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1
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Doi T, Ishikawa T, Moriguchi M, Itoh Y. Current status of cancer genome medicine for pancreatic ductal adenocarcinoma. Jpn J Clin Oncol 2025; 55:443-452. [PMID: 39893577 DOI: 10.1093/jjco/hyaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/17/2025] [Indexed: 02/04/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden-high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.
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Affiliation(s)
- Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Cancer Genome Medical Center, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Cancer Genome Medical Center, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Department of Medical Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
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2
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Wang X, Zhang Y, Fan G, Wu H, Qi X, Cui X, Zhou C. Case Report: A case of synchronous multiple early gastric cancer with a microsatellite instability-high phenotype. Front Oncol 2025; 15:1527495. [PMID: 40248200 PMCID: PMC12003148 DOI: 10.3389/fonc.2025.1527495] [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: 12/05/2024] [Accepted: 03/04/2025] [Indexed: 04/19/2025] Open
Abstract
Synchronous multiple early gastric cancer (SMEGC) is a relatively uncommon variant of early gastric cancer (EGC). In this report, we present a case of SMEGC accompanied by a microsatellite instability-high (MSI-H) phenotype. The patient was a 69-year-old man who presented to our hospital with abdominal pain. The endoscopic examination revealed two lesions. Both lesions were pathologically confirmed as EGC, then the patient subsequently underwent endoscopic submucosal dissection (ESD). Nine months post-procedure, the patient returned with recurrent abdominal pain, leading to the diagnosis of a new EGC. Immunohistochemical analysis demonstrated that all lesions exhibited an MSI-H phenotype and BRAF mutant expression, suggesting that these lesions are not associated with Lynch syndrome-related EGC. The case was ultimately diagnosed as SMEGC with an MSI-H phenotype. The current evidence and clinical experience suggest that patients with advanced MSI-H are likely to benefit from immunotherapy and should be considered for early systemic treatment with immunotherapy as a central component. At present, research studies on the molecular characteristics of SMEGC are limited, underscoring the importance of conducting comprehensive molecular diagnostics of each EGC patient, which could help clinicians thoroughly understand the lesion's characteristics.
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Affiliation(s)
- Xinshuo Wang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yifan Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Guangyan Fan
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Honglei Wu
- Department of Gastroenterology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xing Qi
- Department of Gastroenterology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiujie Cui
- Department of Pathology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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3
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Thakur BK, Malaise Y, Choudhury SR, Neustaeter A, Turpin W, Streutker C, Copeland J, Wong EOY, Navarre WW, Guttman DS, Jobin C, Croitoru K, Martin A. Dietary fibre counters the oncogenic potential of colibactin-producing Escherichia coli in colorectal cancer. Nat Microbiol 2025; 10:855-870. [PMID: 40033140 DOI: 10.1038/s41564-025-01938-4] [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: 08/05/2024] [Accepted: 01/14/2025] [Indexed: 03/05/2025]
Abstract
Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used Il10-/- mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus or colibactin-producing (polyketide synthase-positive (pks+)) Escherichia coli and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet. Mechanistically, mucosal inflammation was increased in the LC-diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. The pks+ E. coli also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.
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Affiliation(s)
| | - Yann Malaise
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | - Anna Neustaeter
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Williams Turpin
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Catherine Streutker
- Department of Laboratory Medicine, Unity Health Toronto, Toronto, Ontario, Canada
| | - Julia Copeland
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
| | - Erin O Y Wong
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - William W Navarre
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - David S Guttman
- Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Christian Jobin
- Department of Infectious Diseases and Pathology, University of Florida College of Veterinary Medicine, Gainesville, FL, USA
| | - Kenneth Croitoru
- Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alberto Martin
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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4
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Chen Y, Fang JY. The role of colonic microbiota amino acid metabolism in gut health regulation. CELL INSIGHT 2025; 4:100227. [PMID: 39926315 PMCID: PMC11803165 DOI: 10.1016/j.cellin.2025.100227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/05/2025] [Accepted: 01/05/2025] [Indexed: 02/11/2025]
Abstract
The human gut microbiota plays a critical role in maintaining host homeostasis through metabolic activities. Among these, amino acid (AA) metabolism by the microbiota in the large intestine is highly heterogeneous and relevant to host health. Despite increasing interest, microbial AA metabolism remains relatively unexplored. This review highlights recent advances in colonic microbial AA metabolism, including auxotrophies, AA synthesis, and dissimilatory AA metabolites, and their implications in gut health, focusing on major gastrointestinal diseases including colorectal cancer, inflammatory bowel disease, and irritable bowel syndrome.
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Affiliation(s)
- Youli Chen
- State Key Laboratory of Systems Medicine for Cancer, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Jing-Yuan Fang
- State Key Laboratory of Systems Medicine for Cancer, NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
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5
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Fumarola S, Cianfruglia L, Cecati M, Giammarchi C, Vaiasicca S, Gasparrini M. Polyphenol Intake in Elderly Patients: A Novel Approach to Counteract Colorectal Cancer Risk? Int J Mol Sci 2025; 26:2497. [PMID: 40141143 PMCID: PMC11942013 DOI: 10.3390/ijms26062497] [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: 02/07/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Colorectal cancer (CRC) accounts for approximately 10% of all cancers worldwide with an incidence of approximately 60% in patients older than 70 years. In the elderly, the definition of a better therapeutic strategy depends on several factors including the patient's frailty and comorbidity status, life expectancy, and chemotherapy tolerance. In older patients, adverse drug reactions require a reduction in the dose of treatment, resulting in worse oncologic outcomes. In recent years, an increasing number of studies have focused on the potential effects of polyphenols on human health and their use in cancer therapy. In this comprehensive review, we searched the major databases and summarized experimental data of the most important polyphenols in the CRC chemoprevention, with a focus on the molecular mechanisms involved and the antitumor effects in the elderly population. In vitro and in vivo studies have shown that polyphenols exert chemopreventive activity by modulating cell signaling, resulting in the inhibition of cancer development or progression. However, the efficacy seen in experimental studies has not been confirmed in clinical trials, mainly due to their low bioavailability and non-toxic doses. Further research is needed to increase polyphenol bioavailability and reduce side effects in order to suggest their possible use to increase the efficacy of chemotherapeutic treatment.
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Affiliation(s)
- Stefania Fumarola
- Advanced Technology Center for Aging Research, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale di Ricovero e Cura per Anziani (IRCCS-INRCA), 60121 Ancona, Italy; (S.F.); (L.C.)
| | - Laura Cianfruglia
- Advanced Technology Center for Aging Research, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale di Ricovero e Cura per Anziani (IRCCS-INRCA), 60121 Ancona, Italy; (S.F.); (L.C.)
| | - Monia Cecati
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Cinzia Giammarchi
- Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale di Ricovero e Cura per Anziani (IRCCS-INRCA), 60121 Ancona, Italy;
| | - Salvatore Vaiasicca
- Center for Neurobiology of Aging, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale di Ricovero e Cura per Anziani (IRCCS-INRCA), 60121 Ancona, Italy
| | - Massimiliano Gasparrini
- Department of Agriculture, Food and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
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6
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Liu R, Tang L, Liu Y, Hu H, Liu J. Causal relationship between immune cell signatures and colorectal cancer: a bi-directional, two-sample mendelian randomization study. BMC Cancer 2025; 25:387. [PMID: 40033246 PMCID: PMC11877943 DOI: 10.1186/s12885-025-13576-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 01/21/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Prior studies have demonstrated the association between immune cells and colorectal cancer (CRC). However, the causal link to specific immunophenotypes is limited. This study intends to elucidate the causal relationship of immune cell signatures on CRC. METHODS We performed a bi-directional and two-sample mendelian randomization (MR) study, utilizing GWAS summary data of 731 immune cell traits (n = 3,757) and CRC statistics (n = 470,002). The primary MR methodology was inverse-variance weighted (IVW) method. Furthermore, heterogeneity was evaluated by Cochran's Q test. MR-PRESSO and MR-Egger were employed to assess horizontal and vertical pleiotropy respectively. Sensitivity analysis and FDR correction were conducted in our results. These results were validated in both the UK Biobank and FinnGen cohorts. We also extracted transcriptomic data of CRC and adjacent non-tumor tissues from TCGA, and used CIBERSORT to compare the infiltration patterns of 22 immune cell panels between normal tissues and the tumor microenvironment (TME). RESULTS Our study indicated nine immune cell signatures had significant causality with the risk of CRC after sensitivity analysis and FDR correction. The positive results covered four panels: B cell, CD8 + T cell, Treg, and monocyte. IgD- CD38br and IgD + CD38br B cell, CD8dim and CD28 + CD45RA- CD8dim T cell, and CD14 on CD14 + CD16- monocyte were the protective factors of CRC. However, CD39 + resting Treg, CX3CR1 on CD14- CD16 + monocyte, FSC-A on HLA DR + T cell, and BAFF-R on B cell increased the risk of CRC. The results were validated in the UK Biobank data and FinnGen cohorts. The data from the TCGA database also confirmed the infiltration of B cell, CD8 + T cell, Treg, and monocyte panels in the TME. CONCLUSION This study highlights the causal link between specific immune cell phenotypes and CRC, providing valuable insights into the immune microenvironment's role in CRC. The validation of our findings using large-scale datasets (UK Biobank, FinnGen) and TCGA underscores the robustness of our results, offering new potential therapeutic targets for CRC treatment.
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Affiliation(s)
- Ruizhi Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liansha Tang
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, Sichuan Province, 610041, China
| | - Yunjia Liu
- Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Handan Hu
- Queen Mary College, Nanchang University, Nanchang, Jiangxi, China
| | - Jiyan Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, Sichuan Province, 610041, China.
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7
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Sánchez-Olivares P, Silva-Nolasco AM, de la Cruz-Morcillo MA, García-Martínez MM, Pinedo-Serrano A, Carmona M, Galán-Moya EM. Synergistic Potential of Argentatins A and B to Improve 5-Fluorouracil Cytotoxicity in Colorectal Cancer Cell Models. J Cell Mol Med 2024; 28:e70294. [PMID: 39707666 DOI: 10.1111/jcmm.70294] [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: 07/31/2024] [Revised: 11/25/2024] [Accepted: 12/04/2024] [Indexed: 12/23/2024] Open
Abstract
Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second most common cause of cancer-related death in both men and women. Although a number of treatments are available to combat this malignancy, the antimetabolite 5-fluorouracil has been the cornerstone of therapy since its synthesis in the 1950s. Unfortunately, the prolonged use of 5-fluorouracil can lead to chemoresistance, which has prompted research into combination regimens to improve efficacy and quality of life and reduce resistance. Here, we evaluated the synergistic potential of two compounds isolated from guayule, and argentatins A and B, alone and in combination with 5-fluorouracil in a panel of colorectal cancer cell lines. Cell viability assays showed that the combination treatment (argentatin A with 5 fluorouracil) significantly enhanced cytotoxicity, especially in RKO, where the analysis using the Bliss independence model indicated a remarkable synergistic effect with the lowest doses of both compounds. In contrast to the combination with argentatin B, in which the additive effect was only found in the HCT-116 cell line. Finally, immunocytometric analysis revealed that combination treatments induced higher rates of apoptosis than single-agent treatments. Collectively, our findings indicate that argentatins A and B may enhance the anti-tumour effects of 5-fluorouracil and may represent a promising strategy to improve the efficacy of anticancer therapies based on this antimetabolite.
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Affiliation(s)
- Paula Sánchez-Olivares
- Cancer Pathophysiology and Therapy Lab, Institute of Biomedicine (IB-UCLM) Universidad de Castilla-La Mancha, Albacete, Spain
| | - Aniela M Silva-Nolasco
- Institute for Regional Development (IDR), Universidad de Castilla-La Mancha, Albacete, Spain
| | | | - María Mercedes García-Martínez
- Universidad de Castilla-La Mancha, E.T.S.I. Agronómica, de Montes y Biotecnología (ETSIAMB), Albacete, Spain
- Instituto Técnico Agronómico Provincial de Albacete, ITAP, Albacete, Spain
| | - Alejandro Pinedo-Serrano
- Cancer Pathophysiology and Therapy Lab, Institute of Biomedicine (IB-UCLM) Universidad de Castilla-La Mancha, Albacete, Spain
| | - Manuel Carmona
- Institute for Regional Development (IDR), Universidad de Castilla-La Mancha, Albacete, Spain
| | - Eva M Galán-Moya
- Cancer Pathophysiology and Therapy Lab, Institute of Biomedicine (IB-UCLM) Universidad de Castilla-La Mancha, Albacete, Spain
- Facultad de Enfermería, Universidad de Castilla-La Mancha, Albacete, Spain
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8
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Rico-Méndez MA, Ayala-Madrigal MDLL, González-Mercado A, Gutiérrez-Angulo M, Ramírez de Arellano Sánchez JA, Beltrán-Ontiveros SA, Contreras-Haro B, Gutiérrez-Hurtado IA, Moreno-Ortiz JM. Microsatellite Instability in Urine: Breakthrough Method for Bladder Cancer Identification. Biomedicines 2024; 12:2726. [PMID: 39767633 PMCID: PMC11727160 DOI: 10.3390/biomedicines12122726] [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: 11/07/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025] Open
Abstract
Bladder cancer (BC) is the most common neoplasm of the urinary system and ranks tenth in global cancer incidence. Due to its high recurrence rate and the need for continuous monitoring, it is the cancer with the highest cost per patient. Cystoscopy is the traditional method for its detection and surveillance; however, this is an invasive technique, while non-invasive methods, such as cytology, have a limited sensitivity. For this reason, new non-invasive strategies have emerged, analyzing useful markers for BC detection from urine samples. The identification of tumor markers is essential for early cancer detection and treatment. Urine analysis offers a non-invasive method to identify these markers. Microsatellite instability (MSI) has been proposed as a promising marker for tumor cell detection and guided targeted therapies. Therefore, this review aims to explore the evidence supporting the identification of MSI in exfoliated bladder tumor cells (EBTCs) in the urine, emphasizing its potential as a non-invasive and clinically effective alternative for tumor identification. Furthermore, establishing clinical guidelines is crucial for standardizing its application in oncological screening and validating its clinical utility.
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Affiliation(s)
- Manuel Alejandro Rico-Méndez
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
| | - María de la Luz Ayala-Madrigal
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
| | - Anahí González-Mercado
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
| | - Melva Gutiérrez-Angulo
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos 47600, Jalisco, Mexico;
| | - Jorge Adrián Ramírez de Arellano Sánchez
- Instituto de Investigación en Ciencias Biomédicas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico;
| | - Saul Armando Beltrán-Ontiveros
- Centrode Investigación y Docencia en Ciencias de la Salud, Universidad Autónoma de Sinaloa, Culiacán Rosales 80030, Sinaloa, Mexico;
| | - Betsabe Contreras-Haro
- Unidad de Investigación Biomédica 02, Unidades Médicas de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44329, Jalisco, Mexico;
| | - Itzae Adonai Gutiérrez-Hurtado
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Miguel Moreno-Ortiz
- Doctorado en Genética Humana, Instituto de Genética Humana “Dr. Enrique Corona Rivera”, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (M.A.R.-M.); (M.d.l.L.A.-M.); (A.G.-M.)
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9
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Kamal R, Awasthi A, Paul P, Mir MS, Singh SK, Dua K. Novel drug delivery systems in colorectal cancer: Advances and future prospects. Pathol Res Pract 2024; 262:155546. [PMID: 39191194 DOI: 10.1016/j.prp.2024.155546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 08/10/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
Colorectal cancer (CRC) is an abnormal proliferation of cells within the colon and rectum, leading to the formation of polyps and disruption of mucosal functions. The disease development is influenced by a combination of factors, including inflammation, exposure to environmental mutagens, genetic alterations, and impairment in signaling pathways. Traditional treatments such as surgery, radiation, and chemotherapy are often used but have limitations, including poor solubility and permeability, treatment resistance, side effects, and post-surgery issues. Novel Drug Delivery Systems (NDDS) have emerged as a superior alternative, offering enhanced drug solubility, precision in targeting cancer cells, and regulated drug release. Thereby addressing the shortcomings of conventional therapies and showing promise for more effective CRC management. The present review sheds light on the pathogenesis, signaling pathways, biomarkers, conventional treatments, need for NDDS, and application of NDDS against CRC. Additionally, clinical trials, ongoing clinical trials, marketed formulations, and patents on CRC are also covered in the present review.
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Affiliation(s)
- Raj Kamal
- Department of Quality Assurance, ISF College of Pharmacy, Moga, Punjab 142001, India; School of Pharmacy, Desh Bhagat University, Mandi Gobindgarh, Punjab 147301, India
| | - Ankit Awasthi
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab 142001, India; Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
| | - Priyanka Paul
- Department of Pharmaceutical Science, PCTE Group of Institute, Ludhiana, Punjab, India
| | - Mohammad Shabab Mir
- School of Pharmacy, Desh Bhagat University, Mandi Gobindgarh, Punjab 147301, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
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10
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Gu X, Wei S, Lv X. Circulating tumor cells: from new biological insights to clinical practice. Signal Transduct Target Ther 2024; 9:226. [PMID: 39218931 PMCID: PMC11366768 DOI: 10.1038/s41392-024-01938-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/31/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.
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Affiliation(s)
- Xuyu Gu
- Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiyou Wei
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
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11
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Bora A, Pal R, Mandi CS, Dutta S. DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and deficient cancer. NAR Cancer 2024; 6:zcae034. [PMID: 39055333 PMCID: PMC11270466 DOI: 10.1093/narcan/zcae034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 07/27/2024] Open
Abstract
Temozolomide (TMZ) is widely used in cancer treatment, yet resistance to this agent limits its therapeutic effectiveness, particularly in mismatch-repair (MMR) deficient cancer. Concurrently, the Base Excision Repair (BER) pathway exerts a mitigating role. Our results demonstrated that the increasing TMZ concentrations correlate with an elevated accumulation of DNA abasic sites via the BER pathway in both MMR-proficient and deficient cancer cells, implicating abasic sites as promising targets to enhance the TMZ response. Amino-quinoxaline small molecules (RA-1) have been developed, whose hydrophobic core facilitates selective binding to apurinic/apyrimidinic (AP) sites, particularly adenine as the complementary nucleobase opposite to the AP-sites via base stacking. RA-1 effectively cleaves TMZ-induced DNA abasic sites in-vitro at minimal concentrations through Schiff-base formation. Remarkably, the combination of TMZ and RA-1 exerts a notable synergistic effect on both types of cells. The underlying mechanism of this synergy is rooted in the cleavage of TMZ-induced DNA abasic sites, which impairs the BER pathway, leading to the formation of DNA double-strand breaks. Consequently, the ATM-Chk2/ATR-Chk1 signalling pathways are activated, prompting S-phase arrest and ultimately driving apoptosis. These findings provide a compelling rationale for targeting DNA abasic sites to synergistically augment TMZ responses in both MMR-proficient and deficient cancer cells.
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Affiliation(s)
- Achyut Bora
- Nucleic Acids Research Laboratory, Organic and Medicinal Chemistry Division, CSIR- Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ritesh Pal
- Nucleic Acids Research Laboratory, Organic and Medicinal Chemistry Division, CSIR- Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Chandra Sova Mandi
- Nucleic Acids Research Laboratory, Organic and Medicinal Chemistry Division, CSIR- Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India
| | - Sanjay Dutta
- Nucleic Acids Research Laboratory, Organic and Medicinal Chemistry Division, CSIR- Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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12
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Papavassiliou KA, Adamopoulos C, Papavassiliou AG. SOX17: escape route from immune destruction in early CRC. Trends Mol Med 2024; 30:609-611. [PMID: 38594095 DOI: 10.1016/j.molmed.2024.04.001] [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: 03/20/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
In a recent report in Nature, Goto et al. reveal a novel immune-evasion mechanism adopted by early colorectal cancer (CRC) cells that is based on the transcription factor sex determining region Y (SRY)-box transcription factor 17 (SOX17). Leveraging colorectal adenoma and cancer models to perform comprehensive transcriptomic/chromatin analyses, this work shows that SOX17 generates immune-silent leucine-rich repeat-containing G protein-coupled receptor 5- (LGR5-) tumor cells, which suppress interferon gamma (IFNγ) signaling and promote immune escape.
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Affiliation(s)
- Kostas A Papavassiliou
- First University Department of Respiratory Medicine, 'Sotiria' Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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13
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Zhao M, Shuai W, Su Z, Xu P, Wang A, Sun Q, Wang G. Protein tyrosine phosphatases: emerging role in cancer therapy resistance. Cancer Commun (Lond) 2024; 44:637-653. [PMID: 38741380 PMCID: PMC11194456 DOI: 10.1002/cac2.12548] [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: 10/31/2023] [Revised: 04/14/2024] [Accepted: 04/23/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Tyrosine phosphorylation of intracellular proteins is a post-translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross-talk between signaling pathways. In the context of cancer, PTP-mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth-stimulatory signaling pathways or modulation of the immune-suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy. AREAS COVERED This review aimed to elaborate recent insights that supported the involvement of PTP-mediated pathways in the development of resistance to targeted therapy and immune-checkpoint therapy. EXPERT OPINION This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long-term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced-stage tumors.
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Affiliation(s)
- Min Zhao
- Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, West China School of Nursing, Sichuan UniversityChengduSichuanP. R. China
| | - Wen Shuai
- Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, West China School of Nursing, Sichuan UniversityChengduSichuanP. R. China
| | - Zehao Su
- Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, West China School of Nursing, Sichuan UniversityChengduSichuanP. R. China
- West China Biomedical Big Data CenterMed‐X Center for InformaticsSichuan UniversityChengduSichuanP. R. China
| | - Ping Xu
- Emergency DepartmentZigong Fourth People's HospitalChengduSichuanP. R. China
| | - Aoxue Wang
- Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, West China School of Nursing, Sichuan UniversityChengduSichuanP. R. China
| | - Qiu Sun
- Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, West China School of Nursing, Sichuan UniversityChengduSichuanP. R. China
| | - Guan Wang
- Innovation Center of Nursing ResearchNursing Key Laboratory of Sichuan ProvinceDepartment of BiotherapyCancer Center and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, West China School of Nursing, Sichuan UniversityChengduSichuanP. R. China
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14
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Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
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Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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15
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Turrini E, Ulfo L, Costantini PE, Saporetti R, Di Giosia M, Nigro M, Petrosino A, Pappagallo L, Kaltenbrunner A, Cantelli A, Pellicioni V, Catanzaro E, Fimognari C, Calvaresi M, Danielli A. Molecular engineering of a spheroid-penetrating phage nanovector for photodynamic treatment of colon cancer cells. Cell Mol Life Sci 2024; 81:144. [PMID: 38494579 PMCID: PMC10944812 DOI: 10.1007/s00018-024-05174-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 01/17/2024] [Accepted: 01/30/2024] [Indexed: 03/19/2024]
Abstract
Photodynamic therapy (PDT) represents an emerging strategy to treat various malignancies, including colorectal cancer (CC), the third most common cancer type. This work presents an engineered M13 phage retargeted towards CC cells through pentavalent display of a disulfide-constrained peptide nonamer. The M13CC nanovector was conjugated with the photosensitizer Rose Bengal (RB), and the photodynamic anticancer effects of the resulting M13CC-RB bioconjugate were investigated on CC cells. We show that upon irradiation M13CC-RB is able to impair CC cell viability, and that this effect depends on i) photosensitizer concentration and ii) targeting efficiency towards CC cell lines, proving the specificity of the vector compared to unmodified M13 phage. We also demonstrate that M13CC-RB enhances generation and intracellular accumulation of reactive oxygen species (ROS) triggering CC cell death. To further investigate the anticancer potential of M13CC-RB, we performed PDT experiments on 3D CC spheroids, proving, for the first time, the ability of engineered M13 phage conjugates to deeply penetrate multicellular spheroids. Moreover, significant photodynamic effects, including spheroid disruption and cytotoxicity, were readily triggered at picomolar concentrations of the phage vector. Taken together, our results promote engineered M13 phages as promising nanovector platform for targeted photosensitization, paving the way to novel adjuvant approaches to fight CC malignancies.
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Affiliation(s)
- Eleonora Turrini
- Dipartimento di Scienze per la Qualità della Vita (QUVI), Alma Mater Studiorum, Università Di Bologna, C.So D'Augusto, 237, 47921, Rimini, Italy
| | - Luca Ulfo
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy
| | - Paolo Emidio Costantini
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy
| | - Roberto Saporetti
- Dipartimento di Chimica "Giacomo Ciamician", Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 2, 40126, Bologna, Italy
| | - Matteo Di Giosia
- Dipartimento di Chimica "Giacomo Ciamician", Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 2, 40126, Bologna, Italy
| | - Michela Nigro
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy
| | - Annapaola Petrosino
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy
| | - Lucia Pappagallo
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy
| | - Alena Kaltenbrunner
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy
| | - Andrea Cantelli
- Dipartimento di Chimica "Giacomo Ciamician", Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 2, 40126, Bologna, Italy
- CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" Unit of Bologna, Bologna, Italy
| | - Valentina Pellicioni
- Dipartimento di Scienze per la Qualità della Vita (QUVI), Alma Mater Studiorum, Università Di Bologna, C.So D'Augusto, 237, 47921, Rimini, Italy
| | - Elena Catanzaro
- Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Corneel Heymanslaan 10, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Carmela Fimognari
- Dipartimento di Scienze per la Qualità della Vita (QUVI), Alma Mater Studiorum, Università Di Bologna, C.So D'Augusto, 237, 47921, Rimini, Italy
| | - Matteo Calvaresi
- Dipartimento di Chimica "Giacomo Ciamician", Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 2, 40126, Bologna, Italy.
- Interdepartmental Center for Industrial Research (CIRI-SDV), Health Sciences and Technologies, University of Bologna, Bologna, Italy.
| | - Alberto Danielli
- Dipartimento di Farmacia e Biotecnologie (FaBiT), Alma Mater Studiorum, Università Di Bologna, Via Francesco Selmi 3, 40126, Bologna, Italy.
- Interdepartmental Center for Industrial Research (CIRI-SDV), Health Sciences and Technologies, University of Bologna, Bologna, Italy.
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16
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Clerick J, Van Oosterwyck A, Carton S. Transforming the landscape of colorectal cancer treatment with immunotherapy: Evolution and future horizons. Cancer Treat Res Commun 2024; 39:100807. [PMID: 38461691 DOI: 10.1016/j.ctarc.2024.100807] [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: 07/08/2023] [Revised: 09/18/2023] [Accepted: 03/04/2024] [Indexed: 03/12/2024]
Abstract
Colorectal cancer (CRC) continues to be one of the most prevalent and lethal cancers worldwide. Over the past decades, immune checkpoint inhibitors (ICIs) have shown to significantly improve patient outcomes in mismatch repair-deficient metastasized CRC. However, widening the scope of this novel treatment modality has been the object of growing interest. This article will review several landmark trials, while exploring various aspects of this rapidly evolving field, including potential neoadjuvant (or even entirely nonsurgical) and adjuvant indications in localized disease. We will also discuss differences between management of rectal and colon cancer, current and expected challenges (eg. resistance, toxicities, pseudoprogression, biomarkers) and other future opportunities including combinations with other therapeutic agents and the role of ICIs in the treatment of both deficient as well as proficient mismatch repair (dMMR and pMMR respectively) CRC.
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Affiliation(s)
- Jan Clerick
- Department of Gastroenterology and Digestive Oncology, Imeldaziekenhuis, Bonheiden, Belgium
| | - Aude Van Oosterwyck
- Department of Gastroenterology and Digestive Oncology, Imeldaziekenhuis, Bonheiden, Belgium.
| | - Saskia Carton
- Department of Gastroenterology and Digestive Oncology, Imeldaziekenhuis, Bonheiden, Belgium
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17
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Falco EC, Ribaldone DG, Canavese G. Hyper Mucinous Proliferations in the Mucosa of Patients with Inflammatory Bowel Disease: Histological Lesions with a Real Potential for Neoplastic Evolution? Diagnostics (Basel) 2024; 14:499. [PMID: 38472971 DOI: 10.3390/diagnostics14050499] [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: 01/20/2024] [Revised: 02/15/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND AIMS Mucin disfunction is a critical event in the pathogenesis of inflammatory bowel disease (IBD). Although hyper mucinous conditions have a still debated implication in the clinical evolution of this disorder, hyper mucinous villous proliferations were found to have a preneoplastic biologic potential. We studied morphologic and immunophenotypic characteristics of these lesions in ileocolonic resections for IBD to add evidence about the evolutive potential of these lesions in samples with well oriented wall structures. METHODS Morphologic characteristics of bowel samples from 20 patients resected for IBD and with raised lesions at gross examination were studied and sections from cases with hyper mucinous lesions were stained with the following antibodies: Ki 67, p21, and p27, which were employed to evaluate the characteristics of the proliferative and differentiative activity of the epithelial structures; mismatch repair proteins and p53 have been studied as proteins implicated in carcinogenesis in IBD-affected mucosa; mucins subtypes in hyper mucinous structures were evaluated with MUC-2 and MUC-6. The results in 11 cases of saplings were that they harbored hyper mucinous proliferations. The occurrence of hyper mucinous structures was not related to dysplastic lesions, pseudo pyloric metaplasia, subtype of disease, or activity. In only one of our cases, mild cytologic atypia in the proliferative compartment was detected. Proliferation markers (Ki 67, p53) were expressed in the proliferative compartments of mucosal crypts and antiproliferative proteins p21 and p27 were expressed in differentiated epithelium. MMR proteins expression was limited to the proliferative compartment of the hyper mucinous projections. Mucin subtypes distribution was regular in the epithelium of hyper mucinous proliferations. CONCLUSIONS The present monocentric retrospective study was conducted on surgical samplings with well oriented crypts. Collected data show that hyper mucinous features are frequent occurrences in raised lesions in IBD patients. In hyper mucinous proliferations of the selected cases, the status of the proliferative cycle, the expression of the proteins most frequently involved in carcinogenetic pathways of mucosa affected by IBD, and the mucins subtypes expression have no evident anomalies. Findings are not consistent with the increased risk of neoplastic evolution observed in other studies; rather, they suggest a hyperplastic nature. However, the capacity of hyper mucinous raised lesions for neoplastic evolution should be ruled out with more extensive prospective studies to identify functional defects that could explain the hypothesized neoplastic potential.
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Affiliation(s)
| | | | - Gabriella Canavese
- Department of Pathology, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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18
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Gu M, Ren B, Fang Y, Ren J, Liu X, Wang X, Zhou F, Xiao R, Luo X, You L, Zhao Y. Epigenetic regulation in cancer. MedComm (Beijing) 2024; 5:e495. [PMID: 38374872 PMCID: PMC10876210 DOI: 10.1002/mco2.495] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/21/2024] Open
Abstract
Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.
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Affiliation(s)
- Minzhi Gu
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Bo Ren
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Yuan Fang
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Jie Ren
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Xiaohong Liu
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Xing Wang
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Feihan Zhou
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Ruiling Xiao
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Xiyuan Luo
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Lei You
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
| | - Yupei Zhao
- Department of General SurgeryPeking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingP. R. China
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingP. R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College HospitalBeijingP. R. China
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19
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Wang X, Chan S, Chen J, Xu Y, Dai L, Han Q, Wang Z, Zuo X, Yang Y, Zhao H, Wang M, Wang C, Li Z, Zhang H, Chen W. Robust machine-learning based prognostic index using cytotoxic T lymphocyte evasion genes highlights potential therapeutic targets in colorectal cancer. Cancer Cell Int 2024; 24:52. [PMID: 38297270 PMCID: PMC10829178 DOI: 10.1186/s12935-024-03239-y] [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: 12/04/2023] [Accepted: 01/24/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND A minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC). METHODS 101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross-validation framework, and patients with CRC were separated into high- and low-CERPI groups. Relationship between immune cell infiltration levels, immune-related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in-vitro verified. RESULTS The CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low-CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single-cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration. CONCLUSION We developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment.
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Affiliation(s)
- Xu Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Shixin Chan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jiajie Chen
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yuanmin Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Longfei Dai
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Qijun Han
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Zhenglin Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xiaomin Zuo
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yang Yang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Hu Zhao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Ming Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Chen Wang
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Zichen Li
- Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China
| | - Huabing Zhang
- Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui, China.
- The First Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, 239000, Anhui, China.
| | - Wei Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China.
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Shu Y, Zheng S. The current status and prospect of immunotherapy in colorectal cancer. Clin Transl Oncol 2024; 26:39-51. [PMID: 37301804 DOI: 10.1007/s12094-023-03235-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023]
Abstract
Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers.
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Affiliation(s)
- Yefei Shu
- Department of Medical Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Song Zheng
- Department of Medical Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Medical Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- The Fourth Clinical School of Zhejiang Chinese Medical University, Hangzhou, China.
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21
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Li W, Zou C. NXNL2 Promotes Colon Cancer Proliferation and Metastasis by Regulating AKT Pathway. Appl Biochem Biotechnol 2023; 195:7685-7696. [PMID: 37084033 DOI: 10.1007/s12010-023-04513-x] [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] [Accepted: 04/11/2023] [Indexed: 04/22/2023]
Abstract
This study aimed to explore the role of nucleoredoxin-like 2 (NXNL2) in colon cancer (CC). The GEPIA and UALCAN databases were analyzed to explore genes involved in the prognosis of CC patients. DLD1 cells were treated with the DNA methylation inhibitor 5-azacitidine to validate the above findings. The methyltransferase DNMT (DNA methylation) was further knocked down by shRNA, then the expression of NXNL2 was assessed by qPCR. The role of NXNL2 on cell proliferation and metastasis was examined using corresponding assays. NXNL2 was found to exhibit the greatest impact on the prognosis of CC patients. High NXNL2 correlated with poor survival outcomes of CC. The expression of NXNL2 was regulated by DNA methylation. NXNL2 promoted CC cell proliferation and metastasis. Also, NXNL2 promoted the AKT pathway activity. In conclusion, NXNL2 could affect the cancer cell proliferation and metastasis, and has a poor survival prognosis in CC.
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Affiliation(s)
- Wenqin Li
- Department of Gastroenterology, the Second Clinical Medical college, Yangtze University, No. 60 Jingzhong Road, Jingzhou, 434020, Hubei, China
| | - Chuanxin Zou
- Department of Gastroenterology, the Second Clinical Medical college, Yangtze University, No. 60 Jingzhong Road, Jingzhou, 434020, Hubei, China.
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22
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Huang H, Lu L, Li Y, Chen X, Li M, Yang M, Huang X. Development of a 5-mRNAsi-related gene signature to predict the prognosis of colon adenocarcinoma. PeerJ 2023; 11:e16477. [PMID: 38025763 PMCID: PMC10680455 DOI: 10.7717/peerj.16477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Aim To create a prognosis model based on mRNA-based stem index (mRNAsi) for evaluating the prognostic outcomes of colon adenocarcinoma (COAD). Background Generation of heterogeneous COAD cells could be promoted by the self-renewal and differentiation potential of cancer stem cells (CSCs). Biomarkers contributing to the development of COAD stem cells remained to be discovered. Objective To develop and validate an mRNAsi-based risk model for estimating the prognostic outcomes of patients suffering from COAD. Methods Samples were collected from Rectal Adenocarcinoma (TCGA-READ) PanCancer Atlas datasets, The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD), and the GSE87211 dataset. MRNAsi was calculated by one-class logistic regression (OCLR) algorithm. Under the criterion of correlation greater than 0.4, genes related to mRNAsi were screened and clustered. Meanwhile, differentially expressed genes (DEGs) between molecular subtypes were identified to establish a risk model. According to the median risk score value for immunotherapy and results from immune cell infiltration and clinicopathological analyses, clusters and patients were divided into high-RiskScore and low-RiskScore groups. Cell apoptosis and viability were detected by flow cytometer and Cell Counting Kit-8 (CCK-8) assay, respectively. Results A negative correlation between mRNAsi and clinical stages was observed. Three clusters of patients (C1, C2, and C3) were defined based on a total of 165 survival-related mRNAsi genes. Specifically, C1 patients had greater immune cell infiltration and a poorer prognosis. A 5-mRNAsi-gene signature (HEYL, FSTL3, FABP4, ADAM8, and EBF4) served as a prediction index for COAD prognosis. High-RiskScore patients had a poorer prognosis and higher level of immune cell infiltration. In addition, the five genes in the signature all showed a high expression in COAD cells. Knocking down HEYL promoted COAD cell apoptosis and inhibited viability. Conclusion Our mRNAsi risk model could better predict the prognosis of COAD patients.
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Affiliation(s)
- Haifu Huang
- Department of Hematology and Oncology, Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Lin Lu
- Department of Hematology and Oncology, Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Yaoxuan Li
- Department of Hematology and Oncology, Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Xiumei Chen
- Department of Hematology and Oncology, Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Meng Li
- Department of Hematology and Oncology, Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Meiling Yang
- Department of Hematology and Oncology, Shenzhen Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, China
| | - Xuewu Huang
- Tumor Center, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
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Cherkasova V, Ilnytskyy Y, Kovalchuk O, Kovalchuk I. Transcriptome Analysis of Cisplatin, Cannabidiol, and Intermittent Serum Starvation Alone and in Various Combinations on Colorectal Cancer Cells. Int J Mol Sci 2023; 24:14743. [PMID: 37834191 PMCID: PMC10572413 DOI: 10.3390/ijms241914743] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Platinum-derived chemotherapy medications are often combined with other conventional therapies for treating different tumors, including colorectal cancer. However, the development of drug resistance and multiple adverse effects remain common in clinical settings. Thus, there is a necessity to find novel treatments and drug combinations that could effectively target colorectal cancer cells and lower the probability of disease relapse. To find potential synergistic interaction, we designed multiple different combinations between cisplatin, cannabidiol, and intermittent serum starvation on colorectal cancer cell lines. Based on the cell viability assay, we found that combinations between cannabidiol and intermittent serum starvation, cisplatin and intermittent serum starvation, as well as cisplatin, cannabidiol, and intermittent serum starvation can work in a synergistic fashion on different colorectal cancer cell lines. Furthermore, we analyzed differentially expressed genes and affected pathways in colorectal cancer cell lines to understand further the potential molecular mechanisms behind the treatments and their interactions. We found that synergistic interaction between cannabidiol and intermittent serum starvation can be related to changes in the transcription of genes responsible for cell metabolism and cancer's stress pathways. Moreover, when we added cisplatin to the treatments, there was a strong enrichment of genes taking part in G2/M cell cycle arrest and apoptosis.
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Affiliation(s)
| | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (V.C.); (Y.I.)
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24
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Vuković Đerfi K, Salar A, Cacev T, Kapitanović S. EMAST Type of Microsatellite Instability-A Distinct Entity or Blurred Overlap between Stable and MSI Tumors. Genes (Basel) 2023; 14:1474. [PMID: 37510378 PMCID: PMC10380056 DOI: 10.3390/genes14071474] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch repair (dMMR). MSI has been associated with distinct clinical, histological, and molecular features of tumors and has proven its prognostic and therapeutic value in different types of cancer. Recently, another type of microsatellite instability named elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported across many different tumors. EMAST tumors have been associated with chronic inflammation, higher tumor stage, and poor prognosis. Nevertheless, the clinical significance of EMAST and its relation to MSI remains unclear. It has been proposed that EMAST arises as a result of isolated MSH3 dysfunction or as a secondary event in MSI tumors. Even though previous studies have associated EMAST with MSI-low phenotype in tumors, recent studies show a certain degree of overlap between EMAST and MSI-high tumors. However, even in stable tumors, (MSS) frameshifts in microsatellites can be detected as a purely stochastic event, raising the question of whether EMAST truly represents a distinct type of microsatellite instability. Moreover, a significant fraction of patients with MSI tumors do not respond to immunotherapy and it can be speculated that in these tumors, EMAST might act as a modifying factor.
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Affiliation(s)
- Kristina Vuković Đerfi
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
| | - Anamarija Salar
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
| | - Tamara Cacev
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
| | - Sanja Kapitanović
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
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Han X, Yan T, Wang L, He B, Yu H. Knockdown of PTEN promotes colon cancer progression and induces M2 macrophage polarization in the colon cancer cell environment. INDIAN J PATHOL MICR 2023; 66:478-487. [PMID: 37530327 DOI: 10.4103/ijpm.ijpm_786_21] [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: 01/15/2023] Open
Abstract
Objective This article aims to study the effect of phosphate and tension homolog deleted on chromosome ten (PTEN) knockdown on colon cancer progression and macrophage polarization in the cancer environment. Materials and Methods and Results The expression of PTEN in colon cancer tissues and colon cancer cells was significantly lower than in precancerous tissues or CCD-18Co cells, and the decrease was most evident in SW620 cells. The expressions of phosphate (p)-p38, c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), B-cell lymphoma-2 (Bcl-2) protein in colon cancer tissues and cells were significantly higher than in precancerous tissues or CCD-18Co cells (P-values < 0.05). Bcl-2-associated X (Bax) and Caspase-3 expressions in colon cancer tissues and cells were significantly lower than in precancerous tissues or CCD-18Co cells (P-values < 0.05). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was applied to measure cell viability. Transwell evaluated the cell migration and invasion ability. Si-PTEN improved the proliferation, migration, and invasion of SW620 cells (P-values < 0.05). The expression levels of arginase-1 (Arg-1), CD163, CD206 in colon cancer tissues were significantly higher than in precancerous tissues (P-values < 0.05). The cell cycle, the number of M1 and M2 double-positive cells were assessed by flow cytometry. Si-PTEN reduced the expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and inducible nitric oxide synthase (iNOS), which upregulated the expression of Arg-1, CD206, CD163, p-p38, JNK, and AP-1 (P-values < 0.05). Conclusion Si-PTEN promoted colon cancer progression and induced the polarization of M2 tumor-associated macrophages in the colon cancer cell environment.
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Affiliation(s)
- Xu Han
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
| | - Ting Yan
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
| | - Lina Wang
- Department of General Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou City, Henan Province, China
| | - Bin He
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
| | - Huaxu Yu
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
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Nguyen DD, Kim E, Le NT, Ding X, Jaiswal RK, Kostlan RJ, Nguyen TNT, Shiva O, Le MT, Chai W. Deficiency in mammalian STN1 promotes colon cancer development via inhibiting DNA repair. SCIENCE ADVANCES 2023; 9:eadd8023. [PMID: 37163605 PMCID: PMC10171824 DOI: 10.1126/sciadv.add8023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 04/05/2023] [Indexed: 05/12/2023]
Abstract
Despite the high lethality of colorectal cancers (CRCs), only a limited number of genetic risk factors are identified. The mammalian ssDNA-binding protein complex CTC1-STN1-TEN1 protects genome stability, yet its role in tumorigenesis is unknown. Here, we show that attenuated CTC1/STN1 expression is common in CRCs. We generated an inducible STN1 knockout mouse model and found that STN1 deficiency in young adult mice increased CRC incidence, tumor size, and tumor load. CRC tumors exhibited enhanced proliferation, reduced apoptosis, and elevated DNA damage and replication stress. We found that STN1 deficiency down-regulated multiple DNA glycosylases, resulting in defective base excision repair (BER) and accumulation of oxidative damage. Collectively, this study identifies STN1 deficiency as a risk factor for CRC and implicates the previously unknown STN1-BER axis in protecting colon tissues from oxidative damage, therefore providing insights into the CRC tumor-suppressing mechanism.
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Affiliation(s)
- Dinh Duc Nguyen
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Eugene Kim
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Nhat Thong Le
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam
| | - Xianzhong Ding
- Department of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Rishi Kumar Jaiswal
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Raymond Joseph Kostlan
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Thi Ngoc Thanh Nguyen
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Olga Shiva
- Office of Research, Washington State University-Spokane, Spokane, WA, USA
| | - Minh Thong Le
- School of Biotechnology, International University, Ho Chi Minh City, Vietnam
| | - Weihang Chai
- Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
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Ma Y, Zhou J, Ye Y, Wang X, Ma A, Li H. The cost-effectiveness analysis of serplulimab versus regorafenib for treating previously treated unresectable or metastatic microsatellite instability-high or deficient mismatch repair colorectal cancer in China. Front Oncol 2023; 13:1113346. [PMID: 37182176 PMCID: PMC10171919 DOI: 10.3389/fonc.2023.1113346] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/11/2023] [Indexed: 05/16/2023] Open
Abstract
Objective The aim of this study was to investigate the cost-effectiveness of serplulimab versus regorafenib in previously treated unresectable or metastatic microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) colorectal cancer in China. Methods From the perspective of China's health-care system, a Markov model with three health states (progression free, progression, death) was developed for estimating the costs and health outcomes of serplulimab and regorafenib. Data for unanchored matching-adjusted indirect comparison (MAIC), standard parametric survival analysis, the mixed cure model, and transition probabilities calculation were obtained from clinical trials (ASTRUM-010 and CONCUR). Health-care resource utilization and costs were derived from government-published data and expert interviews. Utilities used to calculate quality-adjusted life years (QALYs) were obtained from clinical trials and literature reviews. The primary outcome was the incremental cost-effectiveness ratio (ICER) expressed as cost/QALY gained. Four scenarios were considered in scenario analysis: (a) using original survival data without conducting MAIC; (b) limiting the time horizon to the follow-up time of the clinical trial of serplulimab; (c) adopting a fourfold increase in the risk of death; and (d) applying utilities from two other sources. One-way sensitivity analysis and probabilistic sensitivity analysis were also performed to assess the uncertainty of the results. Results In the base-case analysis, serplulimab provided 6.00 QALYs at a cost of $68,722, whereas regorafenib provided 0.69 QALYs at a cost of $40,106. Compared with that for treatment with regorafenib, the ICER for treatment with serplulimab was $5,386/QALY, which was significantly lower than the triple GDP per capita of China in 2021 ($30,036), which was the threshold used to define the cost-effectiveness. In the scenario analysis, the ICERs were $6,369/QALY, $20,613/QALY, $6,037/QALY, $4,783/QALY, and $6,167/QALY, respectively. In the probabilistic sensitivity analysis, the probability of serplulimab being cost-effective was 100% at the threshold of $30,036/QALY. Conclusion Compared with regorafenib, serplulimab is a cost-effective treatment for patients with previously treated unresectable or metastatic MSI-H/dMMR colorectal cancer in China.
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Affiliation(s)
- Yue Ma
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Jiting Zhou
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Yuxin Ye
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Xintian Wang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Aixia Ma
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Hongchao Li
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
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Li YJ, Liu XZ, Yao YF, Chen N, Li ZW, Zhang XY, Lin XF, Wu AW. Efficacy and safety of preoperative immunotherapy in patients with mismatch repair-deficient or microsatellite instability-high gastrointestinal malignancies. World J Gastrointest Surg 2023; 15:222-233. [PMID: 36896306 PMCID: PMC9988634 DOI: 10.4240/wjgs.v15.i2.222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/08/2023] [Accepted: 02/01/2023] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND Programmed death protein (PD)-1 blockade immunotherapy significantly prolongs survival in patients with metastatic mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal malignancies such gastric and colorectal cancer. However, the data on preoperative immunotherapy are limited. AIM To evaluate the short-term efficacy and toxicity of preoperative PD-1 blockade immunotherapy. METHODS In this retrospective study, we enrolled 36 patients with dMMR/MSI-H gastrointestinal malignancies. All the patients received PD-1 blockade with or without chemotherapy of CapOx regime preoperatively. PD1 blockade 200 mg was given intravenously over 30 min on day 1 of each 21-d cycle. RESULTS Three patients with locally advanced gastric cancer achieved pathological complete response (pCR). Three patients with locally advanced duodenal carcinoma achieved clinical complete response (cCR), followed by watch and wait. Eight of 16 patients with locally advanced colon cancer achieved pCR. All four patients with liver metastasis from colon cancer reached CR, including three with pCR and one with cCR. pCR was achieved in two of five patients with non-liver metastatic colorectal cancer. CR was achieved in four of five patients with low rectal cancer, including three with cCR and one with pCR. cCR was achieved in seven of 36 cases, among which, six were selected for watch and wait strategy. No cCR was observed in gastric or colon cancer. CONCLUSION Preoperative PD-1 blockade immunotherapy in dMMR/MSI-H gastrointestinal malignancies can achieve a high CR, especially in patients with duodenal or low rectal cancer, and can achieve high organ function protection.
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Affiliation(s)
- Ying-Jie Li
- Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xin-Zhi Liu
- Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yun-Feng Yao
- Gastro-intestinal Ward III, Beijing Cancer Hospital, Beijing 100142, China
| | - Nan Chen
- Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhong-Wu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiao-Yan Zhang
- Department of Radiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xin-Feng Lin
- Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Ai-Wen Wu
- Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Li Y, Zhou H, Liu P, Lv D, Shi Y, Tang B, Xu J, Zhong T, Xu W, Zhang J, Zhou J, Ying K, Zhao Y, Sun Y, Jiang Z, Cheng H, Zhang X, Ke Y. SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis. J Clin Invest 2023; 133:162870. [PMID: 36626230 PMCID: PMC9927946 DOI: 10.1172/jci162870] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) was constitutively neddylated on K358 and K364 sites; thus, its autoinhibited conformation was maintained. In response to CD47-liganded SIRPα, SHP2 was deneddylated by sentrin-specific protease 8 (SENP8), which led to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that supplementation with SHP2 allosteric inhibitors sensitized immune treatment-resistant CRC to immunotherapy. Our results emphasize that the CRC subtype that is unresponsive to immunotherapy relies on SIRPαhiSHP2hiNEDD8lo TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy.
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Affiliation(s)
- Yiqing Li
- Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Zhou
- Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Pan Liu
- Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Dandan Lv
- Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yichun Shi
- Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bufu Tang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research at The Lishui Hospital, Zhejiang University School of Medicine, Lishui, China
| | - Jiaqi Xu
- Department of Pathology at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangou, China
| | - Tingting Zhong
- Department of Pathology at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangou, China
| | - Wangting Xu
- Department of Respiratory Medicine at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Zhang
- Department of Urology at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianying Zhou
- Department of Respiratory Medicine at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kejing Ying
- Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongchao Zhao
- Cancer Institute of The Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Sun
- Cancer Institute of The Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhinong Jiang
- Department of Pathology at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangou, China
| | - Hongqiang Cheng
- Department of Pathology and Pathophysiology, and Department of Cardiology at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Zhang
- Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuehai Ke
- Department of Pathology and Pathophysiology, and Department of Respiratory Medicine at Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Nishida H, Kusaba T, Kawamura K, Oyama Y, Daa T. Histopathological Aspects of the Prognostic Factors for Salivary Gland Cancers. Cancers (Basel) 2023; 15:cancers15041236. [PMID: 36831578 PMCID: PMC9954716 DOI: 10.3390/cancers15041236] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/31/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Salivary gland cancers (SGCs) are diagnosed using histopathological examination, which significantly contributes to their progression, including lymph node/distant metastasis or local recurrence. In the current World Health Organization (WHO) Classification of Head and Neck Tumors: Salivary Glands (5th edition), malignant and benign epithelial tumors are classified into 21 and 15 tumor types, respectively. All malignant tumors have the potential for lymph node/distant metastasis or local recurrence. In particular, mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (AdCC), salivary duct carcinoma, salivary carcinoma, not otherwise specified (NOS, formerly known as adenocarcinoma, NOS), myoepithelial carcinoma, epithelial-myoepithelial carcinoma, and carcinoma ex pleomorphic adenoma (PA) are relatively prevalent. High-grade transformation is an important aspect of tumor progression in SGCs. MEC, AdCC, salivary carcinoma, and NOS have a distinct grading system; however, a universal histological grading system for SGCs has not yet been recommended. Conversely, PA is considered benign; nonetheless, it should be cautiously treated to avoid the development of metastasizing/recurrent PA. The aim of this review is to describe the current histopathological aspects of the prognostic factors for SGCs and discuss the genes or molecules used as diagnostic tools that might have treatment target potential in the future.
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Wu X, Lu W, Jiang C, Zhang D, Zhang W, Cui Y, Zhuo Z, Mei H, Wang Y, Zhang M, Chen S. Effect of ERCC1 polymorphisms on the response to platinum-based chemotherapy: A systematic review and meta-analysis based on Asian population. PLoS One 2023; 18:e0284825. [PMID: 37141338 PMCID: PMC10159199 DOI: 10.1371/journal.pone.0284825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 04/06/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Platinum-based chemotherapy is one of the most common treatments for many cancers; however, the effect of chemotherapy varies from individual to individual. Excision repair cross complementation group 1 (ERCC1) is widely recognized as a key gene regulating nucleotide excision repair (NER) and is closely associated with platinum response. Many studies have yielded conflicting results regarding whether ERCC1 polymorphisms can affect the response to platinum and overall survival (OS). Therefore, it is necessary to perform a meta-analysis of patients with specific races and cancer types. METHODS Eight databases (EMBASE, PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, Scopus, VIP, China Biology Medicine disc and Wanfang databases) were searched. Results were expressed in terms of odds ratios (ORs), hazard ratios (HRs) and 95% CIs. RESULTS In this study, rs11615, rs2298881 and rs3212986 SNPs were studied. In the comparison between CT and TT on the response to platinum, esophageal cancer [I2 = 0%, OR = 6.18, 95% CI(1.89,20.23), P = 0.003] and ovarian cancer [I2 = 0%, OR = 4.94, 95% CI(2.21,11.04), P<0.001] showed that the rs11615 CT genotype predicted a better response. In the comparison between CC and TT, ovarian cancer [I2 = 48.0%, OR = 6.15, 95% CI (2.56,14.29), P<0.001] indicated that the CC genotype predicted a better response. In the meta-analysis of OS, the CC genotype was related to longer OS than TT in ovarian cancer [TT vs CC: I2 = 57.7%, HR = 1.71, 95% CI (1.18, 2.49), P<0.001]. CONCLUSION The ERCC1 rs11615 polymorphism was related to the response to platinum and OS, but the correlation is based on specific cancer types in the Asian population.
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Affiliation(s)
- Xiaoqing Wu
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Wenping Lu
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Cuihong Jiang
- Guang'anmen Hospital South Campus, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dongni Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Weixuan Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Yongjia Cui
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Zhili Zhuo
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Heting Mei
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Ya'nan Wang
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Mengfan Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical sciences, Beijing, China
| | - Shuntai Chen
- Beijing University of Chinese Medicine, Beijing, China
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Gao Y, Xiao H, Meng W, Liao J, Chen Q, Zhao G, Li C, Bai L. Locally advanced rectal cancer patients with mismatch repair protein deficiency can obtain better pathological response after regional chemoembolization. Front Oncol 2023; 13:1131690. [PMID: 37182172 PMCID: PMC10174286 DOI: 10.3389/fonc.2023.1131690] [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: 12/26/2022] [Accepted: 04/13/2023] [Indexed: 05/16/2023] Open
Abstract
Background and objective Preoperative transcatheter rectal arterial chemoembolization (TRACE) can enhance the pathological response rate in some patients with locally advanced rectal cancer (LARC). However, how to accurately identify patients who can benefit from this neoadjuvant modality therapy remains to be further studied. Deficient mismatch repair (dMMR) protein plays a crucial role in maintaining genome stability. A proportion of patients with rectal cancer are caused by the loss of mismatch repair (MMR) protein. Given the role of MMR in guiding the efficacy in patients with colorectal carcinoma (CRC), this study is designed to evaluate the effect of dMMR status on the response to neoadjuvant therapy through a retrospective analysis. Methods We launched a retrospective study. First, we selected patients with LARC from the database, and these patients had received preoperative TRACE combined with concurrent chemoradiotherapy. Then, the tumor tissue biopsied by colonoscopy before intervention was taken for immunohistochemistry. According to the expression of MLH-1, MSH-2, MSH-6 and PMS-2, these patients were divided into dMMR protein group and proficient MMR (pMMR) protein group. All patients underwent pathological examination at the end of neoadjuvant therapy, either surgically excised tissue or colonoscopically biopsied tissue. The end point was the pathologic complete response (pCR) after TRACE combined with concurrent chemoradiotherapy. Results From January 2013 to January 2021, a total of 82 patients with LARC received preoperative TRACE combined with concurrent chemoradiotherapy, and the treatment was well tolerated. Among 82 patients, there were 42 patients in the pMMR group and 40 patients in the dMMR group. 69 patients returned to the hospital for radical resection. In 8 patients, the colonoscopy showed good tumor regression grade after 4 weeks of interventional therapy and refused surgery. The remaining five patients were neither surgically treated nor reexamined by colonoscopy. 77 patients were eventually enrolled in the study. Individually, the pCR rates of these two groups (10%, 4/40 vs. 43%, 16/37) showed significant difference (P < 0.05). Biomarker analysis indicated that patients with dMMR protein had a better propensity for pCR. Conclusion In patients with LARC, preoperative TRACE combined with concurrent chemoradiotherapy showed good pCR rates, especially in patients with dMMR. Patients with MMR protein defects have a better propensity for pCR.
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Affiliation(s)
- Yuchen Gao
- Department of Gastrointestinal Surgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
| | - Hualiang Xiao
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing, China
| | - Wenjun Meng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Liao
- Department of Gastrointestinal Surgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
| | - Qi Chen
- Department of Gastrointestinal Surgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
| | - Guowei Zhao
- Department of Gastrointestinal Surgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
| | - Chunxue Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
- *Correspondence: Chunxue Li, ; Lian Bai,
| | - Lian Bai
- Department of Gastrointestinal Surgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
- *Correspondence: Chunxue Li, ; Lian Bai,
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Dai X, Xie Y, Dong M. Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis. Cancer Biol Ther 2022; 23:76-88. [PMID: 35100092 PMCID: PMC8812748 DOI: 10.1080/15384047.2021.2017222] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Colorectal adenocarcinoma (COAD) is a prevalent malignant tumor. Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) (CAFs-EVs) are implicated in COAD treatment. This study explored the mechanism of CAFs-EVs in COAD. CAFs and normal fibroblast (NFs) were isolated from COAD tissues and adjacent normal tissues. Vimentin, α-SMA, and FAP expressions were detected. EVs were isolated from CAFs and identified. SW480 and HCT116 cells were co-incubated with EVs. The EV uptake and COAD cell malignant behaviors were assessed. EV-treated SW480 and HCT116 cells were co-cultured with human umbilical vein endothelial cells (HUVECs). Extensive analyses were conducted to examine HUVEC proliferation, migration, and angiogenesis, and miR-135b-5p expression in COAD cells, and SW480 and HCT116 cells. CAFs were transfected with the miR-135b-5p inhibitor. miR-135b-5p downstream targets were predicted. FOXO1 expression in the co-culture system was determined and then overexpressed to evaluate its role in HUVECs mediated by COAD cells. COAD mouse model was established by transplanting SW480 cells into nude mice and injecting with EVs. Tumor growth rate, volume, and weight were examined. Ki67, VEGF, CD34, FOXO1 expressions, and VEGF content were detected. CAFs-EVs promoted COAD cell malignant behaviors and COAD cells-mediated HUVEC proliferation, migration, and angiogenesis. CAFs-EVs delivered miR-135b-5p into COAD cells. miR-135b-5p targeted FOXO1. Inhibition of miR-135b-5p in EVs or overexpression of FOXO1 partially reversed the effect of EVs on promoting COAD-induced angiogenesis. CAFs-EVs promoted tumor proliferation and angiogenesis of COAD in vivo. CAFs-EVs delivered miR-135b-5p into COAD cells to downregulate FOXO1 and promote HUVECs proliferation, migration, and angiogenesis.
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Affiliation(s)
- Xiaoyu Dai
- Department of Anus & Intestine Sugery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo City, Zhejiang, China
| | - Yangyang Xie
- Pharmacy Department, Ningbo Eye Hospital, Ningbo City, Zhejiang, China
| | - Mingjun Dong
- Department of Anus & Intestine Sugery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo City, Zhejiang, China
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Hou W, Yi C, Zhu H. Predictive biomarkers of colon cancer immunotherapy: Present and future. Front Immunol 2022; 13:1032314. [PMID: 36483562 PMCID: PMC9722772 DOI: 10.3389/fimmu.2022.1032314] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022] Open
Abstract
Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.
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Affiliation(s)
- Wanting Hou
- Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Cheng Yi
- Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Hong Zhu
- Department of Medical Oncology Cancer Center, West China Hospital, Sichuan University, Sichuan, China
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Xie Y, Jiao X, Zeng M, Fan Z, Li X, Yuan Y, Zhang Q, Xia Y. Clinical Significance of Fusobacterium nucleatum and Microsatellite Instability in Evaluating Colorectal Cancer Prognosis. Cancer Manag Res 2022; 14:3021-3036. [PMID: 36262751 PMCID: PMC9576466 DOI: 10.2147/cmar.s382464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/04/2022] [Indexed: 02/05/2023] Open
Abstract
Objective Both genetic and microbial factors play important roles in colorectal cancer (CRC) development. The effects of Fusobacterium nucleatum (F. nucleatum) and microsatellite instability (MSI) on CRC prognosis require more clinical evidence. We aimed to investigate the role of F. nucleatum and MSI as biomarkers in predicting the prognosis of CRC. Methods CRC patients in various TNM stages were enrolled. MSI status and F. nucleatum were detected by immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) specimens. The associations between MSI status and F. nucleatum and clinical parameters were analyzed. Results MSI tumors were more frequently observed in the colon than in the rectum. Cancerous tissues had higher levels of F. nucleatum than adjacent noncancerous tissues. There were no significant differences in F. nucleatum abundance in different age, sex, tumor stage, location, and tumor marker groups. MSI status was associated with tumor location and stage. Survival analyses revealed that disease-free survival (DFS) was significantly longer in the F. nucleatum-negative, younger age, and TNM stage I-II groups (p< 0.05), and age, advanced TNM stage (III and IV), and F. nucleatum status were independent factors for poor prognosis. Multivariate Cox regression and receiver operating characteristic (ROC) curve analyses showed that conventional tumor biomarkers of CRC had more prognostic value than F. nucleatum and MSI. Conclusion Age, advanced TNM stage, and F. nucleatum positivity were independent factors of poor prognosis, suggesting that F. nucleatum and MSI may contribute to the identification of new strategies for the prevention and treatment of CRC.
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Affiliation(s)
- Yanxuan Xie
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Xiaoyang Jiao
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Mi Zeng
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Zhiqiang Fan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Xin Li
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Yumeng Yuan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Qiaoxin Zhang
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
| | - Yong Xia
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, People’s Republic of China
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Xu Z, Liu J, Liu Z, Zhang H. MARCH1 as a novel immune-related prognostic biomarker that shapes an inflamed tumor microenvironment in lung adenocarcinoma. Front Oncol 2022; 12:1008753. [PMID: 36313698 PMCID: PMC9606618 DOI: 10.3389/fonc.2022.1008753] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
E3 ubiquitin ligases (E3s), the second most common cancer-related functional protein family, play vital roles in multiple tumors. However, their importance in prognosis and immunotherapy of lung adenocarcinoma (LUAD) is not clear. First, utilizing the data from The Cancer Genome Atlas (TCGA), we comprehensively assessed the expression profile and immunological association of 13 E3s in LUAD patients. Consequently, MARCH1 was considered a candidate for further study. Second, several algorithms were applied to assess the correlation between MARCH1 and immunological characteristics in the LUAD tumor microenvironment. Third, an immune risk score (IRS) was developed to predict the prognosis. Finally, the immunological relationship of MARCH1 in pan-cancer was also estimated. We found that E3s were disordered in LUAD. Among them, MARCH1 was positively correlated with most immunological characteristics, indicating that MARCH1 designed an inflamed TME in LUAD. Coincidently, LUAD with low MARCH1 expression had a poor prognosis and was not sensitive to immune checkpoint blockers. In addition, the IRS could accurately predict the prognosis. In pan-cancer, MARCH1 was also positively correlated with most immunological characteristics. In conclusion, MARCH1 could be a novel and promising biomarker for immune status and effectiveness of immunotherapy for LUAD patients.
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Affiliation(s)
- Zhiyong Xu
- Department of Oncology, the Second Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Radiotherapy, Southern Theater General Hospital, Guangzhou, China
| | - Jun Liu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of South China University of Technology, Guangzhou, China
| | - Zichuan Liu
- Internal Medicine Section2, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Zichuan Liu, ; Haibo Zhang,
| | - Haibo Zhang
- Department of Oncology, the Second Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Zichuan Liu, ; Haibo Zhang,
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Yang CZ, Yang T, Liu XT, He CF, Guo W, Liu S, Yao XH, Xiao X, Zeng WR, Lin LZ, Huang ZY. Comprehensive analysis of somatic mutator-derived and immune infiltrates related lncRNA signatures of genome instability reveals potential prognostic biomarkers involved in non-small cell lung cancer. Front Genet 2022; 13:982030. [PMID: 36226174 PMCID: PMC9548567 DOI: 10.3389/fgene.2022.982030] [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: 06/30/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The function and features of long non-coding RNAs (lncRNAs) are already attracting attention and extensive research on their role as biomarkers of prediction in lung cancer. However, the signatures that are both related to genomic instability (GI) and tumor immune microenvironment (TIME) have not yet been fully explored in previous studies of non-small cell lung cancer (NSCLC). Method: The clinical characteristics, RNA expression profiles, and somatic mutation information of patients in this study came from The Cancer Genome Atlas (TCGA) database. Cox proportional hazards regression analysis was performed to construct genomic instability-related lncRNA signature (GIrLncSig). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the potential functions of lncRNAs. CIBERSORT was used to calculate the proportion of immune cells in NSCLC. Result: Eleven genomic instability-related lncRNAs in NSCLC were identified, then we established a prognostic model with the GIrLncSig ground on the 11 lncRNAs. Through the computed GIrLncSig risk score, patients were divided into high-risk and low-risk groups. By plotting ROC curves, we found that patients in the low-risk group in the test set and TCGA set had longer overall survival than those in the high-risk group, thus validating the survival predictive power of GIrLncSig. By stratified analysis, there was still a significant difference in overall survival between high and low risk groups of patients after adjusting for other clinical characteristics, suggesting the prognostic significance of GIrLncSig is independent. In addition, combining GIrLncSig with TP53 could better predict clinical outcomes. Besides, the immune microenvironment differed significantly between the high-risk and the low-risk groups, patients with low risk scores tend to have upregulation of immune checkpoints and chemokines. Finally, we found that high-risk scores were associated with increased sensitivity to chemotherapy. Conclusion: we provided a new perspective on lncRNAs related to GI and TIME and revealed the worth of them in immune infiltration and immunotherapeutic response. Besides, we found that the expression of AC027288.1 is associated with PD-1 expression, which may be a potential prognostic marker in immune checkpoint inhibitor response to improve the prediction of clinical survival in NSCLC patients.
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Affiliation(s)
- Cai-Zhi Yang
- The First School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Yang
- The First School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue-Ting Liu
- The First School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Can-Feng He
- The First School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Guo
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shan Liu
- The First School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiao-Hui Yao
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xi Xiao
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei-Ran Zeng
- Oncology Department, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Li-Zhu Lin
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhong-Yu Huang
- Guangzhou First People’s Hospital School of Medicine, South China University of Technology, Guangzhou, China
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
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Zhang J, He Y, Xia L, Yi J, Wang Z, Zhao Y, Song X, Li J, Liu H, Liang X, Nie S, Liu L. Expansion of Colorectal Cancer Biomarkers Based on Gut Bacteria and Viruses. Cancers (Basel) 2022; 14:cancers14194662. [PMID: 36230584 PMCID: PMC9563090 DOI: 10.3390/cancers14194662] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/27/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The current study identified microbial (including bacterial and viral) diagnostic models that could discriminate colorectal tumor patients from healthy controls, expanding the potential biomarkers for colorectal tumors. A combination of five colorectal cancer-associated gut bacteria was identified in this study for the discrimination of colorectal cancer patients from healthy controls, with verifiable performance in multiple cohorts. The gene pathways regulated by aberrant gut bacteria were also identified, providing possible directions for studying bacterial carcinogenesis mechanisms. Furthermore, this study revealed the potential interactions of gut bacteria with viruses and within bacteria in adenoma-carcinoma sequences, which may extend our understanding of dysbiosis in colorectal carcinogenesis. Abstract The alterations in gut bacteria are closely related to colorectal cancer. However, studies on adenoma are still scarce. Besides, the associations of gut viruses with colorectal tumor, and the interactions of bacteria with viruses in colorectal tumors are still under exploration. Therefore, a metagenomic sequencing of stool samples from patients with colorectal adenoma (CRA), colorectal cancer (CRC), and healthy controls was performed to identify changes in gut microbiome in patients with colorectal tumors. Five CRC-enriched bacteria (Peptostreptococcus stomatis, Clostridium symbiosum, Hungatella hathewayi, Parvimonas micra, and Gemella morbillorum) were identified as a diagnostic model to identify CRC patients, and the efficacy of the diagnostic model was verifiable in 1523 metagenomic samples from ten cohorts of eight different countries. We identified the positive association of Bacteroides fragilis with PD-L1 expression and PD-1 checkpoint pathway, providing a possible direction for studying bacterial carcinogenesis mechanisms. Furthermore, the increased interactions within the microbiome in patients may play roles in the development of CRC. In conclusion, this study identified novel microbiota combinations with discrimination for colorectal tumor, and revealed the potential interactions of gut bacteria with viruses in the adenoma-carcinoma sequence, which implies that the microbiome, but not only bacteria, should be paid more attention in further studies.
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Affiliation(s)
- Jia Zhang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yangting He
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lu Xia
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jing Yi
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhen Wang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yingying Zhao
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xuemei Song
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jia Li
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongli Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430023, China
| | - Xinjun Liang
- Department of Medical Oncology, Tongji Medical College, Hubei Cancer Hospital, Huazhong University of Science and Technology, Wuhan 430079, China
- Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan 430079, China
- Colorectal Cancer Clinical Research Center of Wuhan, Wuhan 430079, China
| | - Shaofa Nie
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Correspondence: ; Tel.: +86-27-86393763; Fax: +86-27-83692701
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Ding K, He Y, Wei J, Fu S, Wang J, Chen Z, Zhang H, Qu Y, Liang K, Gong X, Qiu L, Chen D, Xiao B, Du H. A score of DNA damage repair pathway with the predictive ability for chemotherapy and immunotherapy is strongly associated with immune signaling pathway in pan-cancer. Front Immunol 2022; 13:943090. [PMID: 36081518 PMCID: PMC9445361 DOI: 10.3389/fimmu.2022.943090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
DNA damage repair (DDR) is critical in maintaining normal cellular function and genome integrity and is associated with cancer risk, progression, and therapeutic response. However, there is still a lack of a thorough understanding of the effects of DDR genes’ expression level in cancer progression and therapeutic resistance. Therefore, we defined a tumor-related DDR score (TR-DDR score), utilizing the expression levels of 20 genes, to quantify the tumor signature of DNA damage repair pathways in tumors and explore the possible function and mechanism for the score among different cancers. The TR-DDR score has remarkably predictive power for tumor tissues. It is a more accurate indicator for the response of chemotherapy or immunotherapy combined with the tumor-infiltrating lymphocyte (TIL) and G2M checkpoint score than the pre-existing predictors (CD8 or PD-L1). This study points out that the TR-DDR score generally has positive correlations with patients of advanced-stage, genome-instability, and cell proliferation signature, while negative correlations with inflammatory response, apoptosis, and p53 pathway signature. In the context of tumor immune response, the TR-DDR score strongly positively correlates with the number of T cells (CD4+ activated memory cells, CD8+ cells, T regs, Tfh) and macrophages M1 polarization. In addition, by difference analysis and correlation analysis, COL2A1, MAGEA4, FCRL4, and ZIC1 are screened out as the potential modulating factors for the TR-DDR score. In summary, we light on a new biomarker for DNA damage repair pathways and explore its possible mechanism to guide therapeutic strategies and drug response prediction.
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Affiliation(s)
- Ke Ding
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Youhua He
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Jinfen Wei
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Shuying Fu
- College of Life Science, Zhaoqing University, Zhaoqing, China
| | - Jiajian Wang
- Clinical Laboratory Department of Longgang District People’s Hospital of Shenzhen & The Second Affiliated Hospital of the Chinese University of Hong Kong, Shenzhen, China
| | - Zixi Chen
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Haibo Zhang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Yimo Qu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Keying Liang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Xiaocheng Gong
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Li Qiu
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Dong Chen
- Fangrui Institute of Innovative Drugs, South China University of Technology, Guangzhou, China
| | - Botao Xiao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- *Correspondence: Botao Xiao, ; Hongli Du,
| | - Hongli Du
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- *Correspondence: Botao Xiao, ; Hongli Du,
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Zhu Y, Huang G, Li S, Xiong H, Chen R, Zuo L, Liu H. CircSMARCA5: A key circular RNA in various human diseases. Front Genet 2022; 13:921306. [PMID: 36081987 PMCID: PMC9445203 DOI: 10.3389/fgene.2022.921306] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/13/2022] [Indexed: 11/16/2022] Open
Abstract
Circular RNAs (circRNAs) are recognized as a novel type of single-stranded endogenous noncoding RNA molecule with the characteristics of tissue specificity, sequence conservation and structural stability. Accumulating studies have shown that circRNAs play a unique biological role in different kinds of diseases. CircRNAs can affect tumor proliferation, migration, metastasis and other behaviors by modulating the expression of downstream genes. CircSMARCA5, an example of a circRNA, is dysregulated in various noninfectious diseases, such as tumors, osteoporosis, atherosclerosis and coronary heart disease. Furthermore, recent studies have demonstrated that circSMARCA5 is associated with the occurrence and development of a variety of tumors, including gastric cancer, glioblastoma, hepatocellular carcinoma, multiple myeloma, colorectal cancer, breast cancer and osteosarcoma. Mechanistically, circSMARCA5 primarily acts as a sponge of miRNAs to regulate the expression of downstream genes, and can serve as a potential biomarker for the diagnosis of malignant tumors. This review summarizes the biological roles of circSMARCA5 and its molecular mechanism of action in various diseases. Moreover, the meta-analysis of some publications showed that the expression of circSMARCA5 was significantly correlated with the prognosis of patients and tumor TNM stage, showing that circSMARCA5 has the potential to be a prognostic marker.
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Affiliation(s)
- Yi Zhu
- Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Gaozhen Huang
- Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shihao Li
- Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hong Xiong
- Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ruiqi Chen
- Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ling Zuo
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- *Correspondence: Ling Zuo, ; Hongwei Liu,
| | - Hongwei Liu
- Department of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- *Correspondence: Ling Zuo, ; Hongwei Liu,
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Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
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Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
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Williams FN, Scaglione KM. Insights on Microsatellite Characteristics, Evolution, and Function From the Social Amoeba Dictyostelium discoideum. Front Neurosci 2022; 16:886837. [PMID: 35769695 PMCID: PMC9234386 DOI: 10.3389/fnins.2022.886837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Microsatellites are repetitive sequences commonly found in the genomes of higher organisms. These repetitive sequences are prone to expansion or contraction, and when microsatellite expansion occurs in the regulatory or coding regions of genes this can result in a number of diseases including many neurodegenerative diseases. Unlike in humans and other organisms, the social amoeba Dictyostelium discoideum contains an unusually high number of microsatellites. Intriguingly, many of these microsatellites fall within the coding region of genes, resulting in nearly 10,000 homopolymeric repeat proteins within the Dictyostelium proteome. Surprisingly, among the most common of these repeats are polyglutamine repeats, a type of repeat that causes a class of nine neurodegenerative diseases in humans. In this minireview, we summarize what is currently known about homopolymeric repeats and microsatellites in Dictyostelium discoideum and discuss the potential utility of Dictyostelium for identifying novel mechanisms that utilize and regulate regions of repetitive DNA.
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Affiliation(s)
- Felicia N. Williams
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States
| | - K. Matthew Scaglione
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States
- Department of Neurology, Duke University, Durham, NC, United States
- Duke Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, NC, United States
- *Correspondence: K. Matthew Scaglione,
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Lv L, Sun X, Liu B, Song J, Wu DJH, Gao Y, Li A, Hu X, Mao Y, Ye D. Genetically Predicted Serum Albumin and Risk of Colorectal Cancer: A Bidirectional Mendelian Randomization Study. Clin Epidemiol 2022; 14:771-778. [PMID: 35761866 PMCID: PMC9233496 DOI: 10.2147/clep.s367547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 06/03/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Colorectal cancer (CRC) is the third–most frequently diagnosed cancer globally. Studies have linked low serum albumin with increased risk of CRC, but the causal nature of the association remains unclear. In the present study, we explored the potential causal relationship using bidirectional Mendelian randomization (MR). Methods Instrumental variants for albumin were obtained from a genome-wide association study (GWAS) on 102,223 Eastern Asian participants to investigate the effect of albumin on CRC. Summary statistics of CRC were obtained from a GWAS on 7,062 CRC cases and 195,745 controls of Eastern Asian ancestry. Bidirectional MR analysis was performed using inverse variance weighting (IVW) for primary analysis, supplemented with a maximum likelihood–based method, MR-PRESSO test, leave-one-out analysis, and MR-Egger regression. Stratification analyses were further performed. Results We found that genetically predicted serum albumin per unit was associated with a lower risk of CRC (OR 0.75, 95% CI 0.59–0.95 with IVW). No evidence of pleiotropy was observed. Sex-stratified MR analysis showed that serum albumin was inversely associated with risk of CRC in men (OR 0.71, 95% CI 0.53–0.96), but not in women (OR 0.81, 95% CI 0.55–1.19) using IVW. Reverse MR analysis suggested a genetic predisposition toward CRC was not associated with serum albumin. Conclusion Our study revealed a suggestive sex disparity in the effect of albumin, which deserves further exploration of the potential biological mechanism.
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Affiliation(s)
- Linshuoshuo Lv
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Xiaohui Sun
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Bin Liu
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Jie Song
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - David J H Wu
- University of Minnesota Medical School, Minneapolis, MN, 55455, USA
| | - Yun Gao
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Aole Li
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Xiaoqin Hu
- Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China
| | - Yingying Mao
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Ding Ye
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Correspondence: Ding Ye; Yingying Mao, Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, 548 Binwen Road, Zhejiang, Hangzhou, 310053, People’s Republic of China, Tel +86-571-8663-3305, Email ;
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Orc6 is a component of the replication fork and enables efficient mismatch repair. Proc Natl Acad Sci U S A 2022; 119:e2121406119. [PMID: 35622890 DOI: 10.1073/pnas.2121406119] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Significance Origin recognition complex (ORC) is required for the initiation of DNA replication. Unlike other ORC components, the role of human Orc6 in replication remains to be resolved. We identified an unexpected role for hOrc6, which is to promote S-phase progression after prereplication complex assembly and DNA damage response. Orc6 localizes at the replication fork, is an accessory factor of the mismatch repair complex, and plays a fundamental role in genome surveillance during S phase.
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Shan E, Hao Y, Wang H, Zhang Z, Hu J, Wang G, Liu W, Yan B, Hiroaki H, Yang J. Differentiated embryonic chondrocyte expressed gene-1 (DEC1) enhances the development of colorectal cancer with an involvement of the STAT3 signaling. Neoplasia 2022; 27:100783. [PMID: 35334277 PMCID: PMC8956864 DOI: 10.1016/j.neo.2022.100783] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 03/03/2022] [Accepted: 03/03/2022] [Indexed: 01/25/2023]
Abstract
Colorectal cancer (CRC) is the second deadly and the third most common malignancy worldwide. It has been projected that annual new cases of CRC will increase by 63% in 2040, constituting an even greater health challenge for decades to come. This study has linked DEC1 (differentiated embryonic chondrocyte expressed gene 1) to the pathogenesis of CRC. Based on the analysis of patient samples and database data, DEC1 is expressed much higher in CRC than the adjacent normal tissues. CRC patients with higher DEC1 expression have a shorter survival time. The carcinogenesis protocol with azoxymethane/dextran sulfate induces a higher number of tumors with larger sizes in DEC1+/+ than DEC1−/− mice. Overexpression of DEC1 increases the expression of proliferation- and antiapoptosis-related genes, but decreases the level of proapoptotic genes. Mechanistically, this study has shown that DEC1 is functionally looped to the IL-6/STAT3 signaling pathway (interleukin-6/signal transducer and activator of transcription 3). IL-6 induces DEC1, and DEC1 enhances the phosphorylation of STAT3, resulting in increased pSTAT3/STAT3 ratio. DEC1 and STAT3 are present in reciprocal immunocomplexes, pointing to physical interactions (presumably with pSTAT3). These findings establish that DEC1 is a CRC enhancer. The enhancement is achieved largely through the IL-6/STAT3 pathway. The potential of the physical interaction between DEC1 and STAT3 will likely serve as a foundation to develop intervention strategies for CRC prevention and therapy.
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Lin Y, Kong DX, Zhang YN. Does the Microbiota Composition Influence the Efficacy of Colorectal Cancer Immunotherapy? Front Oncol 2022; 12:852194. [PMID: 35463305 PMCID: PMC9023803 DOI: 10.3389/fonc.2022.852194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the second most common malignancy globally, and many people with CRC suffer the fate of death. Due to the importance of CRC and its negative impact on communities, treatment strategies to control it or increase patient survival are being studied. Traditional therapies, including surgery and chemotherapy, have treated CRC patients. However, with the advancement of science, we are witnessing the emergence of novel therapeutic approaches such as immunotherapy for CRC treatment, which have had relatively satisfactory clinical outcomes. Evidence shows that gastrointestinal (GI) microbiota, including various bacterial species, viruses, and fungi, can affect various biological events, regulate the immune system, and even treat diseases like human malignancies. CRC has recently shown that the gut microorganism pattern can alter both antitumor and pro-tumor responses, as well as cancer immunotherapy. Of course, this is also true of traditional therapies because it has been revealed that gut microbiota can also reduce the side effects of chemotherapy. Therefore, this review summarized the effects of gut microbiota on CRC immunotherapy.
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Affiliation(s)
- Yan Lin
- Health Management Center, Department of General Practice, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Yan Lin, ; You-Ni Zhang,
| | - De-Xia Kong
- Health Management Center, Department of General Practice, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - You-Ni Zhang
- Department of Laboratory Medicine, Tiantai People’s Hospital, Taizhou, China
- *Correspondence: Yan Lin, ; You-Ni Zhang,
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Zhang X, Wu T, Cai X, Dong J, Xia C, Zhou Y, Ding R, Yang R, Tan J, Zhang L, Zhang Y, Wang Y, Dong C, Li Y. Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities. Front Immunol 2022; 13:795972. [PMID: 35371084 PMCID: PMC8968082 DOI: 10.3389/fimmu.2022.795972] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/22/2022] [Indexed: 12/26/2022] Open
Abstract
Patients with locally advanced colorectal cancer (LACRC) have a high risk of recurrence and metastasis, although neoadjuvant therapy may provide some benefit. However, patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) LACRC receive little benefit from neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT). The 2015 KEYNOTE-016 trial identified MSI-H/dMMR as a biomarker indicative of immunotherapy efficacy, and pointed to the potential use of immune checkpoint inhibitors (ICIs). In 2017, the FDA approved two ICIs (pembrolizumab and nivolumab) for treatment of MSI-H/dMMR metastatic CRC (mCRC). In 2018, the CheckMate-142 trial demonstrated successful treatment of mCRC based on “double immunity” provided by nivolumab with ipilimumab, a regimen that may become a standard first-line treatment for MSI-H mCRC. In 2018, the FDA approved nivolumab alone or with ipilimumab for patients who progressed to MSI-H/dMMR mCRC after standard chemotherapy. The FDA then approved pembrolizumab alone as a first-line treatment for patients with MSI-H/dMMR CRC that was unresectable or metastatic. There is now interest in using these drugs in neoadjuvant immunotherapy (nIT) for patients with MSI-H/dMMR non-mCRC. In 2020, the NICHE trial marked the start of using nIT for CRC. This novel treatment of MSI-H/dMMR LACRC may change the approaches used for neoadjuvant therapy of other cancers. Our review of immunotherapy for CRC covers diagnosis and treatment, clinical prognostic characteristics, the mechanism of nIT, analysis of completed prospective and retrospective studies, and ongoing clinical trials, and the clinical practice of using nIT for MSI-H/dMMR LACRC. Our team also proposes a new organ-preservation strategy for patients with MSI-H/dMMR low LARC.
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Affiliation(s)
- Xuan Zhang
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tao Wu
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xinyi Cai
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jianhua Dong
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Cuifeng Xia
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yongchun Zhou
- Laboratory of Molecular Diagnosis Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Rong Ding
- Department of Minimally Invasive Intervention, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Renfang Yang
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jing Tan
- Department of Imaging, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lijuan Zhang
- Department of Pathology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ya Zhang
- Department of Imaging, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yuqin Wang
- Department of Pathology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chao Dong
- Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yunfeng Li
- Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
- *Correspondence: Yunfeng Li,
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A Comprehensive View on the Quercetin Impact on Colorectal Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27061873. [PMID: 35335239 PMCID: PMC8953922 DOI: 10.3390/molecules27061873] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) represents the third type of cancer in incidence and second in mortality worldwide, with the newly diagnosed case number on the rise. Among the diagnosed patients, approximately 70% have no hereditary germ-line mutations or family history of pathology, thus being termed sporadic CRC. Diet and environmental factors are to date considered solely responsible for the development of sporadic CRC; therefore; attention should be directed towards the discovery of preventative actions to combat the CRC initiation, promotion, and progression. Quercetin is a polyphenolic flavonoid plant secondary metabolite with a well-characterized antioxidant activity. It has been extensively reported as an anti-carcinogenic agent in the scientific literature, and the modulated targets of quercetin have been also characterized in the context of CRC, mainly in original research publications. In this fairly comprehensive review, we summarize the molecular targets of quercetin reported to date in in vivo and in vitro CRC models, while also giving background information about the signal transduction pathways that it up- and downregulates. Among the most relevant modulated pathways, the Wnt/β-catenin, PI3K/AKT, MAPK/Erk, JNK, or p38, p53, and NF-κB have been described. With this work, we hope to encourage further quests in the elucidation of quercetin anti-carcinogenic activity as single agent, as dietary component, or as pharmaconutrient delivered in the form of plant extracts.
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Lynch-like Syndrome: Potential Mechanisms and Management. Cancers (Basel) 2022; 14:cancers14051115. [PMID: 35267422 PMCID: PMC8909420 DOI: 10.3390/cancers14051115] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Lynch-like syndrome (LLS) is defined as colorectal cancer cases with microsatellite instability (MSI) and loss of expression of MLH1, MSH2, MSH6, or PMS2 by immunohistochemistry (IHC) in the absence of a germline mutation in these genes that cannot be explained by BRAF mutation or MLH1 hypermethylation. The application of the universal strategy for the diagnosis of Lynch syndrome (LS) in all CRCs is leading to an increase in the incidence of cases of LLS. It has been described that risk of cancer in relatives of LLS patients is in between of that found in Lynch syndrome families and sporadic cases. That makes LLS patients and their families a challenging group for which the origin of CRC is unknown, being a mixture between unidentified hereditary CRC and sporadic cases. The potential causes of LLS are discussed in this review, as well as methods for identification of truly hereditary cases. Abstract Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity.
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Kim S, Park JW, Seo H, Kim M, Park J, Kim G, Lee JO, Shin Y, Bae JM, Koo B, Jeong S, Ku J. Multifocal Organoid Capturing of Colon Cancer Reveals Pervasive Intratumoral Heterogenous Drug Responses. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103360. [PMID: 34918496 PMCID: PMC8844556 DOI: 10.1002/advs.202103360] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/15/2021] [Indexed: 06/14/2023]
Abstract
Intratumor heterogeneity (ITH) stands as one of the main difficulties in the treatment of colorectal cancer (CRC) as it causes the development of resistant clones and leads to heterogeneous drug responses. Here, 12 sets of patient-derived organoids (PDOs) and cell lines (PDCs) isolated from multiple regions of single tumors from 12 patients, capturing ITH by multiregion sampling of individual tumors, are presented. Whole-exome sequencing and RNA sequencing of the 12 sets are performed. The PDOs and PDCs of the 12 sets are also analyzed with a clinically relevant 24-compound library to assess their drug responses. The results reveal unexpectedly widespread subregional heterogeneity among PDOs and PDCs isolated from a single tumor, which is manifested by genetic and transcriptional heterogeneity and strong variance in drug responses, while each PDO still recapitulates the major histologic, genomic, and transcriptomic characteristics of the primary tumor. The data suggest an imminent drawback of single biopsy-originated PDO-based clinical diagnosis in evaluating CRC patient responses. Instead, the results indicate the importance of targeting common somatic driver mutations positioned in the trunk of all tumor subregional clones in parallel with a comprehensive understanding of the molecular ITH of each tumor.
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Affiliation(s)
- Soon‐Chan Kim
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
- Ischemic/Hypoxic Disease InstituteSeoul National University College of MedicineSeoul03080South Korea
| | - Ji Won Park
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
- Department of SurgerySeoul National University College of MedicineSeoul03080South Korea
- Division of Colorectal SurgeryDepartment of SurgerySeoul National University HospitalSeoul03080South Korea
| | - Ha‐Young Seo
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
| | - Minjung Kim
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
- Department of SurgerySeoul National University College of MedicineSeoul03080South Korea
- Division of Colorectal SurgeryDepartment of SurgerySeoul National University HospitalSeoul03080South Korea
| | - Jae‐Hyeon Park
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
| | - Ga‐Hye Kim
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
| | - Ja Oh Lee
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
| | - Young‐Kyoung Shin
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
- Ischemic/Hypoxic Disease InstituteSeoul National University College of MedicineSeoul03080South Korea
| | - Jeong Mo Bae
- Department of PathologySeoul National University College of MedicineSeoul03080South Korea
| | - Bon‐Kyoung Koo
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna Biocenter (VBC)Dr. Bohr‐Gasse 3Vienna1030Austria
| | - Seung‐Yong Jeong
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
- Department of SurgerySeoul National University College of MedicineSeoul03080South Korea
- Division of Colorectal SurgeryDepartment of SurgerySeoul National University HospitalSeoul03080South Korea
| | - Ja‐Lok Ku
- Korean Cell Line BankLaboratory of Cell BiologyCancer Research InstituteSeoul National University College of MedicineSeoul03080South Korea
- Department of Biomedical SciencesSeoul National University College of MedicineSeoul03080South Korea
- Cancer Research InstituteSeoul National UniversitySeoul03080South Korea
- Ischemic/Hypoxic Disease InstituteSeoul National University College of MedicineSeoul03080South Korea
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