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1
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Xie Y, Wang X, Wang W, Pu N, Liu L. Epithelial-mesenchymal transition orchestrates tumor microenvironment: current perceptions and challenges. J Transl Med 2025; 23:386. [PMID: 40176117 PMCID: PMC11963649 DOI: 10.1186/s12967-025-06422-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/25/2025] [Indexed: 04/04/2025] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, facilitating tumor cells to develop invasive traits and augmenting their migratory capabilities. EMT is primed by tumor microenvironment (TME)-derived signals, whereupon cancer cells undergoing EMT in turn remodel the TME, thereby modulating tumor progression and therapeutic response. This review discusses the mechanisms by which EMT coordinates TME dynamics, including secretion of soluble factors, direct cell contact, release of exosomes and enzymes, as well as metabolic reprogramming. Recent evidence also indicates that cells undergoing EMT may differentiate into cancer-associated fibroblasts, thereby establishing themselves as functional constituents of the TME. Elucidating the relationship between EMT and the TME offers novel perspectives for therapeutic strategies to enhance cancer treatment efficacy. Although EMT-directed therapies present significant therapeutic potential, the current lack of effective targeting approaches-attributable to EMT complexity and its microenvironmental context dependency-underscores the necessity for mechanistic investigations and translational clinical validation.
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Affiliation(s)
- Yuqi Xie
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xuan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ning Pu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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2
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Shang T, Jia Z, Li J, Cao H, Xu H, Cong L, Ma D, Wang X, Liu J. Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance. J Hematol Oncol 2025; 18:32. [PMID: 40102937 PMCID: PMC11921735 DOI: 10.1186/s13045-025-01684-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 03/05/2025] [Indexed: 03/20/2025] Open
Abstract
In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.
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Affiliation(s)
- Tongxuan Shang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Ziqi Jia
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiayi Li
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China
| | - Heng Cao
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hengyi Xu
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Cong
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Dongxu Ma
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiang Wang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jiaqi Liu
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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3
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Meier C, Brieger A. The role of IL-8 in cancer development and its impact on immunotherapy resistance. Eur J Cancer 2025; 218:115267. [PMID: 39899909 DOI: 10.1016/j.ejca.2025.115267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/05/2025]
Abstract
Tumors are structures of high complexity. Plurality of their structural and functional components - heterogeneity, diversity, directionality, interdependence and integration of signaling pathways - seem to follow isolated local rules, whereby a superordinate structure remains largely unknown. Understanding the complexity of cancer is the mainstay in finding determinants and developing effective therapies. Interleukin 8 (IL-8) is a potent pro-inflammatory chemokine that is significantly elevated in many different tumor entities. In contrast to its initially postulated anti-tumor properties, an increasing number of studies have been published in recent years linking this chemokine with tumor-promoting features and poor prognosis. This review summarizes the current state and diversity of the role of IL-8 in the development of cancer.
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Affiliation(s)
- Clara Meier
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt am Main, Germany
| | - Angela Brieger
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Biomedical Research Laboratory, Frankfurt am Main, Germany.
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4
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Nadukkandy AS, Blaize B, Kumar CD, Mori G, Cordani M, Kumar LD. Non-coding RNAs as mediators of epithelial to mesenchymal transition in metastatic colorectal cancers. Cell Signal 2025; 127:111605. [PMID: 39842529 DOI: 10.1016/j.cellsig.2025.111605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/06/2025] [Accepted: 01/12/2025] [Indexed: 01/24/2025]
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.
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Affiliation(s)
- Aisha Shigna Nadukkandy
- Cancer Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India
| | - Britny Blaize
- Cancer Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India
| | - Chethana D Kumar
- Department of Surgical ICU, Christian Medical College, IDA Scudder Road, Vellore 632004, Tamil Nadu, India
| | - Giulia Mori
- Department Of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Lekha Dinesh Kumar
- Cancer Biology, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad 500007, India.
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5
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Teng H, Huang H, Lin C, Twu Y, Yang W, Lin W, Lan H, Lin Y, Hwang W. CT45A1-mediated MLC2 (MYL9) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell-in-cell structure, potentiating the progression of microsatellite instability-high colorectal cancer. Mol Oncol 2025; 19:430-451. [PMID: 39322998 PMCID: PMC11793002 DOI: 10.1002/1878-0261.13736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 07/15/2024] [Accepted: 09/10/2024] [Indexed: 09/27/2024] Open
Abstract
Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) have high tumor mutation burden and tumor immunogenicity, exhibiting a higher response rate to immunotherapy and better survival. However, a portion of MSI-H CRC patients still experience adverse disease outcomes. We aimed to identify the tumor-autonomous regulators determining these heterogeneous clinical outcomes. The Cancer Genome Atlas (TCGA) dataset was used to identify regulators in MSI-H CRC patients with unfavorable outcomes. Stable CRC tumor clones expressing targeted regulators were established to evaluate migratory and stemness properties, immune cell vulnerability, and cell-in-cell (CIC) structure formation. RNA-sequencing (RNA-seq) was used to identify enriched biological pathways in stable CRC tumor clones. Clinicopathological characterization of formalin-fixed paraffin-embedded (FFPE) MSI-H CRC specimens was performed to explore the underlying mechanisms involved. We showed that cancer/testis antigen family 45 member A1 (CT45A1) expression was upregulated in MSI-H CRC patients with poor survival outcomes. CT45A1-expressing microsatellite stable (MSS) CRC cells showed enhanced migratory ability. However, CT45A1-expressing MSI-H CRC cells, but not MSS CRC cells, showed higher resistance to natural killer (NK) cell cytotoxicity and served as outer cells in homotypic CIC structures, preventing exogenous or therapeutic antibody access to inner CRC cells. Inactivating RHO-ROCK/MLCK-MLC2 signaling with small-molecule inhibitors or short-hairpin RNAs (shRNAs) targeting myosin light chain kinase (MYLK) abolished NK cell resistance and reduced the outer cell fate of CT45A1-expressing MSI-H CRC cells. In MSI-H CRC patients, CT45A1-positive tumors exhibited increased MLC2 phosphorylation, increased outer cell fate, and decreased survival. We demonstrated that CT45A1 potentiates the advanced progression of MSI-H CRC, and targeting MLC2 phosphorylation may enhance immunotherapy efficacy in CT45A1-positive MSI-H CRC patients.
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Affiliation(s)
- Hao‐Wei Teng
- Division of Medical Oncology, Department of OncologyTaipei Veterans General HospitalTaiwan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Hsiang‐Yueh Huang
- Department of Biotechnology and Laboratory Science in MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Chun‐Chi Lin
- Division of Colon and Rectum Surgery, Department of SurgeryTaipei Veterans General HospitalTaiwan
- Department of Surgery, Faculty of Medicine, School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Yuh‐Ching Twu
- Department of Biotechnology and Laboratory Science in MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Wen‐Hao Yang
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular MedicineChina Medical UniversityTaichungTaiwan
| | - Wen‐Chun Lin
- Department of Biotechnology and Laboratory Science in MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Hsin‐Yi Lan
- Department of Biotechnology and Laboratory Science in MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Yen‐Yu Lin
- Department of Pathology, Fu Jen Catholic University HospitalFu Jen Catholic UniversityNew Taipei CityTaiwan
- School of Medicine, College of MedicineFu Jen Catholic UniversityNew Taipei CityTaiwan
| | - Wei‐Lun Hwang
- Department of Biotechnology and Laboratory Science in MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Cancer and Immunology Research CenterNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
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6
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Tocci S, Das S, Sayed IM. An Update on Blastocystis: Possible Mechanisms of Blastocystis-Mediated Colorectal Cancer. Microorganisms 2024; 12:1924. [PMID: 39338600 PMCID: PMC11433781 DOI: 10.3390/microorganisms12091924] [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: 08/28/2024] [Revised: 09/15/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Blastocystis is an anaerobic parasite that colonizes the intestinal tract of humans and animals. When it was first discovered, Blastocystis was considered to be a normal flora with beneficial effects on human health, such as maintaining gut hemostasis and improving intestinal barrier integrity. Later, with increasing research on Blastocystis, reports showed that Blastocystis sp. is associated with gastrointestinal disorders, colorectal cancer (CRC), and neurological disorders. The association between Blastocystis sp. and CRC has been confirmed in several countries. Blastocystis sp. can mediate CRC via similar mechanisms to CRC-associated bacteria, including infection-mediated inflammation, increased oxidative stress, induced gut dysbiosis, and damage to intestinal integrity, leading to a leaky gut. IL-8 is the main inflammatory cytokine released from epithelial cells and can promote CRC development. The causal association of Blastocystis sp. with other diseases needs further investigation. In this review, we have provided an update on Blastocystis sp. and summarized the debate about the beneficial and harmful effects of this parasite. We have also highlighted the possible mechanisms of Blastocystis-mediated CRC.
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Affiliation(s)
- Stefania Tocci
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Soumita Das
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Ibrahim M Sayed
- Department of Biomedical & Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
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7
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Sun F, Ding Z, Shao F, Gao X, Tian H, Zhang X, Chen H, Wang C. Albumin-Based MUC13 Peptide Nanomedicine Suppresses Liver Cancer Stem Cells via JNK-ERK Signaling Pathway-Mediated Autophagy Inhibition. ACS APPLIED MATERIALS & INTERFACES 2024; 16:38968-38978. [PMID: 39024013 DOI: 10.1021/acsami.4c06034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Targeting liver cancer stem cells (LCSCs) is a promising strategy for hepatocellular carcinoma (HCC) therapy. Target selection and corresponding inhibitor screening are of vital importance for eliminating the stemness of LCSCs. Peptide-based agents are hopeful but have long been hindered for in vivo application. Herein, we selected a clinically significant target MUC13 and screened out a suitable peptide for preparation of an albumin-based MUC13 peptide nanomedicine, P3@HSA, which suppressed liver cancer stem cells via JNK-ERK signaling pathway-mediated autophagy inhibition. The selected target MUC13 was highly expressed in LCSCs and associated with the prognosis of liver cancer patients. Encouraged by this observation, we screened the corresponding peptide-based inhibitor P3 for further evaluation. P3 could interact with albumin through the intrinsic hydrophobic force and formed the nanomedicine P3@HSA. The prepared nanomedicine could inhibit LCSCs through JNK-ERK signaling pathway-mediated autophagy inhibition and exert potent antitumor effect both in vitro and in vivo. Together, this study provides a promising peptide-based nanomedicine for high-performance HCC treatment.
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Affiliation(s)
- Fen Sun
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zongyao Ding
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Fengying Shao
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Xiaoyang Gao
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Haina Tian
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Xiao Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
- Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huaqing Chen
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Changlong Wang
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
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8
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Chang YM, Huang WY, Yang SH, Jan CI, Nieh S, Lin YS, Chen SF, Lin YC. Interleukin-8/CXCR1 Signaling Contributes to the Progression of Pulmonary Adenocarcinoma Resulting in Malignant Pleural Effusion. Cells 2024; 13:968. [PMID: 38891100 PMCID: PMC11172099 DOI: 10.3390/cells13110968] [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: 03/18/2024] [Revised: 05/18/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Pulmonary adenocarcinoma (PADC) treatment limited efficacy in preventing tumor progression, often resulting in malignant pleural effusion (MPE). MPE is filled with various mediators, especially interleukin-8 (IL-8). However, the role of IL-8 and its signaling mechanism within the fluid microenvironment (FME) implicated in tumor progression warrants further investigation. Primary cultured cells from samples of patients with MPE from PADC, along with a commonly utilized lung cancer cell line, were employed to examine the role of IL-8 and its receptor, CXCR1, through comparative analysis. Our study primarily assessed migration and invasion capabilities, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties. Additionally, IL-8 levels in MPE fluid versus serum, along with immunohistochemical expression of IL-8/CXCR1 signaling in tumor tissue and cell blocks were analyzed. IL-8/CXCR1 overexpression enhanced EMT and CSC properties. Furthermore, the immunocytochemical examination of 17 cell blocks from patients with PADC and MPE corroborated the significant correlation between upregulated IL-8 and CXCR1 expression and the co-expression of IL-8 and CXCR1 in MPE with distant metastasis. In summary, the IL-8/ CXCR1 axis in FME is pivotal to tumor promotion via paracrine and autocrine signaling. Our study provides a therapeutic avenue for improving the prognosis of PADC patients with MPE.
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Affiliation(s)
- Yi-Ming Chang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-M.C.); (S.-H.Y.)
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan;
| | - Wen-Yen Huang
- Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Shih-Hsien Yang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-M.C.); (S.-H.Y.)
- Office of General Affairs and Occupational Safety, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chia-Ing Jan
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan;
| | - Shin Nieh
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yaoh-Shiang Lin
- Department of Otorhinolaryngology, Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813414, Taiwan;
| | - Su-Feng Chen
- Department of Dentistry, School of Dentistry, China Medical University, Taichung 404333, Taiwan
| | - Yu-Chun Lin
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan;
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9
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Liang J, Liao L, Xie L, Tang W, Yu X, Lu Y, Chen H, Xu J, Sun L, Wu H, Cui C, Tan Y. PITPNC1 Suppress CD8 + T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155. J Transl Med 2024; 22:117. [PMID: 38291470 PMCID: PMC10826121 DOI: 10.1186/s12967-024-04931-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance. METHODS To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8+ T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8+ T cell immune function. RESULTS Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8+ T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8+ T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models. CONCLUSIONS PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8+ T cell immune function, and promotes radioresistance in rectal cancer.
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Affiliation(s)
- Junxian Liang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Limin Liao
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lang Xie
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - WenWen Tang
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiang Yu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yinghao Lu
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hongzhen Chen
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Juanli Xu
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Sun
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huanmei Wu
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Chunhui Cui
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Yujing Tan
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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10
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Zhao Q, Zong H, Zhu P, Su C, Tang W, Chen Z, Jin S. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol 2024; 13:6. [PMID: 38254219 PMCID: PMC10802076 DOI: 10.1186/s40164-024-00474-x] [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: 09/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.
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Affiliation(s)
- Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chang Su
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenxue Tang
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jing‑ba Road, Zhengzhou, 450014, China.
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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11
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Singh S, Singh AP, Mitra R. Cancer-Associated Fibroblasts: Major Co-Conspirators in Tumor Development. Cancers (Basel) 2024; 16:211. [PMID: 38201638 PMCID: PMC10778099 DOI: 10.3390/cancers16010211] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
The tumor microenvironment (TME) is a critical determinant of tumor progression, metastasis, and therapeutic outcomes [...].
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Affiliation(s)
- Shubhangi Singh
- Department of International Studies (Global Health), College of Arts and Sciences, University of South Alabama, Mobile, AL 36688, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | - Ajay P. Singh
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
- Department of Pathology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36617, USA
- Department of Biochemistry and Molecular Biology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Ranjana Mitra
- Biomedical Sciences, College of Medicine, Roseman University of Health Sciences, Las Vegas, NV 89135, USA
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12
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García de Herreros A. Dual role of Snail1 as transcriptional repressor and activator. Biochim Biophys Acta Rev Cancer 2024; 1879:189037. [PMID: 38043804 DOI: 10.1016/j.bbcan.2023.189037] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 12/05/2023]
Abstract
Snail1 transcriptional factor plays a key role in the control of epithelial to mesenchymal transition, a process that remodels tumor cells increasing their invasion and chemo-resistance as well as reprograms their metabolism and provides stemness properties. During this transition, Snail1 acts as a transcriptional repressor and, as growing evidences have demonstrated, also as a direct activator of mesenchymal genes. In this review, I describe the different proteins that interact with Snail1 and are responsible for these two different functions on gene expression; I focus on the transcriptional factors that associate to Snail1 in their target promoters, both activated and repressed. I also present working models for Snail1 action both as repressor and activator and raise some issues that still need to be investigated.
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Affiliation(s)
- Antonio García de Herreros
- Programa de Recerca en Càncer, Hospital del Mar Research Institute (IMIM), Unidad Asociada al CSIC, Barcelona, Spain; Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
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13
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Ballarò C, Quaranta V, Giannelli G. Colorectal Liver Metastasis: Can Cytokines Make the Difference? Cancers (Basel) 2023; 15:5359. [PMID: 38001618 PMCID: PMC10670198 DOI: 10.3390/cancers15225359] [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: 09/08/2023] [Revised: 10/20/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Metastasis is the prime driver of CRC-related mortality, and the liver is the organ most frequently involved. Despite the overall success of current treatments, colorectal liver metastasis (CRLM) is associated with poor prognoses and a survival rate of only 14%. Recent studies have highlighted the importance of the tumor microenvironment (TME) and the crosstalk within it in determining the invasion of distant organs by circulating cancer cells. In the TME, cellular communication is mediated via soluble molecules, among which cytokines have recently emerged as key regulators, involved in every aspect of tumor progression and the metastatic cascade. Indeed, in the serum of CRC patients elevated levels of several cytokines are associated with cancer development and progression. The current review evaluates the role of different cytokines during CRLM development. Additionally, considering the increasing amount of data concerning the importance of cytokine complex networks, we outline the potential of combination treatments using targeted cytokines together with other well-established therapies, such as immune checkpoint blockades, chemotherapy, or gene therapy, to improve therapeutic outcomes.
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Affiliation(s)
- Costanza Ballarò
- Laboratory of Molecular Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
| | - Valeria Quaranta
- Laboratory of Personalized Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy;
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy;
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14
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Kielbik M, Przygodzka P, Szulc-Kielbik I, Klink M. Snail transcription factors as key regulators of chemoresistance, stemness and metastasis of ovarian cancer cells. Biochim Biophys Acta Rev Cancer 2023; 1878:189003. [PMID: 37863122 DOI: 10.1016/j.bbcan.2023.189003] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/13/2023] [Accepted: 10/14/2023] [Indexed: 10/22/2023]
Abstract
Ovarian cancer is one of the deadliest gynecological malignancies among women. The reason for this outcome is the frequent acquisition of cancer cell resistance to platinum-based drugs and unresponsiveness to standard therapy. It has been increasingly recognized that the ability of ovarian cancer cells to adopt more aggressive behavior (mainly through the epithelial-to-mesenchymal transition, EMT), as well as dedifferentiation into cancer stem cells, significantly affects drug resistance acquisition. Transcription factors in the Snail family have been implicated in ovarian cancer chemoresistance and metastasis. In this article, we summarize published data that reveal Snail proteins not only as key inducers of the EMT in ovarian cancer but also as crucial links between the acquisition of ovarian cancer stem properties and spheroid formation. These Snail-related characteristics significantly affect the ovarian cancer cell response to treatment and are related to the acquisition of chemoresistance.
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Affiliation(s)
- Michal Kielbik
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland
| | - Patrycja Przygodzka
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland
| | - Izabela Szulc-Kielbik
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland
| | - Magdalena Klink
- Institute of Medical Biology, Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland.
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15
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Lu J, Kornmann M, Traub B. Role of Epithelial to Mesenchymal Transition in Colorectal Cancer. Int J Mol Sci 2023; 24:14815. [PMID: 37834263 PMCID: PMC10573312 DOI: 10.3390/ijms241914815] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a cellular reprogramming process that occurs during embryonic development and adult tissue homeostasis. This process involves epithelial cells acquiring a mesenchymal phenotype. Through EMT, cancer cells acquire properties associated with a more aggressive phenotype. EMT and its opposite, mesenchymal-epithelial transition (MET), have been described in more tumors over the past ten years, including colorectal cancer (CRC). When EMT is activated, the expression of the epithelial marker E-cadherin is decreased and the expression of the mesenchymal marker vimentin is raised. As a result, cells temporarily take on a mesenchymal phenotype, becoming motile and promoting the spread of tumor cells. Epithelial-mesenchymal plasticity (EMP) has become a hot issue in CRC because strong inducers of EMT (such as transforming growth factor β, TGF-β) can initiate EMT and regulate metastasis, microenvironment, and immune system resistance in CRC. In this review, we take into account the significance of EMT-MET in CRC and the impact of the epithelial cells' plasticity on the prognosis of CRC. The analysis of connection between EMT and colorectal cancer stem cells (CCSCs) will help to further clarify the current meager understandings of EMT. Recent advances affecting important EMT transcription factors and EMT and CCSCs are highlighted. We come to the conclusion that the regulatory network for EMT in CRC is complicated, with a great deal of crosstalk and alternate paths. More thorough research is required to more effectively connect the clinical management of CRC with biomarkers and targeted treatments associated with EMT.
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Affiliation(s)
| | | | - Benno Traub
- Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (J.L.); (M.K.)
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16
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Reisenauer KN, Aroujo J, Tao Y, Ranganathan S, Romo D, Taube JH. Therapeutic vulnerabilities of cancer stem cells and effects of natural products. Nat Prod Rep 2023; 40:1432-1456. [PMID: 37103550 PMCID: PMC10524555 DOI: 10.1039/d3np00002h] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
Covering: 1995 to 2022Tumors possess both genetic and phenotypic heterogeneity leading to the survival of subpopulations post-treatment. The term cancer stem cells (CSCs) describes a subpopulation that is resistant to many types of chemotherapy and which also possess enhanced migratory and anchorage-independent growth capabilities. These cells are enriched in residual tumor material post-treatment and can serve as the seed for future tumor re-growth, at both primary and metastatic sites. Elimination of CSCs is a key goal in enhancing cancer treatment and may be aided by application of natural products in conjunction with conventional treatments. In this review, we highlight molecular features of CSCs and discuss synthesis, structure-activity relationships, derivatization, and effects of six natural products with anti-CSC activity.
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Affiliation(s)
| | - Jaquelin Aroujo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Yongfeng Tao
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | | | - Daniel Romo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Joseph H Taube
- Department of Biology, Baylor University, Waco, TX, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
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17
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Niu Y, Han X, Zeng Y, Nanding A, Bai Q, Guo S, Hou Y, Yu Y, Zhang Q, Li X. The significance of spread through air spaces in the prognostic assessment model of stage I lung adenocarcinoma and the exploration of its invasion mechanism. J Cancer Res Clin Oncol 2023; 149:7125-7138. [PMID: 36881149 DOI: 10.1007/s00432-023-04619-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/27/2023] [Indexed: 03/08/2023]
Abstract
PURPOSE Spread through air spaces (STAS) is a crucial invasive mode of lung cancer and has been shown to be associated with early recurrence and metastasis. We aimed to develop a prognostic risk assessment model for stage I lung adenocarcinoma based on STAS and other pathological features and to explore the potential relationship between CXCL-8, Smad2, Snail, and STAS. METHODS 312 patients who underwent surgery at Harbin Medical University Cancer Hospital with pathologically diagnosed stage I lung adenocarcinoma were reviewed in the study. STAS and other pathological features were identified by H&E staining, and a prognostic risk assessment model was established. The expression levels of CXCL8, Smad2, and Snail were determined by immunohistochemistry. RESULTS The nomogram was established based on age, smoking history, STAS, tumor lymphocyte infiltration, tissue subtype, nuclear grade, and tumor size. The C-index for DFS was (training set 0.84 vs validation set 0.77) and for OS was (training set 0.83 vs validation set 0.78). Decision curve analysis showed that the model constructed has a better net benefit than traditional reporting. The prognostic risk score validated the risk stratification value for stage I lung adenocarcinoma. STAS was an important prognostic factor associated with stronger invasiveness and higher expression of CXCL8, Smad2, and Snail. CXCL8 was associated with poorer DFS and OS. CONCLUSIONS We developed and validated a survival risk assessment model and the prognostic risk score formula for stage I lung adenocarcinoma. Additionally, we found that CXCL8 could be used as a potential biomarker for STAS and poor prognosis, and its mechanism may be related to EMT.
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Affiliation(s)
- YangYang Niu
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - XinHao Han
- Department of Biostatistics, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yuan Zeng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Abiyasi Nanding
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Qiang Bai
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - SaiNan Guo
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - YaLi Hou
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yan Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China.
| | - QiuJu Zhang
- Department of Biostatistics, School of Public Health, Harbin Medical University, 157 Baojian Road, Harbin, 150081, Heilongjiang Province, People's Republic of China.
| | - XiaoMei Li
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, Heilongjiang Province, People's Republic of China.
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18
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Waryah C, Alves E, Mazzieri R, Dolcetti R, Thompson EW, Redfern A, Blancafort P. Unpacking the Complexity of Epithelial Plasticity: From Master Regulator Transcription Factors to Non-Coding RNAs. Cancers (Basel) 2023; 15:3152. [PMID: 37370762 DOI: 10.3390/cancers15123152] [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: 03/22/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Cellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to enable immune evasion. Epithelial plasticity is one form of cellular plasticity, which is intrinsically linked with epithelial-mesenchymal transition (EMT). Traditionally, EMT has been regarded as a binary state. Yet, increasing evidence suggests that EMT involves a spectrum of quasi-epithelial and quasi-mesenchymal phenotypes governed by complex interactions between cellular metabolism, transcriptome regulation, and epigenetic mechanisms. Herein, we review the complex cross-talk between the different layers of epithelial plasticity in cancer, encompassing the core layer of transcription factors, their interacting epigenetic modifiers and non-coding RNAs, and the manipulation of cancer immunogenicity in transitioning between epithelial and mesenchymal states. In examining these factors, we provide insights into promising therapeutic avenues and potential anti-cancer targets.
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Affiliation(s)
- Charlene Waryah
- Cancer Epigenetics Group, Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- School of Human Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Eric Alves
- Cancer Epigenetics Group, Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- School of Human Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Roberta Mazzieri
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Riccardo Dolcetti
- Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Erik W Thompson
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
- Translational Research Institute, Brisbane, QLD 4102, Australia
| | - Andrew Redfern
- School of Medicine, University of Western Australia, Perth, WA 6009, Australia
| | - Pilar Blancafort
- Cancer Epigenetics Group, Harry Perkins Institute of Medical Research, Perth, WA 6009, Australia
- School of Human Sciences, University of Western Australia, Perth, WA 6009, Australia
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19
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Jain SM, Deka D, Das A, Paul S, Pathak S, Banerjee A. Role of Interleukins in Inflammation-Mediated Tumor Immune Microenvironment Modulation in Colorectal Cancer Pathogenesis. Dig Dis Sci 2023:10.1007/s10620-023-07972-8. [PMID: 37277647 DOI: 10.1007/s10620-023-07972-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/10/2023] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Tumor cells invade and spread through a procedure termed as epithelial-to-mesenchymal cell transition (EMT). EMT is triggered by any alterations in the genes that encode the extracellular matrix (ECM) proteins, the enzymes that break down the ECM, and the activation of the genes that causes the epithelial cell to change into a mesenchymal type. The transcription factors NF-κB, Smads, STAT3, Snail, Zeb, and Twist are activated by inflammatory cytokines, for instance, Tumor Necrosis Factor, Tumor Growth Factors, Interleukin-1, Interleukin-8, and Interleukin-6, which promotes EMT. MATERIALS The current piece of work has been reviewed from the literature works published in last 10 years on the role interleukins in inflammation-mediated tumor immune microenvironment modulation in colorectal cancer pathogenesis utilizing the databases like Google Scholar, PubMed, Science Direct. RESULTS Recent studies have demonstrated that pathological situations, such as epithelial malignancies, exhibit EMT characteristics, such as the downregulation of epithelial markers and the overexpression of mesenchymal markers. Several growing evidence have also proved its existence in the human colon during the carcinogenesis of colorectal cancer. Most often, persistent inflammation is thought to be one factor contributing to the initiation of human cancers, such as colorectal cancer (CRC). Therefore, according to epidemiologic and clinical research, people with ulcerative colitis and Crohn's disease have a greater probability of developing CRC. CONCLUSION A substantial amount of data points to the involvement of the NF-κB system, SMAD/STAT3 signaling cascade, microRNAs, and the Ras-mitogen-activated protein kinase/Snail/Slug in the epithelial-to-mesenchymal transition-mediated development of colorectal malignancies. As a result, EMT is reported to play an active task in the pathogenesis of colorectal cancer, and therapeutic interventions targeting the inflammation-mediated EMT might serve as a novel strategy for treating CRC. The illustration depicts the relationship between interleukins and their receptors as a driver of CRC development and the potential therapeutic targets.
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Affiliation(s)
- Samatha M Jain
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, 603103, India
| | - Dikshita Deka
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, 603103, India
| | - Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, 603103, India
| | - Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No.500 Fracc. San Pablo, 76130, Querétaro, CP, Mexico
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, 603103, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, 603103, India.
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20
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Dahal S, Chaudhary P, Jung YS, Kim JA. Megakaryocyte-Derived IL-8 Acts as a Paracrine Factor for Prostate Cancer Aggressiveness through CXCR2 Activation and Antagonistic AR Downregulation. Biomol Ther (Seoul) 2023; 31:210-218. [PMID: 36787954 PMCID: PMC9970838 DOI: 10.4062/biomolther.2023.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/18/2023] [Accepted: 01/25/2023] [Indexed: 02/16/2023] Open
Abstract
Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.
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Affiliation(s)
- Sadan Dahal
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Prakash Chaudhary
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Yi-Sook Jung
- College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea
| | - Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea
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21
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Wei W, Wang J, Hu Y, Chen S, Liu J. Emodin reverses resistance to gemcitabine in pancreatic cancer by suppressing stemness through regulation of the epithelial‑mesenchymal transition. Exp Ther Med 2022; 25:7. [PMID: 36545274 PMCID: PMC9748633 DOI: 10.3892/etm.2022.11706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
The present study aimed to explore the effects and underlying mechanisms of emodin (Emo) on gemcitabine (GEM)-resistant pancreatic cancer. GEM-resistant SW1990 cells (SW1990/GZ) were established by successively doubling the concentration of GEM. Cell viability was measured using the CCK-8 assay and flow cytometry was used to measure cell apoptosis. Cell migration was assessed using a Transwell assay. Sphere and colony-formation assays were used to evaluate cell self-renewal. The expression levels of epithelial-mesenchymal transition (EMT) and stem cell biomarkers were determined using western blotting. Snail family transcriptional repressor 1 gene (Snail) was overexpressed by transfecting cells with pcDNA3.1-Snail plasmids. A xenograft model was established in nude mice by using SW1990/GZ and Snail-overexpressing SW1990/GZ cells. Proliferation, migration, self-renewal and EMT progression of GEM-treated SW1990/GZ cells were significantly suppressed in vitro by Emo treatment, whereas the overexpression of Snail abolished the aforementioned effects. In in vivo, the antitumor activity of GEM and the inhibitory effect of GEM against EMT progression and stem-like characteristics were enhanced by treatment with Emo, whilst overexpression of Snail reversed these effects. In conclusion, Emo reversed GEM resistance in pancreatic cancer by suppressing stemness and regulating EMT progression.
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Affiliation(s)
- Weitian Wei
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Jiangfeng Wang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Yuqian Hu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Sheng Chen
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Jinshi Liu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China,Correspondence to: Dr Jinshi Liu, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
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22
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DiNatale A, Castelli MS, Nash B, Meucci O, Fatatis A. Regulation of Tumor and Metastasis Initiation by Chemokine Receptors. J Cancer 2022; 13:3160-3176. [PMID: 36118530 PMCID: PMC9475358 DOI: 10.7150/jca.72331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/10/2022] [Indexed: 12/13/2022] Open
Abstract
Tumor-initiating cells (TICs) are a rare sub-population of cells within the bulk of a tumor that are major contributors to tumor initiation, metastasis, and chemoresistance. TICs have a stem-cell-like phenotype that is dictated by the expression of master regulator transcription factors, including OCT4, NANOG, and SOX2. These transcription factors are expressed via activation of multiple signaling pathways that drive cancer initiation and progression. Importantly, these same signaling pathways can be activated by select chemokine receptors. Chemokine receptors are increasingly being revealed as major drivers of the TIC phenotype, as their signaling can lead to activation of stemness-controlling transcription factors. Additionally, the cell surface expression of chemokine receptors provides a unique therapeutic target to disrupt signaling pathways that control the expression of master regulator transcription factors and the TIC phenotype. This review summarizes the master regulator transcription factors known to dictate the TIC phenotype, along with the complex signaling pathways that can mediate their expression and the chemokine receptors that are most upstream of this phenotype.
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Affiliation(s)
- Anthony DiNatale
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Present Address: Janssen Oncology, Spring House, PA, USA
| | - Maria Sofia Castelli
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Bradley Nash
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - Olimpia Meucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Program in Immune Cell Regulation & Targeting, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Alessandro Fatatis
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.,Program in Translational and Cellular Oncology, Sidney Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA 19107, USA
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23
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Rizzo M, Varnier L, Pezzicoli G, Pirovano M, Cosmai L, Porta C. IL-8 and its role as a potential biomarker of resistance to anti-angiogenic agents and immune checkpoint inhibitors in metastatic renal cell carcinoma. Front Oncol 2022; 12:990568. [PMID: 36059687 PMCID: PMC9437355 DOI: 10.3389/fonc.2022.990568] [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: 07/10/2022] [Accepted: 08/01/2022] [Indexed: 11/24/2022] Open
Abstract
The therapeutic armamentarium of metastatic Renal Cell Carcinoma (mRCC) has consistently expanded in recent years, with the introduction of VEGF/VEGFR (Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor) inhibitors, mTOR (mammalian Target Of Rapamycin) inhibitors and Immune Checkpoint (IC) inhibitors. Currently, for the first-tline treatment of mRCC it is possible to choose between a VEGFR-TKI (VEGFR-Tyrosine Kinase Inhibitor) monotherapy, an ICI-ICI (Immune Checkpoint Inhibitor) combination and an ICI-VEGFRTKI combination. However, a consistent part of patients does not derive benefit from first-line therapy with ICIs; moreover, the use of combination regimens exposes patients to significant toxicities. Therefore, there is a critical need to develop prognostic and predictive biomarkers of response to VEGFR-TKIs and ICIs, and measurement of serum IL-8 is emerging as a potential candidate in this field. Recent retrospective analyses of large phase II and phase III trials found that elevated baseline serum IL-8 correlated with higher levels of tumor and circulating immunosuppressive myeloid cells, decreased T cell activation and poor response to treatment. These findings must be confirmed in prospective clinical trials; however, they provide evidence for a potential use of serum IL-8 as biomarker of resistance to VEGFR-TKIs and ICIs. Considering the amount of new agents and treatment regimens which are transforming the management of metastatic renal cell carcinoma, serum IL-8 could become a precious resource in tailoring the best therapy for each individual patient with the disease.
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Affiliation(s)
- Mimma Rizzo
- Division of Medical Oncology, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, Bari, Italy
- *Correspondence: Mimma Rizzo,
| | - Luca Varnier
- Department of Pediatrics, Meyer’ Childrens University Hospital, Florence, Italy
| | - Gaetano Pezzicoli
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “A. Moro”, Bari, Italy
| | - Marta Pirovano
- Division of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Milan, Italy
| | - Laura Cosmai
- Division of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Milan, Italy
| | - Camillo Porta
- Division of Medical Oncology, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, Bari, Italy
- Chair of Oncology, Interdisciplinary Department of Medicine, University of Bari “A. Moro”, Bari, Italy
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24
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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25
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Cytokine chemokine network in tumor microenvironment: Impact on CSC properties and therapeutic applications. Cytokine 2022; 156:155916. [DOI: 10.1016/j.cyto.2022.155916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/27/2022] [Accepted: 05/16/2022] [Indexed: 12/21/2022]
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26
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Cheng HY, Hsieh CH, Lin PH, Chen YT, Hsu DSS, Tai SK, Chu PY, Yang MH. Snail-regulated exosomal microRNA-21 suppresses NLRP3 inflammasome activity to enhance cisplatin resistance. J Immunother Cancer 2022; 10:jitc-2022-004832. [PMID: 36002186 PMCID: PMC9413180 DOI: 10.1136/jitc-2022-004832] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Compared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed. METHODS Tumor-derived exosomes were purified by differential ultracentrifugation and validated by nanoparticle tracking analysis and transmission electron microscopy. A proximity ligation assay and interleukin-1β (IL-1β) level were used for detecting activation of NLRP3 inflammasomes. RNA sequencing was used to analyze the exosomal RNAs. MIR21 knocked out human monocytic THP cells and mir21 knocked out murine oral cancer MTCQ1 cells were generated for confirming the exosomal delivery of microRNA (miR)-21. Syngeneic murine models for head and neck cancer (C57BLJ/6J), breast cancer (BALB/C) and lung cancer (C57BL/6J) were applied for examining the impact of Snail-miR21 axis on inflammasome activation in vivo. Single-cell RNA sequencing was used for analyzing the tumor-infiltrated immune cells. Head and neck patient samples were used for validating the findings in clinical samples. RESULTS We demonstrated that in cancer cells undergoing Snail-induced epithelial-mesenchymal transition (EMT), tumor cells suppress NLRP3 inflammasome activities of tumor-associated macrophages (TAMs) in response to chemotherapy through the delivery of exosomal miR-21. Mechanistically, miR-21 represses PTEN and BRCC3 to facilitate NLRP3 phosphorylation and lysine-63 ubiquitination, inhibiting NLRP3 inflammasome assembly. Furthermore, the Snail-miR-21 axis shapes the post-chemotherapy tumor microenvironment (TME) by repopulating TAMs and by activating CD8+ T cells. In patients with head and neck cancer, the Snail-high cases lacked post-chemotherapy IL-1β surge and were correlated with a worse response. CONCLUSIONS This finding reveals the mechanism of EMT-mediated resistance beyond cancer stemness through modulation of post-treatment inflammasome activity. It also highlights the dynamic remodeling of the TME throughout metastatic evolution.
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Affiliation(s)
- Han-Ying Cheng
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Hsin Hsieh
- Institute of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Po-Han Lin
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Tung Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | | | - Shyh-Kuan Tai
- Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Pen-Yuan Chu
- Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan .,Institute of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Divsion of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
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27
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Mullins R, Pal A, Barrett TF, Neal MEH, Puram SV. Epithelial-Mesenchymal Plasticity in Tumor Immune Evasion. Cancer Res 2022; 82:2329-2343. [PMID: 35363853 PMCID: PMC9256788 DOI: 10.1158/0008-5472.can-21-4370] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/05/2022] [Accepted: 03/29/2022] [Indexed: 01/07/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a fundamental process that occurs during embryogenesis and tissue repair. However, EMT can be hijacked by malignant cells, where it may promote immune evasion and metastasis. Classically considered a dichotomous transition, EMT in cancer has recently been considered a plastic process whereby malignant cells display and interconvert among hybrid epithelial/mesenchymal (E/M) states. Epithelial-mesenchymal plasticity (EMP) and associated hybrid E/M states are divergent from classical EMT, with unique immunomodulatory effects. Here, we review recent insights into the EMP-immune cross-talk, highlighting possible mechanisms of immune evasion conferred by hybrid E/M states and roles of immune cells in EMP.
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Affiliation(s)
- Riley Mullins
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, U.S.A.,Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A
| | - Ananya Pal
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, U.S.A.,Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A
| | - Thomas F Barrett
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, U.S.A.,Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A
| | - Molly E Heft Neal
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A
| | - Sidharth V Puram
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, U.S.A.,Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, U.S.A.,Corresponding author: Sidharth V. Puram, MD PhD, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8115, St. Louis, MO 63110, (314) 362-7509,
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28
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Ichikawa Y, Takahashi H, Chinen Y, Arita A, Sekido Y, Hata T, Ogino T, Miyoshi N, Uemura M, Yamamoto H, Mizushima T, Doki Y, Eguchi H. Low G9a expression is a tumor progression factor of colorectal cancer via IL-8 promotion. Carcinogenesis 2022; 43:797-807. [PMID: 35640269 DOI: 10.1093/carcin/bgac050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 05/15/2022] [Accepted: 05/26/2022] [Indexed: 11/14/2022] Open
Abstract
The histone methyltransferase G9a is expressed in various types of cancer cells, including colorectal cancer (CRC) cells. Interleukin (IL)-8, also known as C-X-C motif chemokine ligand 8 (CXCL8), is a chemokine that plays a pleiotropic function in the regulation of inflammatory responses and cancer development. Here, we examined the relationship between G9a and IL-8 and the clinical relevance of this association. We immunohistochemically analyzed 235 resected CRC samples to correlate clinical features. Samples with high G9a expression had better overall survival and relapse-free survival than those with low G9a expression. Univariate and multivariate analyses demonstrated that low G9a expression remained a significant independent prognostic factor for increased disease recurrence and decreased survival (P<0.05). G9a was expressed at high levels in commercially available CRC cell lines HCT116 and HT29. Knockdown of G9a by siRNA, shRNA, or the G9a-specific inhibitor BIX01294 upregulated IL-8 expression. The number of spheroids was significantly increased in HCT116 cells with stably suppressed G9a expression, and the number of spheroids was significantly decreased in HCT116 cells with stably suppressed IL-8 expression. Thus, the suppression of IL-8 by G9a may result in a better prognosis in CRC cases with high G9a expression. Furthermore, G9a may suppress cancer stemness and increase chemosensitivity by controlling IL-8. Therefore, G9a is a potential novel marker for predicting CRC prognosis, and therapeutic targeting of G9a in CRC should be contraversial.
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Affiliation(s)
- Yoshitoshi Ichikawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshinao Chinen
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Asami Arita
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuki Sekido
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tsuyoshi Hata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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29
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Pavlič A, Hauptman N, Boštjančič E, Zidar N. Long Non-Coding RNAs as Potential Regulators of EMT-Related Transcription Factors in Colorectal Cancer—A Systematic Review and Bioinformatics Analysis. Cancers (Basel) 2022; 14:cancers14092280. [PMID: 35565409 PMCID: PMC9105237 DOI: 10.3390/cancers14092280] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Emerging evidence highlights long non-coding RNAs as important regulators of epithelial–mesenchymal transition. Numerous studies have attempted to define their possible diagnostic, prognostic and therapeutic values in various human cancers. The aim of this review is to summarize long non-coding RNAs involved in the regulation of epithelial–mesenchymal transition in colorectal carcinoma. Additional candidate long non-coding RNAs are identified through a bioinformatics analysis. Abstract Epithelial–mesenchymal transition (EMT) plays a pivotal role in carcinogenesis, influencing cancer progression, metastases, stemness, immune evasion, metabolic reprogramming and therapeutic resistance. EMT in most carcinomas, including colorectal carcinoma (CRC), is only partial, and can be evidenced by identification of the underlying molecular drivers and their regulatory molecules. During EMT, cellular reprogramming is orchestrated by core EMT transcription factors (EMT-TFs), namely ZEB1/2, TWIST1/2, SNAI1 (SNAIL) and SNAI2 (SLUG). While microRNAs have been clearly defined as regulators of EMT, the role of long non-coding RNAs (lncRNAs) in EMT is poorly defined and controversial. Determining the role of lncRNAs in EMT remains a challenge, because they are involved in a number of cellular pathways and are operating through various mechanisms. Adding to the complexity, some lncRNAs have controversial functions across different tumor types, acting as EMT promotors in some tumors and as EMT suppressors in others. The aim of this review is to summarize the role of lncRNAs involved in the regulation of EMT-TFs in human CRC. Additional candidate lncRNAs were identified through a bioinformatics analysis.
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30
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Sharma V, Sachdeva N, Gupta V, Nada R, Jacob J, Sahni D, Aggarwal A. CCR4 + monocytic myeloid-derived suppressor cells are associated with the increased epithelial-mesenchymal transition in pancreatic adenocarcinoma patients. Immunobiology 2022; 227:152210. [PMID: 35358941 DOI: 10.1016/j.imbio.2022.152210] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 03/06/2022] [Accepted: 03/20/2022] [Indexed: 12/13/2022]
Abstract
Among all the cancer-related deaths globally, pancreatic ductal adenocarcinoma (PDAC) accounts for the seventh leading cause of mortality. A dysregulated immune system disrupts anti-tumor immunity by abnormal accumulation of myeloid-derived suppressor cells (MDSCs), but the underlying mechanisms are still inconclusive. To gain new insights into the role of MDSCs in tumor settings, we aimed to determine the mechanism of expansion of various subsets of MDSCs in PDAC patients and their role in promoting invasiveness. We assessed the load of MDSCs, chemokines responsible for the recruitment of MDSCs in PDAC patients by flow cytometry. We investigated the chemokine profile of tumor tissue using qRT-PCR and the status of epithelial-mesenchymal transition (EMT) related markers E-Cadherin, N-Cadherin, Snail, and ZEB1 by qRT-PCR and immunohistochemistry. We found a higher frequency of tumor infiltrated MDSCs in PDAC patients. Chemokine ligands CCL2 and the receptor CCR4 were markedly elevated in the PDAC tumor, while CCR4+ monocytic MDSCs (M-MDSCs) were found significantly elevated in peripheral blood and tumor tissue. In tumor tissue, expression of E-Cadherin was significantly reduced, while N-Cadherin, Snail, and ZEB1 were markedly raised. The frequency of CCR4+ M-MDSCs significantly correlated with the expression of mesenchymal transition markers N-Cadherin, Snail, and ZEB1. Collectively, these results suggest that the CCL2-CCR4 axis plays a crucial role in driving the recruitment of M-MDSCs, which is associated with increased invasiveness in PDAC. This study sheds light on the expansion mechanism of MDSCs, which can serve as a crucial target of future anti-cancer strategies to inhibit tumor cell invasiveness.
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Affiliation(s)
- Vinit Sharma
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Vikas Gupta
- Department of Surgical Gastroenterology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Justin Jacob
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Daisy Sahni
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Anjali Aggarwal
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
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31
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Nagao K, Koshino A, Sugimura-Nagata A, Nagano A, Komura M, Ueki A, Ebi M, Ogasawara N, Tsuzuki T, Kasai K, Takahashi S, Kasugai K, Inaguma S. The Complete Loss of p53 Expression Uniquely Predicts Worse Prognosis in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23063252. [PMID: 35328677 PMCID: PMC8948732 DOI: 10.3390/ijms23063252] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/06/2022] [Accepted: 03/14/2022] [Indexed: 02/04/2023] Open
Abstract
p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.
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Affiliation(s)
- Kazuhiro Nagao
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (K.N.); (A.K.); (A.S.-N.); (M.E.); (N.O.); (K.K.)
| | - Akira Koshino
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (K.N.); (A.K.); (A.S.-N.); (M.E.); (N.O.); (K.K.)
| | - Akane Sugimura-Nagata
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (K.N.); (A.K.); (A.S.-N.); (M.E.); (N.O.); (K.K.)
| | - Aya Nagano
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (A.N.); (M.K.); (A.U.); (S.T.)
| | - Masayuki Komura
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (A.N.); (M.K.); (A.U.); (S.T.)
| | - Akane Ueki
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (A.N.); (M.K.); (A.U.); (S.T.)
| | - Masahide Ebi
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (K.N.); (A.K.); (A.S.-N.); (M.E.); (N.O.); (K.K.)
| | - Naotaka Ogasawara
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (K.N.); (A.K.); (A.S.-N.); (M.E.); (N.O.); (K.K.)
| | - Toyonori Tsuzuki
- Department of Surgical Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan;
| | - Kenji Kasai
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan;
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (A.N.); (M.K.); (A.U.); (S.T.)
| | - Kunio Kasugai
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (K.N.); (A.K.); (A.S.-N.); (M.E.); (N.O.); (K.K.)
| | - Shingo Inaguma
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; (A.N.); (M.K.); (A.U.); (S.T.)
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan;
- Department of Pathology, Nagoya City University East Medical Center, Nagoya 464-8547, Japan
- Correspondence:
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Chang YH, Yang HJ, Chen HW, Hsiao CW, Hsieh YC, Chan YW, Chang SW, Hwang WL, Chen WS, Cheng HH, Chou TY, Chang FP, Ho HL, Chu FY, Lo YL, Chen CJ, Tsai HF, Shiau MY. Characterization of Collapsin Response Mediator Protein 2 in Colorectal Cancer Progression in Subjects with Diabetic Comorbidity. Cells 2022; 11:727. [PMID: 35203376 PMCID: PMC8869905 DOI: 10.3390/cells11040727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via regulating collpasin response mediator protein-2 (CRMP2). Accordingly, roles of CRMP2 in CRC and CRC-DM patients were investigated for elucidating the molecular convergence of CRC and DM. METHODS CRMP2 profile in tumor tissues from CRC and CRC-DM patients was investigated to explore the link between CRC and DM etiology. Meanwhile, molecular mechanism of glucose to regulate CRMP2 profile and CRC characteristics was examined in vitro and in vivo. RESULTS CRMP2 was significantly lower in tumor lesions and associated with advanced tumor stage in CRC-DM patients. Physiological hyperglycemia suppressed CRMP2 expression/activity and augmented malignant characteristics of CRC cells. Hyperglycemia promotes actin de-polymerization, cytoskeleton flexibility and cell proliferation/metastasis by downregulating CRMP2 profile and thus contributes to CRC disease progression. CONCLUSIONS This study uncovers molecular evidence to substantiate and elucidate the link between CRC and T2DM, as well as characterizing the roles of CRMP2 in CRC-DM. Accordingly, altered metabolic adaptations are promising targets for anti-diabetic and cancer strategies.
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Affiliation(s)
- Yih-Hsin Chang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
| | - Hui-Ju Yang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (W.-S.C.); (H.-H.C.)
| | - Huan-Wen Chen
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
| | - Chiao-Wan Hsiao
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
- Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 115, Taiwan
| | - Yi-Chen Hsieh
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
| | - Yu-Wei Chan
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
| | - Shu-Wen Chang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
- Department of Nursing, College of Nursing, Hungkuang University, Taichung 433, Taiwan
| | - Wei-Lun Hwang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (Y.-H.C.); (H.-J.Y.); (H.-W.C.); (C.-W.H.); (Y.-C.H.); (Y.-W.C.); (S.-W.C.); (W.-L.H.)
| | - Wei-Shone Chen
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (W.-S.C.); (H.-H.C.)
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Hou-Hsuan Cheng
- Department of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; (W.-S.C.); (H.-H.C.)
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Teh-Ying Chou
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-Y.C.); (F.-P.C.); (H.-L.H.)
| | - Fu-Pang Chang
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-Y.C.); (F.-P.C.); (H.-L.H.)
| | - Hsiang-Ling Ho
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-Y.C.); (F.-P.C.); (H.-L.H.)
| | - Fang-Yeh Chu
- Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan;
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu 300, Taiwan
- School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei 110, Taiwan
| | - Yu-Li Lo
- Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan;
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan
| | - Hui-Fang Tsai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan;
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Ming-Yuh Shiau
- Department of Nursing, College of Nursing, Hungkuang University, Taichung 433, Taiwan
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Anti-Colon Cancer Activity of Novel Peptides Isolated from In Vitro Digestion of Quinoa Protein in Caco-2 Cells. Foods 2022; 11:foods11020194. [PMID: 35053925 PMCID: PMC8774364 DOI: 10.3390/foods11020194] [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: 10/16/2021] [Revised: 12/31/2021] [Accepted: 01/07/2022] [Indexed: 02/07/2023] Open
Abstract
Quinoa peptides are the bioactive components obtained from quinoa protein digestion, which have been proved to possess various biological activities. However, there are few studies on the anticancer activity of quinoa peptides, and the mechanism has not been clarified. In this study, the novel quinoa peptides were obtained from quinoa protein hydrolysate and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The anticancer activity of these peptides was predicted by PeptideRanker and evaluated using an antiproliferative assay in colon cancer Caco-2 cells. Combined with the result of histone deacetylase 1 (HDAC1) inhibitory activity assay, the highly anticancer activity peptides FHPFPR, NWFPLPR, and HYNPYFPG were screened and further investigated. Molecular docking was used to analyze the binding site between peptides and HDAC1, and results showed that three peptides were bound in the active pocket of HDAC1. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot showed that the expression of HDAC1, NFκB, IL-6, IL-8, Bcl-2 was significantly decreased, whereas caspase3 expression showed a remarkable evaluation. In conclusion, quinoa peptides may have the potential to protect against cancer development by inhibiting HDAC1 activity and regulating the expression of the cancer-related genes, which indicates that these peptides could be explored as functional foods to alleviate colon cancer.
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Ebrahimi N, Adelian S, Shakerian S, Afshinpour M, Chaleshtori SR, Rostami N, Hamblin MR, Aref AR. Crosstalk between ferroptosis and the epithelial-mesenchymal transition: implications for inflammation and cancer therapy. Cytokine Growth Factor Rev 2022; 64:33-45. [DOI: 10.1016/j.cytogfr.2022.01.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/19/2022] [Indexed: 02/07/2023]
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Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, Qian X. Emerging mechanisms progress of colorectal cancer liver metastasis. Front Endocrinol (Lausanne) 2022; 13:1081585. [PMID: 36568117 PMCID: PMC9772455 DOI: 10.3389/fendo.2022.1081585] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastasis. The hepatic portal venous system, responsible for collecting most intestinal blood, makes the liver the most common site of CRC metastasis. The formation of liver metastases from colorectal cancer is a long and complex process. It involves the maintenance of primary tumors, vasculature invasion, distant colonization, and metastasis formation. In this review, we serve on how the CRC cells acquire stemness, invade the vascular, and colonize the liver. In addition, we highlight how the resident cells of the liver and immune cells interact with CRC cells. We also discuss the current immunotherapy approaches and challenges we face, and finally, we look forward to finding new therapeutic targets based on novel sequencing technologies.
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Masuo K, Chen R, Yogo A, Sugiyama A, Fukuda A, Masui T, Uemoto S, Seno H, Takaishi S. SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2. Cancer Sci 2021; 112:4987-4999. [PMID: 34628696 PMCID: PMC8645768 DOI: 10.1111/cas.15162] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer has an extremely poor prognosis because of its resistance to conventional therapies. Cancer stem cell (CSC)-targeted therapy is considered a promising approach for this disease. Epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) contribute to CSC properties in some solid tumors; however, this mechanism has not been fully elucidated in pancreatic cancer. Zinc finger protein, SNAIL2 (also known as SLUG), is a member of the SNAIL superfamily of EMT-TFs and is commonly overexpressed in pancreatic cancer. Patients exhibiting high SNAIL2 expression have a poor prognosis. In this study, we showed that the suppression of SNAIL2 expression using RNA interference decreased tumorigenicity in vitro (sphere formation assay) and in vivo (xenograft assay) in 2 pancreatic cancer cell lines, KLM1 and KMP5. In addition, SNAIL2 suppression resulted in increased sensitivity to gemcitabine and reduced the expression of CD44, a pancreatic CSC marker. Moreover, experiments on tumor spheroids established from surgically resected pancreatic cancer tissues yielded similar results. A microarray analysis revealed that the mechanism was mediated by insulin-like growth factor (IGF) binding protein 2. These results indicate that IGFBP2 regulated by SNAIL2 may represent an effective therapeutic target for pancreatic cancer.
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Affiliation(s)
- Kenji Masuo
- DSK ProjectMedical Innovation CenterGraduate School of MedicineKyoto UniversityKyotoJapan
- Department of Gastroenterology and HepatologyGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Ru Chen
- DSK ProjectMedical Innovation CenterGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Akitada Yogo
- DSK ProjectMedical Innovation CenterGraduate School of MedicineKyoto UniversityKyotoJapan
- Department of Hepato‐Biliary‐Pancreatic Surgery and TransplantationGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Aiko Sugiyama
- DSK ProjectMedical Innovation CenterGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Akihisa Fukuda
- Department of Gastroenterology and HepatologyGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Toshihiko Masui
- Department of Hepato‐Biliary‐Pancreatic Surgery and TransplantationGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Shinji Uemoto
- Department of Hepato‐Biliary‐Pancreatic Surgery and TransplantationGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroshi Seno
- Department of Gastroenterology and HepatologyGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Shigeo Takaishi
- DSK ProjectMedical Innovation CenterGraduate School of MedicineKyoto UniversityKyotoJapan
- Department of Gastroenterology and HepatologyGraduate School of MedicineKyoto UniversityKyotoJapan
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Chen T, Wang Y, Nan Z, Wu J, Li A, Zhang T, Qu X, Li C. Interaction Between Macrophage Extracellular Traps and Colon Cancer Cells Promotes Colon Cancer Invasion and Correlates With Unfavorable Prognosis. Front Immunol 2021; 12:779325. [PMID: 34925357 PMCID: PMC8671452 DOI: 10.3389/fimmu.2021.779325] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/15/2021] [Indexed: 01/03/2023] Open
Abstract
BackgroundMacrophage extracellular traps (METs) and tumor-infiltrating macrophages contribute to the progression of several diseases. But the role of METs and tumor-infiltrating macrophages in colon cancer (CC) has not been illuminated. In this study, we aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo.MethodsA training cohort consisting of 116 patients and a validation cohort of 94 patients were enrolled in this study. Immunofluorescence (IF) staining was conducted to determine METs formation in CC patients. Cox regression was used to perform prognostic analysis and screen out the best prognostic model. A nomogram was established to predict 5-year overall survival (OS). The correlation between METs with clinicopathological features and inflammatory markers was analyzed. The formation of METs in vitro was detected by SYTOX® green and IF staining, and the effect of METs on CC cells was detected by transwell assays. PAD2-IN-1, a selective inhibitor of peptidylarginine deiminase 2 (PAD2), was introduced to destroy the crosstalk between CC cells and METs in vitro and in vivo.ResultsMETs levels were higher in CC tissues and were an independent prognostic factor for CC patients. The prognostic model consisting of age, tumors local invasion, lymph node metastasis and METs were confirmed to be consistent and accurate for predicting the 5-year OS of CC patients. Besides, METs were correlated with distant metastasis and inflammation. Through in vitro experiments, we confirmed that there was a positive feedback loop between CC cells and METs, in that METs promoted the invasion of CC cells and CC cells enhanced the production of METs, in turn. This interaction could be blocked by PAD2-IN-1 inhibitors. More importantly, animal experiments revealed that PAD2-IN-1 inhibited METs formation and CC liver metastasis in vivo.ConclusionsMETs were the potential biomarker of CC patient prognosis. PAD2-IN-1 inhibited the crosstalk between CC cells and METs in vitro and in vivo, which should be emphasized in CC therapy.
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Affiliation(s)
- Tianli Chen
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Wang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhaodi Nan
- Institute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jie Wu
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ailu Li
- Department of Obstetrics and Gynecology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Tingguo Zhang
- Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xun Qu
- Institute of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chen Li
- Department of Ultrasound, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Chen Li,
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Lee YH, Kim SJ, Fang X, Song NY, Kim DH, Suh J, Na HK, Kim KO, Baek JH, Surh YJ. JNK-mediated Ser27 phosphorylation and stabilization of SIRT1 promote growth and progression of colon cancer through deacetylation-dependent activation of Snail. Mol Oncol 2021; 16:1555-1571. [PMID: 34826187 PMCID: PMC8978515 DOI: 10.1002/1878-0261.13143] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/31/2021] [Accepted: 11/25/2021] [Indexed: 01/14/2023] Open
Abstract
Sirtuin 1 (SIRT1), an NAD+ -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients' tissues and human colon cancer cell lines. This prompted us to investigate a role of phospho-SIRT1 in the context of colon cancer progression. A phosphorylation-defective mutant form of SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harboring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells.
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Affiliation(s)
- Yeon-Hwa Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Su-Jung Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Xizhu Fang
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Na-Young Song
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, South Korea
| | - Jinyoung Suh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hye-Kyung Na
- Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, South Korea
| | - Kyung-Ok Kim
- Gachon Medical Research Institute, Gil Medical Center, Gachon University, Incheon, Korea
| | - Jeong-Heum Baek
- Division of Colon and Rectal Surgery, Department of Surgery, Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea
| | - Young-Joon Surh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.,Cancer Research Institute, Seoul National University, Seoul, South Korea
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Fernandes MT, Yassuda V, Bragança J, Link W, Ferreira BI, De Sousa-Coelho AL. Tribbles Gene Expression Profiles in Colorectal Cancer. GASTROINTESTINAL DISORDERS 2021; 3:218-236. [DOI: https:/doi.org/10.3390/gidisord3040021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death due to cancer in the world. Therefore, the identification of novel druggable targets is urgently needed. Tribbles proteins belong to a pseudokinase family, previously recognized in CRC as oncogenes and potential therapeutic targets. Here, we analyzed the expression of TRIB1, TRIB2, and TRIB3 simultaneously in 33 data sets from CRC based on available GEO profiles. We show that all three Tribbles genes are overrepresented in CRC cell lines and primary tumors, though depending on specific features of the CRC samples. Higher expression of TRIB2 in the tumor microenvironment and TRIB3 overexpression in an early stage of CRC development, unveil a potential and unexplored role for these proteins in the context of CRC. Differential Tribbles expression was also explored in diverse cellular experimental conditions where either genetic or pharmacological approaches were used, providing novel hints for future research. This comprehensive bioinformatic analysis provides new insights into Tribbles gene expression and transcript regulation in CRC.
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Affiliation(s)
- Mónica T. Fernandes
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Escola Superior de Saúde (ESS), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - Victor Yassuda
- Escola Superior de Saúde (ESS), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - José Bragança
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisboa, Portugal
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
| | - Bibiana I. Ferreira
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - Ana Luísa De Sousa-Coelho
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Escola Superior de Saúde (ESS), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Centro de Estudos e Desenvolvimento em Saúde (CES), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
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Fernandes MT, Yassuda V, Bragança J, Link W, Ferreira BI, De Sousa-Coelho AL. Tribbles Gene Expression Profiles in Colorectal Cancer. GASTROINTESTINAL DISORDERS 2021; 3:218-236. [DOI: 10.3390/gidisord3040021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death due to cancer in the world. Therefore, the identification of novel druggable targets is urgently needed. Tribbles proteins belong to a pseudokinase family, previously recognized in CRC as oncogenes and potential therapeutic targets. Here, we analyzed the expression of TRIB1, TRIB2, and TRIB3 simultaneously in 33 data sets from CRC based on available GEO profiles. We show that all three Tribbles genes are overrepresented in CRC cell lines and primary tumors, though depending on specific features of the CRC samples. Higher expression of TRIB2 in the tumor microenvironment and TRIB3 overexpression in an early stage of CRC development, unveil a potential and unexplored role for these proteins in the context of CRC. Differential Tribbles expression was also explored in diverse cellular experimental conditions where either genetic or pharmacological approaches were used, providing novel hints for future research. This comprehensive bioinformatic analysis provides new insights into Tribbles gene expression and transcript regulation in CRC.
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Affiliation(s)
- Mónica T. Fernandes
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Escola Superior de Saúde (ESS), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - Victor Yassuda
- Escola Superior de Saúde (ESS), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - José Bragança
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisboa, Portugal
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
| | - Bibiana I. Ferreira
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Faculdade de Medicina e Ciências Biomédicas (FMCB), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - Ana Luísa De Sousa-Coelho
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Escola Superior de Saúde (ESS), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
- Centro de Estudos e Desenvolvimento em Saúde (CES), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
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Asif PJ, Longobardi C, Hahne M, Medema JP. The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis. Cancers (Basel) 2021; 13:4720. [PMID: 34572947 PMCID: PMC8472587 DOI: 10.3390/cancers13184720] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/13/2021] [Accepted: 09/18/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs.
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Affiliation(s)
- Paris Jabeen Asif
- Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (P.J.A.); (C.L.)
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Ciro Longobardi
- Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (P.J.A.); (C.L.)
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Michael Hahne
- Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, 34090 Montpellier, France;
| | - Jan Paul Medema
- Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (P.J.A.); (C.L.)
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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SenGupta S, Hein LE, Parent CA. The Recruitment of Neutrophils to the Tumor Microenvironment Is Regulated by Multiple Mediators. Front Immunol 2021; 12:734188. [PMID: 34567000 PMCID: PMC8461236 DOI: 10.3389/fimmu.2021.734188] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different mediators collaborate by integrating their signaling network, and particularly focus on TGF-β, a cytokine that is highly expressed in invasive tumors, and CXCR2 ligands, which are crucial neutrophil recruiting chemokines. Finally, we highlight gaps in the field and the need to expand current knowledge of the secretory machineries and cross-talks among mediators to develop novel neutrophil targeting strategies as effective therapeutic options in the treatment of cancer.
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Affiliation(s)
- Shuvasree SenGupta
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Lauren E. Hein
- Cancer Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Carole A. Parent
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
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43
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Yu X, Wang Q, Liu B, Zhang N, Cheng G. Vitamin D Enhances Radiosensitivity of Colorectal Cancer by Reversing Epithelial-Mesenchymal Transition. Front Cell Dev Biol 2021; 9:684855. [PMID: 34422809 PMCID: PMC8371408 DOI: 10.3389/fcell.2021.684855] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 07/15/2021] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is often resistant to conventional therapies. Previous studies have reported the anticancer effects of vitamin D in several cancers, its role in radiotherapy (RT) remains unknown. We found that 1α, 25-dihydroxyvitamin D3 (VD3), the biologically active form of vitamin D, had antitumor effect on CRC and sensitized CRC cells to ionizing radiation (IR). VD3 demonstrated synergistic effect in combination with IR, which were detected by colony formation and cell proliferation assay. Radiosensitivity restoration induced by VD3 was associated with a series of phenotypes, including apoptosis, autophagy, and epithelial-mesenchymal transition (EMT). Using proteomics, “regulation of cell migration” and “cadherin” were found to be obviously enriched GO terms. Moreover, cystatin D and plasminogen activator inhibitor-1 (PAI-1), the differentially expressed proteins, were associated with EMT. Next, we confirmed the contributions of these two genes in enhancing IR sensitivity of CRC cells upon inhibition of EMT. As determined by proteomics, the mechanism underlying such sensitivity involved partially block of JAK/STAT3 signaling pathway. Furthermore, VD3 also elicited sensitization to RT in xenograft CRC models without additional toxicity. Our study revealed that VD3 was able to act in synergy with IR both in vitro and in vivo and could also confer radiosensitivity by regulating EMT, thereby providing a novel insight for elevating the efficacy of therapeutic regimens.
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Affiliation(s)
- Xinyue Yu
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qian Wang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Baocai Liu
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ning Zhang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Guanghui Cheng
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
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Comprehensive Omics Analysis of a Novel Small-Molecule Inhibitor of Chemoresistant Oncogenic Signatures in Colorectal Cancer Cell with Antitumor Effects. Cells 2021; 10:cells10081970. [PMID: 34440739 PMCID: PMC8392328 DOI: 10.3390/cells10081970] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 01/10/2023] Open
Abstract
Tumor recurrence from cancer stem cells (CSCs) and metastasis often occur post-treatment in colorectal cancer (CRC), leading to chemoresistance and resistance to targeted therapy. MYC is a transcription factor in the nuclei that modulates cell growth and development, and regulates immune response in an antitumor direction by mediating programmed death ligand 1 (PD-L1) and promoting CRC tumor recurrence after adjuvant chemotherapy. However, the molecular mechanism through which c-MYC maintains stemness and confers treatment resistance still remains elusive in CRC. In addition, recent reports demonstrated that CRC solid colon tumors expresses C-X-C motif chemokine ligand 8 (CXCL8). Expression of CXCL8 in CRC was reported to activate the expression of PD-L1 immune checkpoint through c-MYC, this ultimately induces chemoresistance in CRC. Accumulating studies have also demonstrated increased expression of CXCL8, matrix metalloproteinase 7 (MMP7), tissue inhibitor of metalloproteinase 1 (TIMP1), and epithelial-to-mesenchymal transition (EMT) components, in CRC tumors suggesting their potential collaboration to promote EMT and CSCs. TIMP1 is MMP-independent and regulates cell development and apoptosis in various cancer cell types, including CRC. Recent studies showed that TIMP1 cleaves CXCL8 on its chemoattractant, thereby influencing its mechanistic response to therapy. This therefore suggests crosstalk among the c-MYC/CXCL8/TIMP1 oncogenic signatures. In this study, we explored computer simulations through bioinformatics to identify and validate that the MYC/CXCL8/TIMP1 oncogenic signatures are overexpressed in CRC, Moreover, our docking results exhibited putative binding affinities of the above-mentioned oncogenes, with our novel small molecule, RV59, Finally, we demonstrated the anticancer activities of RV59 against NCI human CRC cancer cell lines both as single-dose and dose-dependent treatments, and also demonstrated the MYC/CXCL8/TIMP1 signaling pathway as a potential RV59 drug target.
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Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9959807. [PMID: 34336125 PMCID: PMC8315867 DOI: 10.1155/2021/9959807] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/22/2021] [Accepted: 06/21/2021] [Indexed: 01/05/2023]
Abstract
Background Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.
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Fultang N, Chakraborty M, Peethambaran B. Regulation of cancer stem cells in triple negative breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2021; 4:321-342. [PMID: 35582030 PMCID: PMC9019272 DOI: 10.20517/cdr.2020.106] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/28/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022]
Abstract
Triple Negative Breast Cancer (TNBC) is the most lethal subtype of breast cancer. Despite the successes of emerging targeted therapies, relapse, recurrence, and therapy failure rates in TNBC significantly outpace other subtypes of breast cancer. Mounting evidence suggests accumulation of therapy resistant Cancer Stem Cell (CSC) populations within TNBCs contributes to poor clinical outcomes. These CSCs are enriched in TNBC compared to non-TNBC breast cancers. The mechanisms underlying CSC accumulation have been well-characterized and discussed in other reviews. In this review, we focus on TNBC-specific mechanisms that allow the expansion and activity of self-renewing CSCs. We highlight cellular signaling pathways and transcription factors, specifically enriched in TNBC over non-TNBC breast cancer, contributing to stemness. We also analyze publicly available single-cell RNA-seq data from basal breast cancer tumors to highlight the potential of emerging bioinformatic approaches in identifying novel drivers of stemness in TNBC and other cancers.
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Affiliation(s)
- Norman Fultang
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19140, USA
| | - Madhuparna Chakraborty
- Department of Biological Sciences, The University of the Sciences, Philadelphia, PA 19140, USA
| | - Bela Peethambaran
- Department of Biological Sciences, The University of the Sciences, Philadelphia, PA 19140, USA
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Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer. Mediators Inflamm 2021; 2021:9918379. [PMID: 34220337 PMCID: PMC8219436 DOI: 10.1155/2021/9918379] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Tumor cells undergo invasion and metastasis through epithelial-to-mesenchymal cell transition (EMT) by activation of alterations in extracellular matrix (ECM) protein-encoding genes, enzymes responsible for the breakdown of ECM, and activation of genes that drive the transformation of the epithelial cell to the mesenchymal type. Inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive EMT. EMT drives primary tumors to metastasize in different parts of the body. T and B cells, dendritic cells (DCs), and tumor-associated macrophages (TAMs) which are present in the tumor microenvironment induce EMT. The current review elucidates the interaction between EMT tumor cells and immune cells under the microenvironment. Such complex interactions provide a better understanding of tumor angiogenesis and metastasis and in defining the aggressiveness of the primary tumors. Anti-inflammatory molecules in this context may open new therapeutic options for the better treatment of tumor progression. Targeting EMT and the related mechanisms by utilizing natural compounds may be an important and safe therapeutic alternative in the treatment of tumor growth.
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48
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Akabane S, Shimizu W, Takakura Y, Kochi M, Taguchi K, Nakashima I, Sato K, Hattori M, Egi H, Sentani K, Yasui W, Ohdan H. Tumor budding as a predictive marker for 5-fluorouracil response in adjuvant-treated stage III colorectal cancer. Int J Clin Oncol 2021; 26:1285-1292. [PMID: 33881678 DOI: 10.1007/s10147-021-01917-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/02/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Tumor budding (TB) has been described as an adverse prognostic marker for operable colorectal cancer (CRC); however, a limited number of studies have demonstrated the prognostic significance of TB in patients with drug therapy. This study was conducted to determine the predictive power of TB in stage III CRC patients who received adjuvant chemotherapy. METHODS We retrospectively collected clinicopathological data including TB of 237 stage III colorectal cancer patients at Hiroshima University Hospital between July 1, 2006 and June 31, 2019. Differential disease-free survival (DFS) was investigated according to TB status. RESULTS This study included 237 patients with a median age of 67 years, comprising patients who underwent surgery alone (n = 65), 5-fluorouracil (5-FU) monotherapy (n = 129), and oxaliplatin-based chemotherapy (n = 43). Overall, 81 patients developed disease recurrence, and 33 patients died of cancer-related causes. The TB status was categorized into two groups: 99 with low budding (< 5 buds) and 138 with high budding (≥ 5 buds). Overall, the low budding cases demonstrated significantly better DFS. In the 5-FU monotherapy group, low-risk patients (T1, T2, or T3 and N1) with low budding showed a remarkably higher 3-year DFS (91%) compared to high budding (55%). CONCLUSION Our results indicate that TB could play a subsidiary role in selecting patients who could maintain a favorable prognosis with 5-FU monotherapy in stage III CRC.
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Affiliation(s)
- Shintaro Akabane
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Wataru Shimizu
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Yuji Takakura
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masatoshi Kochi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kazuhiro Taguchi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ikki Nakashima
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Koki Sato
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Minoru Hattori
- Center for Medical Education, School of Medicine, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Egi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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Zheng X, Dai F, Feng L, Zou H, Feng L, Xu M. Communication Between Epithelial-Mesenchymal Plasticity and Cancer Stem Cells: New Insights Into Cancer Progression. Front Oncol 2021; 11:617597. [PMID: 33968721 PMCID: PMC8097085 DOI: 10.3389/fonc.2021.617597] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 02/23/2021] [Indexed: 02/05/2023] Open
Abstract
The epithelial–mesenchymal transition (EMT) is closely associated with the acquisition of aggressive traits by carcinoma cells and is considered responsible for metastasis, relapse, and chemoresistance. Molecular links between the EMT and cancer stem cells (CSCs) have indicated that EMT processes play important roles in the expression of CSC-like properties. It is generally thought that EMT-related transcription factors (EMT-TFs) need to be downregulated to confer an epithelial phenotype to mesenchymal cells and increase cell proliferation, thereby promoting metastasis formation. However, the genetic and epigenetic mechanisms that regulate EMT and CSC activation are contradictory. Emerging evidence suggests that EMT need not be a binary model and instead a hybrid epithelial/mesenchymal state. This dynamic process correlates with epithelial–mesenchymal plasticity, which indicates a contradictory role of EMT during cancer progression. Recent studies have linked the epithelial–mesenchymal plasticity and stem cell-like traits, providing new insights into the conflicting relationship between EMT and CSCs. In this review, we examine the current knowledge about the interplay between epithelial–mesenchymal plasticity and CSCs in cancer biology and evaluate the controversies and future perspectives. Understanding the biology of epithelial–mesenchymal plasticity and CSCs and their implications in therapeutic treatment may provide new opportunities for targeted intervention.
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Affiliation(s)
- Xiaobo Zheng
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Fuzhen Dai
- Department of General Surgery, The First People's Hospital of Longquanyi District, Chengdu, China
| | - Lei Feng
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zou
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.,General Surgery Center of PLA, General Hospital of Western Theater Command, Chengdu, China
| | - Li Feng
- Department of General Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingqing Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Hepatopancreatobiliary Surgery, Meishan City People's Hospital, Meishan Hospital of West China Hospital, Sichuan University, Meishan, China
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Liao TT, Cheng WC, Yang CY, Chen YQ, Su SH, Yeh TY, Lan HY, Lee CC, Lin HH, Lin CC, Lu RH, Chiou AET, Jiang JK, Hwang WL. The microRNA-210-Stathmin1 Axis Decreases Cell Stiffness to Facilitate the Invasiveness of Colorectal Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13081833. [PMID: 33921319 PMCID: PMC8069838 DOI: 10.3390/cancers13081833] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/06/2021] [Accepted: 04/09/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Metastasis of tumor cells is the leading cause of death in cancer patients. Concurrent therapy with surgical removal of primary and metastatic lesions is the main approach for cancer therapy. Currently, therapeutic resistant properties of cancer stem cells (CSCs) are known to drive malignant cancer progression, including metastasis. Our study aimed to identify molecular tools dedicated to the detection and treatment of CSCs. We confirmed that microRNA-210-3p (miR-210) was upregulated in colorectal stem-like cancer cells, which targeted stathmin1 (STMN1), to decrease cell elasticity for increasing mobility. We envision that strategies for softening cellular elasticity will reduce the onset of CSC-orientated metastasis. Abstract Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.
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Affiliation(s)
- Tsai-Tsen Liao
- Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (T.-T.L.); (H.-Y.L.)
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Wei-Chung Cheng
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, China Medical University, Taichung 406, Taiwan;
- Research Center for Cancer Biology, China Medical University, Taichung 406, Taiwan
| | - Chih-Yung Yang
- Department of Education and Research, Taipei City Hospital, Taipei 106, Taiwan;
- General Education Center, University of Taipei, Taipei 100, Taiwan
| | - Yin-Quan Chen
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Shu-Han Su
- Institution of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan; (S.-H.S.); (T.-Y.Y.)
| | - Tzu-Yu Yeh
- Institution of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan; (S.-H.S.); (T.-Y.Y.)
| | - Hsin-Yi Lan
- Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (T.-T.L.); (H.-Y.L.)
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan
| | - Chih-Chan Lee
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Hung-Hsin Lin
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan;
| | - Chun-Chi Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan;
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Ruey-Hwa Lu
- Department of Surgery, Zhongxing Branch, Taipei City Hospital, Taipei 106, Taiwan;
| | - Arthur Er-Terg Chiou
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Jeng-Kai Jiang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan;
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: (J.-K.J.); (W.-L.H.); Tel.: +886-2-2826-7000 (ext. 65832) (W.-L.H.)
| | - Wei-Lun Hwang
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan
- Correspondence: (J.-K.J.); (W.-L.H.); Tel.: +886-2-2826-7000 (ext. 65832) (W.-L.H.)
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