteristics of cancer cells is presented and debated. Finally, combinatorial approaches to determine the malignant potential of tumors, such as the involvement of the ECM, the cells in a homogeneous or heterogeneous association, or biological multi-omics analyses, together with the dynamic-mechanical analysis of cancer cells, are highlighted as new frontiers of research.
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Affiliation(s)
- Claudia Tanja Mierke
- Faculty of Physics and Earth System Sciences, Peter Debye Institute of Soft Matter Physics, Biological Physics Division, Leipzig University, 04103 Leipzig, Germany
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27
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Xu X, Huang Z, Han H, Yu Z, Ye L, Zhao Z, Qian Y, Li Y, Zhao R, Zhang T, Liu Y, Cai J, Lin S, Zhai E, Chen J, Cai S. N 7-methylguanosine tRNA modification promotes gastric cancer progression by activating SDHAF4-dependent mitochondrial oxidative phosphorylation. Cancer Lett 2025; 615:217566. [PMID: 39965707 DOI: 10.1016/j.canlet.2025.217566] [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: 07/23/2024] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/20/2025]
Abstract
N7-methylguanosine (m7G) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of m7G tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated m7G tRNA modifications in promoting GC progression. Upregulation of m7G methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression in vitro and in vivo. Mechanistically, METTL1 knockdown reduces the expression of m7G-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated m7G tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.
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Affiliation(s)
- Xiang Xu
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Zhixin Huang
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Hui Han
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Zihan Yu
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Linying Ye
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Zeyu Zhao
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Yan Qian
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Ying Li
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, Guangdong, China
| | - Risheng Zhao
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Tianhao Zhang
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Yinan Liu
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Junchao Cai
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510000, Guangdong, China
| | - Shuibin Lin
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China
| | - Ertao Zhai
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
| | - Jianhui Chen
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China; Department of General Surgery, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-sen University, Nanning, 530000, Guangxi, China.
| | - Shirong Cai
- Division of Gastrointestinal Surgery Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
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Regeni I, Bonnet S. Supramolecular approaches for the treatment of hypoxic regions in tumours. Nat Rev Chem 2025:10.1038/s41570-025-00705-7. [PMID: 40185999 DOI: 10.1038/s41570-025-00705-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2025] [Indexed: 04/07/2025]
Abstract
Supramolecular chemistry provides a range of 'weak' intermolecular interactions that allow drugs and prodrugs to self-assemble. In the complex biological setting of blood and tumours, these interactions must be stable enough for efficient and selective drug delivery to the tumour site, but weak enough to allow the release of the cytotoxic load. The non-covalent nature of supramolecular interactions enables the detachment of smaller (pro)drug monomers that can penetrate cancer cells differently to the original nanoparticles. Hypoxic tumours show low oxygen levels due to poor vascularization, which poses challenges for drug delivery and generates biological resistances. Supramolecular building blocks specifically designed for hypoxic tumours offer targeted activation of prodrug self-assemblies, enhancing effectiveness against hypoxic cancer cells and hypoxic regions in tumours. This Review explores how supramolecular chemistry can improve (pro)drug delivery and activation in hypoxic tumours.
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Affiliation(s)
- Irene Regeni
- Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
| | - Sylvestre Bonnet
- Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
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Tan J, Chen L, Zhu R. Concerns on Potential Risk of Roxadustat in Promoting Tumor Progression: Double-Edged Sword of Hypoxia-Inducible Factor-1α Activation. J Clin Oncol 2025; 43:1266. [PMID: 39805074 DOI: 10.1200/jco-24-02305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 10/27/2024] [Accepted: 12/09/2024] [Indexed: 01/16/2025] Open
Affiliation(s)
- Jing Tan
- Jing Tan, MD, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China; Lin Chen, MM, School of Medicine, North Scihuan Medical College, Nanchong, Sichuan, China; and Rui Zhu, MM, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China
| | - Lin Chen
- Jing Tan, MD, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China; Lin Chen, MM, School of Medicine, North Scihuan Medical College, Nanchong, Sichuan, China; and Rui Zhu, MM, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China
| | - Rui Zhu
- Jing Tan, MD, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China; Lin Chen, MM, School of Medicine, North Scihuan Medical College, Nanchong, Sichuan, China; and Rui Zhu, MM, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China
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30
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Liu YC, Feng GL, Jie JL, Zhou W, Liu GJ, Zhang Y, Su HM, Xing GW. Hepatoma Metastasis-Inhibiting Supramolecular Nanoglycocalyx for Enhanced Type I Photodynamic Therapy. Adv Healthc Mater 2025; 14:e2404253. [PMID: 40045640 DOI: 10.1002/adhm.202404253] [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: 10/30/2024] [Revised: 02/25/2025] [Indexed: 04/08/2025]
Abstract
Type I photodynamic therapy (PDT) is well demonstrated to have low oxygen dependency. However, fully suppressing the risk of hypoxia-induced tumor metastasis during PDT remains a great challenge. In this study, a tetra-lactosylated amphiphilic Aza-BODIPY glycocluster (TLBP) is reported that self-assembles into a supramolecular nanoglycocalyx on hepatoma cell membranes, serving as an artificial extracellular matrix (ECM) to inhibit hepatoma metastasis while facilitating efficient Type I PDT. Molecular engineering demonstrates that multi-glycosylation promotes the transition of nanostructures from disordered to ordered self-assembly by regulating intermolecular interactions. This modification enables the TLBP glycocalyx to exhibit significant intermolecular electron transfer, generating superoxide anion radicals (O2 -•) for Type I PDT. Moreover, the TLBP glycocalyx inhibits the PI3K-Akt signaling pathway by reducing Na+/K+-ATPase activity, leading to decreased migration and invasion of HepG2 cells. The synergistic antitumor effect of TLBP glycocalyx is further verified in a HepG2-bearing mouse model. This work innovatively utilizes glycosylation to regulate microelectronic properties and macroscopic nanoscale self-assembly characteristics, providing a novel concept for developing efficient synergistic anti-hepatoma strategies.
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Affiliation(s)
- Yi-Chen Liu
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Gai-Li Feng
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Jia-Long Jie
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Wei Zhou
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Guang-Jian Liu
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Yuan Zhang
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Hong-Mei Su
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
| | - Guo-Wen Xing
- College of Chemistry, Beijing Normal University, Beijing, 100875, China
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31
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Wang P, Zhang XP, Liu F, Wang W. Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia. RESEARCH (WASHINGTON, D.C.) 2025; 8:0651. [PMID: 40171017 PMCID: PMC11960303 DOI: 10.34133/research.0651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/26/2025] [Accepted: 03/08/2025] [Indexed: 04/03/2025]
Abstract
Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.
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Affiliation(s)
- Ping Wang
- Kuang Yaming Honors School,
Nanjing University, Nanjing 210023, China
- Key Laboratory of High Performance Scientific Computation, School of Science,
Xihua University, Chengdu 610039, China
| | - Xiao-Peng Zhang
- Kuang Yaming Honors School,
Nanjing University, Nanjing 210023, China
- Institute of Brain Sciences,
Nanjing University, Nanjing 210093, China
| | - Feng Liu
- Institute of Brain Sciences,
Nanjing University, Nanjing 210093, China
- National Laboratory of Solid State Microstructures and Department of Physics,
Nanjing University, Nanjing 210093, China
| | - Wei Wang
- Institute of Brain Sciences,
Nanjing University, Nanjing 210093, China
- National Laboratory of Solid State Microstructures and Department of Physics,
Nanjing University, Nanjing 210093, China
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Wang Y, Zhou H, Ju S, Dong X, Zheng C. The solid tumor microenvironment and related targeting strategies: a concise review. Front Immunol 2025; 16:1563858. [PMID: 40207238 PMCID: PMC11979131 DOI: 10.3389/fimmu.2025.1563858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 03/12/2025] [Indexed: 04/11/2025] Open
Abstract
The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.
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Affiliation(s)
- Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Huimin Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Xiangjun Dong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
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Wowui PI, Mprah R, Ndzie Noah ML, Adu-Amankwaah J, Kanoseh AWL, Tao L, Chulu D, Yalley SK, Shaheen S, Sun H. Estrogen via GPER downregulated HIF-1a and MIF expression, attenuated cardiac arrhythmias, and myocardial inflammation during hypobaric hypoxia. Mol Med 2025; 31:107. [PMID: 40108505 PMCID: PMC11924608 DOI: 10.1186/s10020-025-01144-2] [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: 12/09/2024] [Accepted: 02/27/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND The human body is highly dependent on adequate oxygenation of the cellular space for physiologic homeostasis mediation. The insufficient oxygenation of the cellular space leads to hypoxia. Hypobaric hypoxia (HH) is the reduction in oxygen partial pressure and atmospheric pressure during ascent to high altitudes. This state induces a maladaptive response. Women and how hormones like estrogen influence hypoxia have not been explored with most research being conducted on males. In this study, we investigated the effects of estrogen and GPER on HIF-1a and MIF expression, cardiac arrhythmias, and inflammation during hypobaric hypoxia. METHODS Ovariectomy and SHAM operations were done on FVB wild-type (WT) female mice. 2 weeks after the operation, the mice were treated with estrogen (40 mg/kg) as a therapeutic intervention and placed in a hypoxic chamber at an altitude of 6000 m for 7 days. Cardiac electrical activity was assessed using electrocardiography. Alterations in protein expression, inflammatory, and GPER pathways were investigated using western blotting, ELISA, and immunofluorescence. Histological assessment was performed using Masson's trichrome staining. Peritoneal macrophages were isolated for in vitro study. RESULTS Under hypobaric hypoxia (HH), the ovariectomized (OVX) group showed increased macrophage migration inhibitory factor (MIF) and hypoxia-inducible factor-1 alpha (HIF-1α) expression. In contrast, these factors were downregulated in the estrogen-treated and control groups. HH also caused cardiac inflammation and fibrosis, especially in the OVX + HH group, which had elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) and decreased anti-inflammatory cytokines (TGF-β, IL-10). Inhibition with G15 (a GPER antagonist) increased MIF and HIF-1α, whereas activation with G1 (a GPER agonist) decreased their expression, highlighting GPER's crucial role in regulating MIF during HH. CONCLUSION Estrogen regulates HIF-1α and MIF expression through the GPER during hypobaric hypoxia, suggesting a potential therapeutic pathway to mitigate maladaptive responses during high-altitude ascent.
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Affiliation(s)
- Prosperl Ivette Wowui
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Richard Mprah
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Marie Louise Ndzie Noah
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Joseph Adu-Amankwaah
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | | | - Li Tao
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Diana Chulu
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Simon Kumah Yalley
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Saffia Shaheen
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China
| | - Hong Sun
- Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
- Xuzhou Key Laboratory of Physiological Function and Injury, Xuzhou Medical University, Xuzhou, China.
- National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, China.
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Dai H, Zhang X, Zhao Y, Nie J, Hang Z, Huang X, Ma H, Wang L, Li Z, Wu M, Fan J, Jiang K, Luo W, Qin C. ADME gene-driven prognostic model for bladder cancer: a breakthrough in predicting survival and personalized treatment. Hereditas 2025; 162:42. [PMID: 40108724 PMCID: PMC11921678 DOI: 10.1186/s41065-025-00409-4] [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: 01/15/2025] [Accepted: 03/05/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Genes that participate in the absorption, distribution, metabolism, excretion (ADME) processes occupy a central role in pharmacokinetics. Meanwhile, variability in clinical outcomes and responses to treatment is notable in bladder cancer (BLCA). METHODS Our study utilized expansive datasets from TCGA and the GEO to explore prognostic factors in bladder cancer. Utilizing both univariate Cox regression and the lasso regression techniques, we identified ADME genes critical for patient outcomes. Utilizing genes identified in our study, a model for assessing risk was constructed. The evaluation of this model's predictive precision was conducted using Kaplan-Meier survival curves and assessments based on ROC curves. Furthermore, we devised a predictive nomogram, offering a straightforward visualization of crucial prognostic indicators. To explore the potential factors mediating the differences in outcomes between high and low risk groups, we performed comprehensive analyses including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)-based enrichment analyses, immune infiltration variations, somatic mutation landscapes, and pharmacological sensitivity response assessment etc. Immediately following this, we selected core genes based on the PPI network and explored the prognostic potential of the core genes as well as immune modulation, and pathway activation. And the differential expression was verified by immunohistochemistry and qRT-PCR. Finally we explored the potential of the core genes as pan-cancer biomarkers. RESULTS Our efforts culminated in the establishment of a validated 17-gene ADME-centered risk prediction model, displaying remarkable predictive accuracy for BLCA prognosis. Through separate cox regression analyses, the importance of the model's risk score in forecasting BLCA outcomes was substantiated. Furthermore, a novel nomogram incorporating clinical variables alongside the risk score was introduced. Comprehensive studies established a strong correlation between the risk score and several key indicators: patterns of immune cell infiltration, reactions to immunotherapy, landscape of somatic mutation and profiles of drug sensitivity. We screened the core prognostic gene CYP2C8, explored its role in tumor bioregulation and validated its upregulated expression in bladder cancer. Furthermore, we found that it can serve as a reliable biomarker for pan-cancer. CONCLUSION The risk assessment model formulated in our research stands as a formidable instrument for forecasting BLCA prognosis, while also providing insights into the disease's progression mechanisms and guiding clinical decision-making strategies.
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Affiliation(s)
- Haojie Dai
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
- The First Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xi Zhang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
- Department of Urology, The First Affliated Hospital of Nanjing Medical University, Nanjing, China
| | - You Zhao
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Jun Nie
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Zhenyu Hang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Xin Huang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Hongxiang Ma
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Li Wang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Zihao Li
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ming Wu
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Jun Fan
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ke Jiang
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China.
| | - Weiping Luo
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China.
| | - Chao Qin
- The Affliated Liyang People's Hospital of Kangda College of Nanjing Medical University, Changzhou, Jiangsu, China
- Department of Urology, The First Affliated Hospital of Nanjing Medical University, Nanjing, China
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Shang T, Jia Z, Li J, Cao H, Xu H, Cong L, Ma D, Wang X, Liu J. Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance. J Hematol Oncol 2025; 18:32. [PMID: 40102937 PMCID: PMC11921735 DOI: 10.1186/s13045-025-01684-4] [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: 12/15/2024] [Accepted: 03/05/2025] [Indexed: 03/20/2025] Open
Abstract
In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.
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Affiliation(s)
- Tongxuan Shang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Ziqi Jia
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiayi Li
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China
| | - Heng Cao
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hengyi Xu
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Cong
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Dongxu Ma
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiang Wang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jiaqi Liu
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Wang Q, Suo Y, Tian X. 5-Aminolaevulinic Acid-Mediated Photodynamic Therapy Combined with Tirapazamine Enhances Efficacy in Ovarian Cancer. Biomedicines 2025; 13:724. [PMID: 40149700 PMCID: PMC11939993 DOI: 10.3390/biomedicines13030724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/13/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
Objectives: Ovarian cancer is a common gynaecological malignancy. Photodynamic therapy (PDT) mediated by 5-aminolaevulinic acid (5-ALA-PDT) is widely used in clinical practice. However, hypoxia may impact the efficacy of this treatment. In the present study, we combined the bioreductively active drug tirapazamine (TPZ) with PDT to explore its potential in enhancing ovarian cancer cell death. Methods: A cell counting kit-8 assay was used to determine cytotoxicity under different intervention conditions. The distribution of protoporphyrin IX, a metabolite of 5-ALA, was observed using in vivo fluorescence imaging. The effect of the combined treatment was assessed by measuring changes in tumour size following the corresponding interventions and by haematoxylin and eosin staining of tumour tissues. Immunohistochemical staining was used to detect the expression levels of relevant proteins. Results: TPZ exhibited no cytotoxicity under normoxic conditions but was activated under hypoxic conditions, inducing cytotoxic effects that were enhanced when combined with PDT. Over time, protoporphyrin IX achieved systemic distribution, and high drug concentrations were maintained within the tumour. The combination therapy suppressed tumour growth, and pathological staining showed that necrotic tumour areas were significantly enlarged after treatment. The enhanced therapeutic effect may be attributable to the inhibition of the hypoxia-inducible factor-1α/vascular endothelial growth factor axis and PI3K/Akt/mTOR pathway. Conclusions: 5-ALA-PDT combined with TPZ can overcome both the hypoxic state of ovarian cancer tissues and the increased hypoxia induced by PDT, thereby inhibiting tumour growth.
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Affiliation(s)
- Qian Wang
- Fifth Clinical Medical College, Shanxi Medical University, Taiyuan 030012, China; (Q.W.); (X.T.)
| | - Yuping Suo
- Fifth Clinical Medical College, Shanxi Medical University, Taiyuan 030012, China; (Q.W.); (X.T.)
- Department of Gynaecology and Obstetrics, Shanxi Provincial People’s Hospital, Taiyuan 030012, China
| | - Xiaojuan Tian
- Fifth Clinical Medical College, Shanxi Medical University, Taiyuan 030012, China; (Q.W.); (X.T.)
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Sun J, Liu Y, Sun J, Ding J, Chen X. Biomaterials‐Involved Construction of Extracellular Matrices for Tumor Blockade Therapy. EXPLORATION 2025. [DOI: 10.1002/exp.20240229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 01/28/2025] [Indexed: 05/14/2025]
Abstract
ABSTRACTExtracellular matrices (ECMs) play a crucial role in the onset and progression of tumors by providing structural support and promoting the proliferation and metastases of tumor cells. Current therapeutic approaches targeting tumor ECMs focus on two main strategies: Inhibiting matrix degradation to prevent metastases and facilitating matrix degradation to enhance the penetration of drugs and immune cells. However, these strategies may lead to unintended consequences, such as tumor growth promotion, drug resistance, and side effects like fibrotic changes in healthy tissues. Biomaterials have made significant progress in fabricating artificial ECMs for tumor therapy by inducing biomineralization, fibrogenesis, or gelation. This perspective explores the fundamental concepts, benefits, and challenges of each technique. Additionally, future improvements and research directions in artificial ECMs are discussed, highlighting their potential to advance tumor therapy.
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Affiliation(s)
- Jinfeng Sun
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun P. R. China
- College of Chemistry Jilin University Changchun P. R. China
| | - Yang Liu
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun P. R. China
- School of Applied Chemistry and Engineering University of Science and Technology of China Hefei P. R. China
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL) Lausanne Switzerland
| | - Jingshan Sun
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun P. R. China
- School of Applied Chemistry and Engineering University of Science and Technology of China Hefei P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun P. R. China
- School of Applied Chemistry and Engineering University of Science and Technology of China Hefei P. R. China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun P. R. China
- College of Chemistry Jilin University Changchun P. R. China
- School of Applied Chemistry and Engineering University of Science and Technology of China Hefei P. R. China
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Lan H, Zhu J, Hou H, Zhang C, Huo X, Zhang Y, Yang F, Zhou N, Zhang X. Combination therapy with Chicoric acid and PD-1/PD-L1 blockade improves the immunotherapy response in patient-derived ovarian cancer xenograft model. Cell Commun Signal 2025; 23:137. [PMID: 40087780 PMCID: PMC11909847 DOI: 10.1186/s12964-025-02146-7] [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: 12/16/2024] [Accepted: 03/08/2025] [Indexed: 03/17/2025] Open
Abstract
PURPOSE Limited treatment options exist for refractory ovarian cancer (OC) due to its poor response to immune therapies. Therefore, there is an urgent need to develop new effective treatment strategies. Chicoric acid (CA) is reported to have immune-enhancing properties, but its efficacy in cancer treatment is not well understood. We hypothesize that CA might improve the efficacy of PD-1/PD-L1 blockade immunotherapy in refractory OC patients. METHODS Patient-derived xenograft (PDX) models were constructed from chemoresistant advanced high-grade serous ovarian cancer patients. These models were treated with CA, aPD-1/aPD-L1 antibodies, or a combination of both. Single-cell RNA sequencing was performed to analyze the cellular composition of the tumor microenvironment (TME), evaluate treatment efficacy, and explore therapeutic mechanisms. Variations in peripheral blood lymphocytes were analyzed via fluorescence-activated cell sorting. Immunohistochemistry confirmed the variations in tumor-infiltrating lymphocytes and tumor cells. RESULTS Immunocompetent peripheral blood mononuclear cell (PBMC)-PDX models were successfully constructed using malignant ascites fluid and PBMCs. After treatment, 158,734 cells from 15 samples were categorized into epithelial cells, T lymphocytes, myeloid cells, fibroblasts, and endothelial cells. CA enhanced the antitumor ability of immune cells against OC cells. Notably, CA stimulated the proliferation of CD45 + and CD3 + cells and promoted the migration of CD8 + and CD4 + T cells from peripheral blood to infiltrate the TME. Additionally, CA enhanced the response of OCs to aPD-L1/aPD-1 treatment, strengthened the interaction between tumor and nontumor cells, and identified APP/CD74 as a critical ligand‒receptor pair. CHI3L1 was also found to be a potential marker for predicting immunotherapy efficacy in OC. CONCLUSION This study demonstrated that combination therapy with CA and aPD-1/aPD-L1 might be a promising strategy for treating OC effectively.
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Affiliation(s)
- Hongwei Lan
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China
| | - Jingjuan Zhu
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China
| | - Helei Hou
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Chuantao Zhang
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Xingfa Huo
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China
| | - Yuming Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China
| | - Fangfang Yang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China
| | - Na Zhou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China.
| | - Xiaochun Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, No. 56 Haier Road, Qingdao, 266000, Shandong, China.
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Ou Z, Zhu L, Chen X, Liu T, Cheng G, Liu R, Zhang S, Tan W, Lin D, Wu C. Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma. Cancer Res 2025; 85:1064-1081. [PMID: 39661488 DOI: 10.1158/0008-5472.can-24-1185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/12/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024]
Abstract
Cancer-associated fibroblasts (CAF) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against protumorigenic CAFs. In this study, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAF), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove IL1α production to trigger CAF senescence and IGF1 secretion via nuclear factor I A. Knockout of IGF1 in CAFs or nuclear factor erythroid 2-related factor 2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC. Significance: A hypoxic microenvironment and cancer cells cooperate to induce a senescent fibroblast subset that supports tumor stemness, suggesting that targeting this cancer-associated fibroblast subpopulation is a potential therapeutic strategy to overcome chemoresistance.
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Affiliation(s)
- Zhengjie Ou
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Liang Zhu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Xinjie Chen
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Tianyuan Liu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Guoyu Cheng
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Rucheng Liu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Shaosen Zhang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Wen Tan
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
- CAMS Oxford Institute, Chinese Academy of Medical Sciences, Beijing, China
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Jing SY, Wang HQ, Lin P, Yuan J, Tang ZX, Li H. Quantifying and interpreting biologically meaningful spatial signatures within tumor microenvironments. NPJ Precis Oncol 2025; 9:68. [PMID: 40069556 PMCID: PMC11897387 DOI: 10.1038/s41698-025-00857-1] [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: 08/22/2024] [Accepted: 02/25/2025] [Indexed: 03/15/2025] Open
Abstract
The tumor microenvironment (TME) plays a crucial role in orchestrating tumor cell behavior and cancer progression. Recent advances in spatial profiling technologies have uncovered novel spatial signatures, including univariate distribution patterns, bivariate spatial relationships, and higher-order structures. These signatures have the potential to revolutionize tumor mechanism and treatment. In this review, we summarize the current state of spatial signature research, highlighting computational methods to uncover spatially relevant biological significance. We discuss the impact of these advances on fundamental cancer biology and translational research, address current challenges and future research directions.
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Affiliation(s)
- Si-Yu Jing
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - He-Qi Wang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Ping Lin
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Jiao Yuan
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Zhi-Xuan Tang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China
| | - Hong Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
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Clemens C, Gehring R, Riedl P, Pompe T. Matrix deformation and mechanotransduction as markers of breast cancer cell phenotype alteration at matrix interfaces. Biomater Sci 2025; 13:1578-1589. [PMID: 39960148 DOI: 10.1039/d4bm01589d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2025]
Abstract
The dissemination of metastatic cells from the primary tumor into the surrounding tissue is a key event in the progression of cancer. This process involves the migration of cells across defined tissue interfaces that separate the dense tumor tissue from the adjacent healthy tissue. Prior research showed that cell transmigration across collagen I matrix interfaces induces a switch towards a more aggressive phenotype including a change in directionality of migration and chemosensitivity correlated to increased DNA damage during transmigration. Hence, mechanical forces acting at the nucleus during transmigration are hypothesized to trigger phenotype switching. Here, we present results from a particle image velocimetry (PIV) based live cell analysis of breast cancer cell transmigration across sharp matrix interfaces constituted of two collagen type I networks with different pore sizes. We found strong and highly localized collagen network deformation caused by cellular forces at the moment of crossing interfaces from dense into open matrices. Additionally, an increased contractility of transmigrated cells was determined for cells with the switch phenotype. Moreover, studies on mechanotransductive signaling at the nucleus, emerin translocation and YAP activation, indicated a misregulation of these signals for transmigrated cells with altered phenotype. These findings show that matrix interfaces between networks of different pore sizes mechanically challenge invasive breast cancer cells during transmigration by a strong asymmetry of contracting forces, impeding nuclear mechanotransduction pathways, with a subsequent trigger of more aggressive phenotypes.
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Affiliation(s)
- Cornelia Clemens
- Institute of Biochemistry, Leipzig University, Johannisallee 21-23, 04103, Leipzig, Germany.
| | - Rosa Gehring
- Institute of Biochemistry, Leipzig University, Johannisallee 21-23, 04103, Leipzig, Germany.
| | - Philipp Riedl
- Institute of Biochemistry, Leipzig University, Johannisallee 21-23, 04103, Leipzig, Germany.
| | - Tilo Pompe
- Institute of Biochemistry, Leipzig University, Johannisallee 21-23, 04103, Leipzig, Germany.
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Yu Z, Fu J, Mantareva V, Blažević I, Wu Y, Wen D, Battulga T, Wang Y, Zhang J. The role of tumor-derived exosomal LncRNA in tumor metastasis. Cancer Gene Ther 2025; 32:273-285. [PMID: 40011710 DOI: 10.1038/s41417-024-00852-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/22/2024] [Accepted: 11/05/2024] [Indexed: 02/28/2025]
Abstract
Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.
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Affiliation(s)
- Zhile Yu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Jiali Fu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Vanya Mantareva
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bld. 9, 1113, Sofia, Bulgaria
| | - Ivica Blažević
- Department of Organic Chemistry, Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia
| | - Yusong Wu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Dianchang Wen
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Tungalag Battulga
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.
| | - Yuqing Wang
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China.
- The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, 510140, PR China.
| | - Jianye Zhang
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China.
- The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, 511518, PR China.
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Chen Y, Xue Y, Yan C, Jin J, Liu Y, Li J, Han S, Liu J. Bioprinted Fibroblast Mediated Heterogeneous Tumor Microenvironment for Studying Tumor-Stroma Interaction and Drug Screening. Adv Healthc Mater 2025; 14:e2404642. [PMID: 39840601 DOI: 10.1002/adhm.202404642] [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: 11/20/2024] [Revised: 01/06/2025] [Indexed: 01/23/2025]
Abstract
Cancer-associated fibroblasts (CAFs) are crucial stromal cells in the tumor microenvironment, affecting cancer growth, angiogenesis, and matrix remodeling. Developing an effective in vitro tumor model that accurately recapitulates the dynamic interplay between tumor and stromal cells remains a challenge. In this study, a 3D bioprinted fibroblast - mediated heterogeneous breast tumor model was created, with tumor cells and fibroblasts in a bionic matrix. The impact of transforming growth factor-β （TGF-β） on the dynamic transformation of normal fibroblasts into CAFs and its subsequent influence on tumor cells is further investigated. These findings reveales a profound correlation between CAFs and several critical biological processes, including epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, gene expression profiles, and tumor progression. Furthermore, tumor models incorporating CAFs exhibits reduced drug sensitivity compared to models containing tumor cells alone or models co-cultured with normal fibroblasts. These results underscore the potential of the in vitro fibroblast-mediated heterogeneous tumor model to simulate real-life physiological conditions, thereby offering a more effective drug screening platform for elucidating tumor pathogenesis and facilitating drug design prior to animal and clinical trials. This model's establishment promotes the understanding of tumor-stromal interactions and their therapeutic implications.
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Affiliation(s)
- You Chen
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Yifan Xue
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Cong Yan
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, Guangdong, 510282, China
| | - Jinlong Jin
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Yadong Liu
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Jing Li
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Shuai Han
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Haizhu District, Guangzhou, Guangdong, 510282, China
| | - Jie Liu
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Guangming District, Shenzhen, Guangdong, 518107, China
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Liu Z, Wang Y, Gao X, Ma J, Hui C, Wang C, Liu Y, Huang Y, Wen Y. Tanshinone IIA Suppresses the Proliferation of MGC803 Cells by Disrupting Glycolysis Under Anaerobic Conditions. Appl Biochem Biotechnol 2025:10.1007/s12010-025-05205-4. [PMID: 40009338 DOI: 10.1007/s12010-025-05205-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2025] [Indexed: 02/27/2025]
Abstract
This study aimed to investigate how Tanshinone IIA (Tan IIA) affects gastric cancer cell (MGC803) proliferation under anaerobic conditions, which are linked to drug resistance and tumor growth. The proliferation of MGC803 cells under both aerobic and anaerobic conditions in response to Tan IIA was assessed using the Cell Counting Kit-8 (CCK-8) assay. To elucidate the molecular mechanisms underlying these effects, proteomics analysis was performed following treatment with 50 µmol/L Tan IIA, focusing on alterations in Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Additionally, in vitro evaluations such as glucose uptake, lactate production, and adenosine triphosphate (ATP) synthesis were employed to validate the alterations in glycolytic activity observed in anaerobic cells treated with Tan IIA. Under anaerobic conditions, Tan IIA enhanced the inhibitory effect on the proliferation of MGC803 cells. Proteomics data revealed that a total of 6629 proteins were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), with 2604 proteins exhibiting significant changes (fold change > 2 or < 0.5, P < 0.05). KEGG analysis highlighted the perturbation of glycolytic pathway by Tan IIA under anaerobic conditions, accompanied by reduced glucose uptake, lactate production, and ATP synthesis. Additionally, a downregulation of glycolytic enzyme expression was observed at both the mRNA and protein levels, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A (LDHA), phosphofructokinase 2 (PFKP), and pyruvate dehydrogenase (PDH). Tan IIA inhibits the proliferation of MGC803 cells by disrupting the glycolysis under anaerobic conditions, offering a potential treatment for anaerobiosis-resistant solid tumors.
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Affiliation(s)
- Zhe Liu
- Department of Pathology, The Ninth Hospital of Xi'an, 710054, Xi'an, Shaanxi, People's Republic of China
| | - Yi Wang
- Department of Pathology, The Ninth Hospital of Xi'an, 710054, Xi'an, Shaanxi, People's Republic of China
| | - Xia Gao
- Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, 710038, Xi'an, Shaanxi, People's Republic of China
| | - Jingwen Ma
- Radiology Department, CT and MRI Room, The Ninth Hospital of Xi'an, 710054, Xi'an, Shaanxi, People's Republic of China
| | - Chan Hui
- Department of Pathology, The Ninth Hospital of Xi'an, 710054, Xi'an, Shaanxi, People's Republic of China
| | - Chao Wang
- Military Hospital, Unit 94162 of the Chinese people's Liberation Army, 710600, Xi'an, Shaanxi, People's Republic of China
| | - Yanfei Liu
- Department of Pathology, The Affiliated Children's Hospital of Xi'an Jiaotong University, 710003, Xi'an, Shaanxi, People's Republic of China
| | - Yao Huang
- Department of Oncology, The Ninth Hospital of Xi'an, 710054, Xi'an, Shaanxi, People's Republic of China.
| | - Yuting Wen
- Department of Pathology, The Ninth Hospital of Xi'an, 710054, Xi'an, Shaanxi, People's Republic of China.
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Lacerda-Abreu MA, Carvalho-Kelly LF, Meyer-Fernandes JR. Hypoxia Modulates Transmembrane Prostatic Acid Phosphatase (TM-PAP) in MCF-7 Breast Cancer Cells. Int J Mol Sci 2025; 26:1918. [PMID: 40076544 PMCID: PMC11900489 DOI: 10.3390/ijms26051918] [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: 01/16/2025] [Revised: 02/09/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
In MCF-7 breast cancer cells, transmembrane prostatic acid phosphatase (TM-PAP) plays a critical role in tumor progression, particularly under hypoxic conditions. In this study, the impact of hypoxia on ectophosphatase activity in MCF-7 cells was examined, and the underlying biological mechanisms that influence the breast cancer microenvironment were explored. Compared with normoxic cells, hypoxic cells presented significant reductions in ectophosphatase activity, indicating that hypoxia altered dephosphorylation processes critical for tumor growth and metastasis. Specific decreases in the hydrolysis of substrates, such as p-nitrophenylphosphate (pNPP) and adenosine monophosphate (AMP), were observed under hypoxic conditions, suggesting that hypoxia impaired TM-PAP activity. Further investigation revealed that hypoxia induced an increase in the concentration of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), which inhibited ectophosphatase activity. This effect was reversed by the introduction of ROS scavengers. Additionally, hypoxia activated protein kinase C (PKC), further modulating ectophosphatase activity in MCF-7 cells. Collectively, these findings enhanced the understanding of the mechanisms through which hypoxia could influence enzyme activity associated with cancer progression and provide valuable insights into the development of targeted therapeutic strategies.
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Affiliation(s)
| | | | - José Roberto Meyer-Fernandes
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil; (M.A.L.-A.); (L.F.C.-K.)
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Lv Y, Chen Z, Wang S, Zou M. Macrophage-Mediated Liquid Metal Nanoparticles for Enhanced Tumor Accumulation and Inhibition. ACS Biomater Sci Eng 2025; 11:903-915. [PMID: 39855913 DOI: 10.1021/acsbiomaterials.4c01130] [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: 01/27/2025]
Abstract
In most studies, the penetration of nanoparticles into tumors was mainly dependent on the enhanced permeability and retention (ERP) effect. However, the penetration of nanoparticles would be limited by tumor-dense structure, immune system, and other factors. To solve these problems, macrophages with active tropism to tumor tissues, loaded nanoparticles with photothermal therapy, and chemotherapy were designed. In detail, liquid metal (gallium indium alloy) nanoparticles were modified with mesoporous silica and then embedded with the chemotherapeutic drug sorafenib (LM@Si/SO) for photothermal therapy and chemotherapy. After that, the LM@Si/SO nanoparticles were carried by the mouse macrophage RAW264.7 cell line (LM@Si/SO@R) to increase the accumulation of the nanoparticles in the tumor site and improve the tumor immune microenvironment. With the enhanced tumor accumulation, LM@Si/SO@R exhibited excellent antitumor ability in vitro and in vivo. Thus, these strategies via the cell carrier to enhance tumor therapeutic efficiency had the potential for the improvement of tumor therapy.
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Affiliation(s)
- Yonggang Lv
- State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan 430200, China
| | - Zhenghang Chen
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, China
| | - Shuai Wang
- Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, China
| | - Meizhen Zou
- State Key Laboratory of New Textile Materials and Advanced Processing Technologies, Wuhan Textile University, Wuhan 430200, China
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47
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Pham DX, Hsu T. Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma. J Biomed Sci 2025; 32:17. [PMID: 39920694 PMCID: PMC11806631 DOI: 10.1186/s12929-024-01111-9] [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: 10/02/2024] [Accepted: 12/11/2024] [Indexed: 02/09/2025] Open
Abstract
Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney malignancy. ccRCC is considered a major health concern worldwide because its numbers of incidences and deaths continue to rise and are predicted to continue rising in the foreseeable future. Therefore new strategy for early diagnosis and therapeutics for this disease is urgently needed. The discovery of cancer stem cells (CSCs) offers hope for early cancer detection and treatment. However, there has been no definitive identification of these cancer progenitors for ccRCC. A majority of ccRCC is characterized by the loss of the von Hippel-Lindau (VHL) tumor suppressor gene function. Recent advances in genome analyses of ccRCC indicate that in ccRCC, tumor-initiating cells (TICs) and metastasis-initiating cells (MICs) are two distinct groups of progenitors. MICs result from various genetic changes during subclonal evolution, while TICs reside in the stem of the ccRCC phylogenetic tree of clonal development. TICs likely originate from kidney tubule progenitor cells bearing VHL gene inactivation, including chromatin 3p loss. Recent studies also point to the importance of microenvironment reconstituted by the VHL-deficient kidney tubule cells in promoting ccRCC initiation and progression. These understandings should help define the progenitors of ccRCC and facilitate early detection and treatment of this disease.
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Affiliation(s)
- Dinh-Xuan Pham
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan, ROC
| | - Tien Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan, ROC.
- Graduate Institute of Biomedical Sciences, China Medical University-Taiwan, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.
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Liu L, Liu Y, Sun Y, Lu X, Ji Y, Zhao X, Li J, Liu C. The changes in the ratio of Dicer1 transcripts can participate in the neuronal hypoxic response by regulating miR-29b. Cereb Cortex 2025; 35:bhae490. [PMID: 39756430 DOI: 10.1093/cercor/bhae490] [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: 08/22/2024] [Revised: 11/13/2024] [Accepted: 12/10/2024] [Indexed: 01/07/2025] Open
Abstract
The nervous system is highly dependent on the supply of oxygen and nutrients, so when demand for oxygen exceeds its supply, hypoxia is induced. The hippocampus is very important in the nervous system. It has the ability to control human behavior, memory, emotion, and so on. Therefore, when the hippocampus is damaged by hypoxia, it may cause nervous system diseases such as Alzheimer's disease, Parkinson's disease, and stroke. Alternative splicing plays an important regulatory role in the processes of growth and disease occurrence and development. However, the function of hypoxia-induced alternative splicing in neurological diseases needs to be further studied. Therefore, we performed hypoxia stress on mouse hippocampal neuron HT22 cells and then analyzed differentially expressed genes and differential alternative splicing events by next-generation sequencing. Through bioinformatics analysis and verification, it was found that hypoxia stress regulated the expression of Rbm15 and the ratio of Dicer1 transcripts in HT22 cells. The change in the ratio of Dicer1 transcripts may be related to the upregulation of miR-29b under hypoxia stress. This study can provide multiple time point sequencing results and a theoretical basis for the study of hypoxia-related gene alternative splicing.
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Affiliation(s)
- Linan Liu
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Yingxin Liu
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Yongfeng Sun
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Xian Lu
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Yong Ji
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Xiujuan Zhao
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Jun Li
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
| | - Chuncheng Liu
- School of Life Science and Technology, Inner Mongolia University of Science & Technology, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, No. 7, Aerding Street, Kundulun District, Baotou 014010, China
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Lee PWT, Kobayashi M, Dohkai T, Takahashi I, Yoshida T, Harada H. 2-Oxoglutarate-dependent dioxygenases as oxygen sensors: their importance in health and disease. J Biochem 2025; 177:79-104. [PMID: 39679914 DOI: 10.1093/jb/mvae087] [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: 07/10/2024] [Revised: 10/22/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024] Open
Abstract
Since low oxygen conditions below physiological levels, hypoxia, are associated with various diseases, it is crucial to understand the molecular basis behind cellular response to hypoxia. Hypoxia-inducible factors (HIFs) have been revealed to primarily orchestrate the hypoxic response at the transcription level and have continuously attracted great attention over the past three decades. In addition to these hypoxia-responsive effector proteins, 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily including prolyl-4-hydroxylase domain-containing proteins (PHDs) and factor inhibiting HIF-1 (FIH-1) has attracted even greater attention in recent years as factors that act as direct oxygen sensors due to their necessity of oxygen for the regulation of the expression and activity of the regulatory subunit of HIFs. Herein, we present a detailed classification of 2-OGDD superfamily proteins, such as Jumonji C-domain-containing histone demethylases, ten-eleven translocation enzymes, AlkB family of DNA/RNA demethylases and lysyl hydroxylases, and discuss their specific functions and associations with various diseases. By introducing the multifaceted roles of 2-OGDD superfamily proteins in the hypoxic response, this review aims to summarize the accumulated knowledge about the complex mechanisms governing cellular adaptation to hypoxia in various physiological and pathophysiological contexts.
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Affiliation(s)
- Peter W T Lee
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Minoru Kobayashi
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Takakuni Dohkai
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Itsuki Takahashi
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Takumi Yoshida
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hiroshi Harada
- Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Department of Genome Repair Dynamics, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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50
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Sung JY, Lim GE, Goo J, Jung KJ, Chung JM, Jung HS, Kim YN, Shim J. TMEM39A and TMEM131 facilitate bulk transport of ECM proteins through large COPII vesicle formation. J Genet Genomics 2025; 52:189-203. [PMID: 39521045 DOI: 10.1016/j.jgg.2024.10.013] [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: 06/06/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
The growth of Caenorhabditis elegans involves multiple molting processes, during which old cuticles are shed and new cuticles are rapidly formed. This process requires the regulated bulk secretion of cuticle components. The transmembrane protein-39 (TMEM-39) mutant exhibits distinct dumpy and ruptured phenotypes characterized by notably thin cuticles. TMEM-39 primarily co-localizes with the coat protein II complex (COPII) in large vesicles rather than small COPII vesicles. These TMEM-39-associated large vesicles (TMEM-39-LVs) form robustly during the molting period and co-localize with various extracellular matrix components, including BLI-1 collagen, BLI-3 dual oxidase, and carboxypeptidases. Through immunoprecipitation using TMEM39A-FLAG and proteomics analysis in human sarcoma cells, we identify TMEM39A-associated proteins, including TMEM131. Knockdown of TMEM131 results in reduced TMEM39A-LV formation and collagen secretion in both C. elegans and human sarcoma cells, indicating a cooperative role between TMEM39A and TMEM131 in the secretion of extracellular components through the formation of large COPII vesicles. Given the conservation of TMEM39A and its associated proteins between C. elegans and humans, TMEM39A-LVs may represent a fundamental machinery for rapid and extensive secretion across metazoans.
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Affiliation(s)
- Jee Young Sung
- Cancer Metastasis Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Ga-Eun Lim
- Cancer Metastasis Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Jarim Goo
- Cancer Metastasis Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si, Gyeonggi-do, 10408, Republic of Korea
| | - Kyung Jin Jung
- Experimental Clinical Research Center, Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, 13620, Republic of Korea
| | - Jeong Min Chung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Kangwon-do, 24341, Republic of Korea
| | - Hyun Suk Jung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Kangwon-do, 24341, Republic of Korea
| | - Yong-Nyun Kim
- Cancer Metastasis Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
| | - Jaegal Shim
- Cancer Metastasis Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
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