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1
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Berk Ş. Comprehensive bibliometric analysis and perspectives on therapies targeting colon cancer stem cells over a 40-year period. Regen Ther 2025; 29:19-34. [PMID: 40124468 PMCID: PMC11930536 DOI: 10.1016/j.reth.2025.02.015] [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: 12/27/2024] [Revised: 02/12/2025] [Accepted: 02/27/2025] [Indexed: 03/25/2025] Open
Abstract
The presence of cancer stem cells (CSCs) is one of the primary causes of recurring therapy resistance because they have two main capacities: self-renewal and avoiding apoptotic pathways. Despite their relevance, no full bibliometric analysis has yet been done in this topic. The goal of this work is to use bibliometric analysis to map the fundamental and emergent areas in therapeutics targeting colon cancer stem cells. To perform bibliometric analysis on colon cancer stem cells (CCSCs) literature, spanning roughly the last 40 years, in order to establish a firm base for future projections by emphasizing the findings of the most notable research. All information pertinent to CCSCs was accessed from Web of Science Core Collection database. In order to identify and analyze the research hotspots and trends related to this topic, Biblioshiny (RStudio) and VOSviewer were utilized to ascertain the countries/regions, institutions, journals, authors, references, and keywords involved. The targeted time span covered 1735 research-, and review articles. The most frequent keywords were "colorectal cancer," "cancer stem cells," and "colon cancer," while the most trending keywords in the last few years were "protein stability," "spheroid formation," "ubiquitination," "exosomes," "patient-derived organoids," and "gut microbiota." Over the past 40 years, there has been a significant advancement in researchers' understanding of colon cancer stem cells. In addition, the cluster map of co-cited literature showed that colon cancer stem cell research has emerged as a research hotspot. It was also anticipated that the main focus of the future efforts appears to involve clinical applications of cell-targeted colon cancer therapy. These results provide researchers with a comprehensive understanding of this field and provide insightful ideas for further research.
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Affiliation(s)
- Şeyda Berk
- Department of Molecular Biology and Genetics, Faculty of Science, Sivas Cumhuriyet University, Sivas, 58140, Turkey
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2
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Li W, Qian Y, Cai X, He Y, Meng X, Zhang L. Therapeutic intervention with anti-TNF alleviates colonic and hepatic toxicity induced by perfluorooctanoic acid (PFOA). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 296:118125. [PMID: 40220356 DOI: 10.1016/j.ecoenv.2025.118125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/10/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
Perfluorooctanoic acid (PFOA) is a prevalent and chemically stable environmental contaminant. Our preliminary data suggest that chronic exposure to PFOA induces colonic damage in mice that resembles inflammatory bowel disease (IBD). Anti-TNF therapies are commonly used in the clinical management of IBD. Building upon our previous findings, we administered anti-TNF treatment to mice exposed to PFOA. Our results show that anti-TNF therapy significantly reduces the colonic inflammatory response, activation of the NLR family pyrin domain containing 3 (NLRP) inflammasome, and apoptosis induced by PFOA. Additionally, anti-TNF treatment restores intestinal barrier integrity, which is disrupted by PFOA exposure, and enhances the regenerative capacity of the colon by promoting intestinal stem cell function. Furthermore, anti-TNF therapy effectively mitigates hepatic inflammation, liver dysfunction, lipid metabolism disturbances, NLRP3 inflammasome activation, and apoptosis in the liver triggered by PFOA. In conclusion, our study provides compelling evidence that anti-TNF therapy can alleviate both colonic and hepatic injuries induced by PFOA exposure. This research expands our understanding of environmental toxin-induced diseases and offers potential therapeutic strategies for managing PFOA-related disorders in the future.
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Affiliation(s)
- Wei Li
- Department of Histology and Embryology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China; Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Yongjing Qian
- Department of Histology and Embryology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China; Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Xiaojing Cai
- Department of Histology and Embryology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Yu He
- Department of Emergency, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, No.9 Chongwen Road, Suzhou, 215000, Jiangsu, China
| | - Xiannan Meng
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Ling Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China; National Demonstration Center for Experimental Basic Medical Science Education (Xuzhou Medical University), 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
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3
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Vinayak V, Basir R, Golloshi R, Toth J, Sant'Anna L, Lakadamyali M, McCord RP, Shenoy VB. Polymer model integrates imaging and sequencing to reveal how nanoscale heterochromatin domains influence gene expression. Nat Commun 2025; 16:3816. [PMID: 40268925 PMCID: PMC12019571 DOI: 10.1038/s41467-025-59001-z] [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: 09/27/2024] [Accepted: 04/08/2025] [Indexed: 04/25/2025] Open
Abstract
Chromatin organization regulates gene expression, with nanoscale heterochromatin domains playing a fundamental role. Their size varies with microenvironmental stiffness and epigenetic interventions, but how these factors regulate their formation and influence transcription remains unclear. To address this, we developed a sequencing-informed copolymer model that simulates chromatin evolution through diffusion and active epigenetic reactions. Our model predicts the formation of nanoscale heterochromatin domains and quantifies how domain size scales with epigenetic reaction rates, showing that epigenetic and compaction changes primarily occur at domain boundaries. We validated these predictions via Hi-C and super-resolution imaging of hyperacetylated melanoma cells and identified differential expression of metastasis-related genes through RNA-seq. We validated our findings in hMSCs, where epigenetic reaction rates respond to microenvironmental stiffness. Conclusively, our simulations reveal that heterochromatin domain boundaries regulate gene expression and epigenetic memory. These findings demonstrate how external cues drive chromatin organization and transcriptional memory in development and disease.
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Affiliation(s)
- Vinayak Vinayak
- Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Ramin Basir
- Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Rosela Golloshi
- Departments of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Giovanis Institute for Translational Cell Biology, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Joshua Toth
- Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Lucas Sant'Anna
- Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Melike Lakadamyali
- Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rachel Patton McCord
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA
| | - Vivek B Shenoy
- Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA.
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4
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Kumari R, Ghava D, Rathod R, Panda AK, Kumar S, Behera SK. Molecular Dynamics of Adenomatous Polyposis Coli (APC) Protein and Its Inhibitors: A Special Insight to Colorectal Cancer. Crit Rev Oncog 2025; 30:91-105. [PMID: 39819437 DOI: 10.1615/critrevoncog.v30.i1.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Colorectal cancer (CRC) initiates in colon or rectum is named as colon or rectal cancer, based on the site of inception. Various genetic alterations responsible for CRC include several signaling pathways. The Wingless/Wnt signaling pathway is the vital pathway which involved in the cancer pathogenesis. The hallmark of human CRC is adenomatous polyposis coli (APC), a negative regulator of the Wnt pathway. Mutations in the APC gene is a critical event in the development of human CRC which may lead to overexpression and stabilization of β-catenin that enters into the nucleus and helps in cancer cell proliferation. Significant obstacles to the therapeutic intervention of the Wnt signaling system still exist, despite promising approaches for the development of anti-cancer medicines targeting this route. The advent of computational techniques for cancer diagnosis, prognosis, and drug development has spurred the researchers to explore CRC at an early stage. This report had unzipped the importance of APC in Wnt signaling pathway associated with current advances and challenges in drug discovery for CRC. A combinatorial computational approach identified the potential anti-cancerous drug among XL888, 5-bromouracil, 5-fluorouracil, and Ganetespib against APC which is often treated as gatekeeper of CRC. This in silico investigation revealed Ganetespib as a potential anti-cancerous drug against APC for CRC therapeutics, which will be an alternative to chemotherapy. In vitro and in vivo studies are needed further to confirm the efficiency and evaluate potency of Ganetespib against the target.
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Affiliation(s)
- Rina Kumari
- National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India 382055
| | - Dilip Ghava
- National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India 382055
| | - Rajeshwari Rathod
- National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India 382055
| | | | - Sunil Kumar
- ICAR-Indian Agricultural Statistics Research Institute, New Delhi, India
| | - Santosh Kumar Behera
- National Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat, India -382055, Gujarat, India
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Rodvold JJ, Grimmer M, Ruiz K, Marsters SA, Oikonomidi I, Tan-Aristy E, Pham VC, Sarkar T, Harnoss JM, Shatz-Binder W, Modrusan ZD, Wu TD, Lill JR, Villemure E, Rudolph J, de Sousa e Melo F, Ashkenazi A. ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway. CANCER RESEARCH COMMUNICATIONS 2024; 4:2734-2755. [PMID: 39324706 PMCID: PMC11492184 DOI: 10.1158/2767-9764.crc-24-0268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/07/2024] [Accepted: 09/24/2024] [Indexed: 09/27/2024]
Abstract
SIGNIFICANCE ATF6 intervention reduces colorectal cancer cell and organoid viability by interrupting dysregulated Wnt signaling, identifying a novel facilitator and potential therapeutic target in colorectal cancer.
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Affiliation(s)
- Jeffrey J. Rodvold
- Department of Research Oncology, Genentech, Inc., South San Francisco, California
| | - Matthew Grimmer
- Department of Computational Science, Genentech, Inc., South San Francisco, California
| | - Karen Ruiz
- Department of Discovery Oncology, Genentech, Inc., South San Francisco, California
| | - Scot A. Marsters
- Department of Research Oncology, Genentech, Inc., South San Francisco, California
| | - Ioanna Oikonomidi
- Department of Research Oncology, Genentech, Inc., South San Francisco, California
| | - Eileen Tan-Aristy
- Department of Research Oncology, Genentech, Inc., South San Francisco, California
| | - Victoria C. Pham
- Department of Microchemistry, Proteomics, and Lipidomics, Genentech, Inc., South San Francisco, California
| | - Tamal Sarkar
- Department of General, Visceral, Thoracic, and Transplantation Surgery, University Hospital Giessen, Giessen, Germany
| | - Jonathan M. Harnoss
- Department of General, Visceral, Thoracic, and Transplantation Surgery, University Hospital Giessen, Giessen, Germany
| | - Whitney Shatz-Binder
- Department of Pharmaceutical Development, Genentech, Inc., South San Francisco, California
| | - Zora D. Modrusan
- Department of Microchemistry, Proteomics, and Lipidomics, Genentech, Inc., South San Francisco, California
| | - Thomas D. Wu
- Department of Computational Science, Genentech, Inc., South San Francisco, California
| | - Jennie R. Lill
- Department of Microchemistry, Proteomics, and Lipidomics, Genentech, Inc., South San Francisco, California
| | - Elisia Villemure
- Department of Discovery Chemistry, Genentech, Inc., South San Francisco, California
| | - Joachim Rudolph
- Department of Discovery Chemistry, Genentech, Inc., South San Francisco, California
| | | | - Avi Ashkenazi
- Department of Research Oncology, Genentech, Inc., South San Francisco, California
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6
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Lee YJ, Kim WR, Park EG, Lee DH, Kim JM, Shin HJ, Jeong HS, Roh HY, Kim HS. Exploring the Key Signaling Pathways and ncRNAs in Colorectal Cancer. Int J Mol Sci 2024; 25:4548. [PMID: 38674135 PMCID: PMC11050203 DOI: 10.3390/ijms25084548] [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: 03/29/2024] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer to be diagnosed, and it has a substantial mortality rate. Despite numerous studies being conducted on CRC, it remains a significant health concern. The disease-free survival rates notably decrease as CRC progresses, emphasizing the urgency for effective diagnostic and therapeutic approaches. CRC development is caused by environmental factors, which mostly lead to the disruption of signaling pathways. Among these pathways, the Wingless/Integrated (Wnt) signaling pathway, Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, Mitogen-Activated Protein Kinase (MAPK) signaling pathway, Transforming Growth Factor-β (TGF-β) signaling pathway, and p53 signaling pathway are considered to be important. These signaling pathways are also regulated by non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). They have emerged as crucial regulators of gene expression in CRC by changing their expression levels. The altered expression patterns of these ncRNAs have been implicated in CRC progression and development, suggesting their potential as diagnostic and therapeutic targets. This review provides an overview of the five key signaling pathways and regulation of ncRNAs involved in CRC pathogenesis that are studied to identify promising avenues for diagnosis and treatment strategies.
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Affiliation(s)
- Yun Ju Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Woo Ryung Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Eun Gyung Park
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Du Hyeong Lee
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Jung-min Kim
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Hae Jin Shin
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Hyeon-su Jeong
- Department of Integrated Biological Sciences, Pusan National University, Busan 46241, Republic of Korea; (Y.J.L.); (W.R.K.); (E.G.P.); (D.H.L.); (J.-m.K.); (H.J.S.); (H.-s.J.)
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
| | - Hyun-Young Roh
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Heui-Soo Kim
- Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea;
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
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7
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Gholamzad A, Khakpour N, Khosroshahi EM, Asadi S, Koohpar ZK, Matinahmadi A, Jebali A, Rashidi M, Hashemi M, Sadi FH, Gholamzad M. Cancer stem cells: The important role of CD markers, Signaling pathways, and MicroRNAs. Pathol Res Pract 2024; 256:155227. [PMID: 38490099 DOI: 10.1016/j.prp.2024.155227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Abstract
For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.
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Affiliation(s)
- Amir Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Niloofar Khakpour
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences,Tonekabon Branch,Islamic Azad University, Tonekabon, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus,Torun,Poland
| | - Ali Jebali
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Deprtment of Medical Nanotechnology,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences,Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | | | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Lamichhane A, Tavana H. Three-Dimensional Tumor Models to Study Cancer Stemness-Mediated Drug Resistance. Cell Mol Bioeng 2024; 17:107-119. [PMID: 38737455 PMCID: PMC11082110 DOI: 10.1007/s12195-024-00798-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/01/2024] [Indexed: 05/14/2024] Open
Abstract
Solid tumors often contain genetically different populations of cancer cells, stromal cells, various structural and soluble proteins, and other soluble signaling molecules. The American Cancer society estimated 1,958,310 new cancer cases and 609,820 cancer deaths in the United States in 2023. A major barrier against successful treatment of cancer patients is drug resistance. Gain of stem cell-like states by cancer cells under drug pressure or due to interactions with the tumor microenvironment is a major mechanism that renders therapies ineffective. Identifying approaches to target cancer stem cells is expected to improve treatment outcomes for patients. Most of our understanding of drug resistance and the role of cancer stemness is from monolayer cell cultures. Recent advances in cell culture technologies have enabled developing sophisticated three-dimensional tumor models that facilitate mechanistic studies of cancer drug resistance. This review summarizes the role of cancer stemness in drug resistance and highlights the various tumor models that are used to discover the underlying mechanisms and test potentially novel therapeutics.
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Affiliation(s)
- Astha Lamichhane
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
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9
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Pallotta MM, Di Nardo M, Musio A. Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts. Cells 2024; 13:608. [PMID: 38607047 PMCID: PMC11011321 DOI: 10.3390/cells13070608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/25/2024] [Accepted: 03/29/2024] [Indexed: 04/13/2024] Open
Abstract
Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings have led to increased interest in cohesin as a potential target in cancer therapy. Synthetic lethality has been suggested as an approach to exploit genetic differences in cancer cells to influence their selective killing. In this study, we show that mutations in ESCO1, NIPBL, PDS5B, RAD21, SMC1A, SMC3, STAG2, and WAPL genes are synthetically lethal with stimulation of WNT signaling obtained following LY2090314 treatment, a GSK3 inhibitor, in several cancer cell lines. Moreover, treatment led to the stabilization of β-catenin and affected the expression of c-MYC, probably due to the occupancy decrease in cohesin at the c-MYC promoter. Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin.
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Affiliation(s)
| | | | - Antonio Musio
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), 56124 Pisa, Italy; (M.M.P.); (M.D.N.)
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10
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Mollanoori H, Ghelmani Y, Hassani B, Dehghani M. Integrated whole transcriptome profiling revealed a convoluted circular RNA-based competing endogenous RNAs regulatory network in colorectal cancer. Sci Rep 2024; 14:91. [PMID: 38167453 PMCID: PMC10761719 DOI: 10.1038/s41598-023-50230-0] [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: 03/28/2023] [Accepted: 12/17/2023] [Indexed: 01/05/2024] Open
Abstract
Recently, it has been identified that circRNAs can act as miRNA sponge to regulate gene expression in various types of cancers, associating them with cancer initiation and progression. The present study aims to identify colorectal cancer-related circRNAs and the underpinning mechanisms of circRNA/miRNA/mRNA networks in the development and progress of Colorectal Cancer. Differentially expressed circRNAs, miRNAs, and mRNAs were identified in GEO microarray datasets using the Limma package of R. The analysis of differentially expressed circRNAs resulted in 23 upregulated and 31 downregulated circRNAs. CeRNAs networks were constructed by intersecting the results of predicted and experimentally validated databases, circbank and miRWalk, and by performing DEMs and DEGs analysis using Cytoscape. Next, functional enrichment analysis was performed for DEGs included in ceRNA networks. Followed by survival analysis, expression profile assessment using TCGA and GEO data, and ROC curve analysis we identified a ceRNA sub-networks that revealed the potential regulatory effect of hsa_circ_0001955 and hsa_circ_0071681 on survival-related genes, namely KLF4, MYC, CCNA2, RACGAP1, and CD44. Overall, we constructed a convoluted regulatory network and outlined its likely mechanisms of action in CRC, which may contribute to the development of more effective approaches for early diagnosis, prognosis, and treatment of CRC.
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Affiliation(s)
- Hasan Mollanoori
- Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Yaser Ghelmani
- Clinical Research Development Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Bita Hassani
- Sarem Gynecology, Obstertrics and Infertility Research Center, Sarem Women's Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mohammadreza Dehghani
- Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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11
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Chowdhury PR, Salvamani S, Gunasekaran B, Peng HB, Ulaganathan V. H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2023; 96:495-509. [PMID: 38161577 PMCID: PMC10751868 DOI: 10.59249/tdbj7410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in several tumor types, one among them is the lncRNA H19. The paternally imprinted oncofetal gene is expressed in the embryo, downregulated at birth, and reappears in tumors. H19 aids in CRC cell growth, proliferation, invasion, and metastasis via various mechanisms of action, significantly through the lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network, where H19 behaves as a miRNA sponge. The RNA transcript of H19 obtained from the first exon of the H19 gene, miRNA-675 also promotes CRC carcinogenesis. Overexpression of H19 in malignant tissues compared to adjacent non-malignant tissues marks H19 as an independent prognostic marker in CRC. Besides its prognostic value, H19 serves as a promising target for therapy in CRC treatment.
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Affiliation(s)
- Prerana R. Chowdhury
- Division of Applied Biomedical Sciences and
Biotechnology, School of Health Sciences, International Medical University,
Kuala Lumpur, Malaysia
| | - Shamala Salvamani
- Division of Applied Biomedical Sciences and
Biotechnology, School of Health Sciences, International Medical University,
Kuala Lumpur, Malaysia
| | - Baskaran Gunasekaran
- Department of Biotechnology, Faculty of Applied
Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Hoh B. Peng
- Division of Applied Biomedical Sciences and
Biotechnology, School of Health Sciences, International Medical University,
Kuala Lumpur, Malaysia
| | - Vaidehi Ulaganathan
- Department of Biotechnology, Faculty of Applied
Sciences, UCSI University, Kuala Lumpur, Malaysia
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12
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Doxtater K, Tripathi MK, Sekhri R, Hafeez BB, Khan S, Zafar N, Behrman SW, Yallapu MM, Jaggi M, Chauhan SC. MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway. Life Sci Alliance 2023; 6:e202301975. [PMID: 37793774 PMCID: PMC10551643 DOI: 10.26508/lsa.202301975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
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Affiliation(s)
- Kyle Doxtater
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Manish K Tripathi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Radhika Sekhri
- Department of Pathology, Montefiore Medical Center College of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bilal B Hafeez
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Nadeem Zafar
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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13
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Hurley K, Clow R, Jadhav A, Azzam EI, Wang Y. Mitigation of acute radiation syndrome (ARS) with human umbilical cord blood. Int J Radiat Biol 2023; 100:317-334. [PMID: 37967239 DOI: 10.1080/09553002.2023.2277372] [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: 05/30/2023] [Accepted: 09/27/2023] [Indexed: 11/17/2023]
Abstract
PURPOSE The growing concern over potential unintended nuclear accidents or malicious activities involving nuclear/radiological devices cannot be overstated. Exposure to whole-body doses of radiation can result in acute radiation syndrome (ARS), colloquially known as "radiation sickness," which can severely damage various organ systems. Long-term health consequences, such as cancer and cardiovascular disease, can develop many years post-exposure. Identifying effective medical countermeasures and devising a strategic medical plan represents an urgent, unmet need. Various clinical studies have investigated the therapeutic use of umbilical cord blood (UCB) for a range of illnesses, including ARS. The objective of this review is to thoroughly discuss ARS and its sub-syndromes, and to highlight recent findings regarding the use of UCB for radiation injury. UCB, a rich source of stem cells, boasts numerous advantages over other stem cell sources, like bone marrow, owing to its ease of collection and relatively low risk of severe graft-versus-host disease. Preclinical studies suggest that treatment with UCB, and often UCB-derived mesenchymal stromal cells (MSCs), results in improved survival, accelerated hematopoietic recovery, reduced gastrointestinal tract damage, and mitigation of radiation-induced pneumonitis and pulmonary fibrosis. Interestingly, recent evidence suggests that UCB-derived exosomes and their microRNAs (miRNAs) might assist in treating radiation-induced damage, largely by inhibiting fibrotic pathways. CONCLUSION UCB holds substantial potential as a radiation countermeasure, and future research should focus on establishing treatment parameters for ARS victims.
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Affiliation(s)
- Kate Hurley
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Rachel Clow
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Ashok Jadhav
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Edouard I Azzam
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
| | - Yi Wang
- Radiobiology and Health, Canadian Nuclear Laboratories, Chalk River, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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14
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Cho HI, Jo S, Kim MS, Kim HB, Liu X, Xuan Y, Cho JW, Jang YK. SETD5 regulates the OGT-catalyzed O-GlcNAcylation of RNA polymerase II, which is involved in the stemness of colorectal cancer cells. Sci Rep 2023; 13:19885. [PMID: 37963940 PMCID: PMC10646014 DOI: 10.1038/s41598-023-46923-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 11/07/2023] [Indexed: 11/16/2023] Open
Abstract
The dosage-dependent recruitment of RNA polymerase II (Pol II) at the promoters of genes related to neurodevelopment and stem cell maintenance is required for transcription by the fine-tuned expression of SET-domain-containing protein 5 (SETD5). Pol II O-GlcNAcylation by O-GlcNAc transferase (OGT) is critical for preinitiation complex formation and transcription cycling. SETD5 dysregulation has been linked to stem cell-like properties in some cancer types; however, the role of SETD5 in cancer cell stemness has not yet been determined. We here show that aberrant SETD5 overexpression induces stemness in colorectal cancer (CRC) cells. SETD5 overexpression causes the upregulation of PI3K-AKT pathway-related genes and cancer stem cell (CSC) markers such as CD133, Kruppel-like factor 4 (KLF4), and estrogen-related receptor beta (ESRRB), leading to the gain of stem cell-like phenotypes. Our findings also revealed a functional relationship between SETD5, OGT, and Pol II. OGT-catalyzed Pol II glycosylation depends on SETD5, and the SETD5-Pol II interaction weakens in OGT-depleted cells, suggesting a SETD5-OGT-Pol II interdependence. SETD5 deficiency reduces Pol II occupancy at PI3K-AKT pathway-related genes and CD133 promoters, suggesting a role for SETD5-mediated Pol II recruitment in gene regulation. Moreover, the SETD5 depletion nullified the SETD5-induced stemness of CRC cells and Pol II O-GlcNAcylation. These findings support the hypothesis that SETD5 mediates OGT-catalyzed O-GlcNAcylation of RNA Pol II, which is involved in cancer cell stemness gain via CSC marker gene upregulation.
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Affiliation(s)
- Hye In Cho
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Initiative for Biological Function & Systems, Yonsei University, Seoul, 03722, Republic of Korea
| | - Sora Jo
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Initiative for Biological Function & Systems, Yonsei University, Seoul, 03722, Republic of Korea
| | - Min Seong Kim
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Han Byeol Kim
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Department of Neurology, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Xingzhe Liu
- Department of Pathology, Yanbian University College of Medicine, No.977, Gongyuan Road, Yanji, 133002, China
| | - Yanhua Xuan
- Department of Pathology, Yanbian University College of Medicine, No.977, Gongyuan Road, Yanji, 133002, China.
| | - Jin Won Cho
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
- Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Yeun Kyu Jang
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
- Initiative for Biological Function & Systems, Yonsei University, Seoul, 03722, Republic of Korea.
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15
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Jiang Y, Tang Y. SALL4 advances the proliferation and tumor cell stemness of colon cancer cells through the transcription and regulation of ROBO2. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:249-263. [PMID: 37660281 DOI: 10.1080/15257770.2023.2253279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 08/24/2023] [Indexed: 09/04/2023]
Abstract
SALL4 is a transcription factor highly expressed in diverse cancers and is implicated in the development of cancer. SALL4 has been implied to play a cancer-promoting role in colon cancer (CC), but the molecular mechanism remains unclear. Chromatin immunoprecipitation assay and dual-luciferase assay were conducted to verify the binding relationship of SALL4 and ROBO2. qRT-PCR detected the mRNA expression levels of SALL4 and ROBO2, and the flow cytometry analyzed the cell cycle distribution. Western blot examined SALL4 expression, and cell cycle/cell stemness-related proteins. The impact of SALL4 and ROBO2 on the proliferation capacity of cells and tumor cell stemness was elucidated by MTT, colony formation, and sphere-forming assays. SALL4 and ROBO2 were up-regulated in CC, and SALL4 could activate the transcription of ROBO2. Down-regulated SALL4 was able to significantly restrain the proliferation capacity of CC cells and arrest the cell cycle in G0/G1 phase by repressing the expression of cyclin B, cyclin E, and cyclin D1. Besides, the rescue assay results indicated that up-regulated ROBO2 could reverse the repressive impact of down-regulated SALL4 on the proliferation of CC cells and accelerate the progression of the cell cycle, thus promoting the sphere-forming of tumor stem cells. SALL4 advanced the proliferation of CC and cell stemness through direct activation of ROBO2 expression, implied the novel mechanism of SALL4 in CC, and pointed out that SALL4/ROBO2 axis was likely to be a potential target for clinical treatment of CC.
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Affiliation(s)
- Yahui Jiang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunhao Tang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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16
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Huang CY, Wei PL, Batzorig U, Makondi PT, Lee CC, Chang YJ. Identification of Moesin (MSN) as a Potential Therapeutic Target for Colorectal Cancer via the β-Catenin-RUNX2 Axis. Int J Mol Sci 2023; 24:10951. [PMID: 37446127 DOI: 10.3390/ijms241310951] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
CRC is the second leading cause of cancer-related death. The complex mechanisms of metastatic CRC limit available therapeutic choice. Thus, identifying new CRC therapeutic targets is essential. Moesin (MSN), a member of the ezrin-radixin-moesin family, connects the cell membrane to the actin-based cytoskeleton and regulates cell morphology. We investigated the role of MSN in the progression of CRC. GENT2 and oncomine were used to study MSN expression and CRC patient outcomes. MSN-specific shRNAs or MSN-overexpressed plasmid were used to establish MSN-KD and MSN overexpressed cell lines, respectively. SRB, migration, wound healing, and flow cytometry were used to test cell survival and migration. Propidium iodide and annexin V stain were used to analyze the cell cycle and apoptosis. MSN expression was found to be higher in CRC tissues than in normal tissues. Higher MSN expression is associated with poor overall survival, disease-free survival, and relapse-free survival rates in CRC patients. MSN silencing inhibits cell proliferation, adhesion, migration, and invasion in vitro, whereas MSN overexpression accelerates cell proliferation, adhesion, migration, and invasion. RNA sequencing was used to investigate differentially expressed genes, and RUNX2 was discovered as a possible downstream target for MSN. In CRC patients, RUNX2 expression was significantly correlated with MSN expression. We also found that MSN silencing decreased cytoplasmic and nuclear β-catenin levels. Additionally, pharmacological inhibition of β-catenin in MSN-overexpressed cells led to a reduction of RUNX2, and activating β-catenin signaling by inhibiting GSK3β rescued the RUNX2 downregulation in MSN-KD cells. This confirms that MSN regulates RUNX2 expression via activation of β-catenin signaling. Finally, our result further determined that RUNX2 silencing reduced the ability of MSN overexpression cells to proliferate and migrate. MSN accelerated CRC progression via the β-catenin-RUNX2 axis. As a result, MSN holds the potential to become a new target for CRC treatment.
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Affiliation(s)
- Chien-Yu Huang
- School of Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Uyanga Batzorig
- Department of Dermatology, University of California, San Diego, CA 92093, USA
| | | | - Cheng-Chin Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Jia Chang
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
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17
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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18
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Bergen J, Karasova M, Bileck A, Pignitter M, Marko D, Gerner C, Del Favero G. Exposure to dietary fatty acids oleic and palmitic acid alters structure and mechanotransduction of intestinal cells in vitro. Arch Toxicol 2023; 97:1659-1675. [PMID: 37117602 PMCID: PMC10182945 DOI: 10.1007/s00204-023-03495-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/04/2023] [Indexed: 04/30/2023]
Abstract
Intestinal cells are continuously exposed to food constituents while adapting to peristaltic movement and fluid shear stress. Oleic acid (OA) and palmitic acid (PA) are among the most prevalent fatty acids with respect to dietary lipids. Despite the central importance of dietary lipids for a balanced diet, awareness about potential detrimental effects related to excessive consumption is increasing; this includes toxicity, metabolic deregulation, and, particularly for cancer cells, a benefit from the uptake of fatty acids related to promotion of metastasis. Expanding on this, we started elucidating the effects of OA and PA (25-500 µM) on non-transformed human intestinal epithelial cells (HCEC-1CT) in comparison to colon carcinoma cells (HCT116), with regard to the mechanosensory apparatus. Hence, intestinal cells' motility is on the one side essential to ensure adaption to peristaltic movement and barrier function, but also to enable metastatic progression. Incubation with both OA and PA (≥ 25 µM) significantly decreased membrane fluidity of HCT116 cells, whereas the effect on HCEC-1CT was more limited. Application of rhodamine-labelled PA demonstrated that the fatty acid is incorporated into the plasma membrane of HCT116, which could not be observed in the non-tumorigenic cell line. Down-streaming into the intracellular compartment, a pronounced rearrangement of actin cytoskeleton was evident in both cell lines (OA and PA; 25 and 100 µM). This was accompanied by a variation of translocation efficiency of the mechanosensitive co-transcription factor YAP1, albeit with a stronger effect seen for PA and the cancer cells. Untargeted proteomic analysis confirmed that exposure to OA and PA could alter the response capacity of HCT116 cells to fluid shear stress. Taken together, OA and PA were able to functionally modulate the mechanosensory apparatus of intestinal cells, implying a novel role for dietary fatty acids in the regulation of intestinal pathophysiology.
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Affiliation(s)
- Janice Bergen
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
- Core Facility Multimodal Imaging, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
| | - Martina Karasova
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
- Core Facility Multimodal Imaging, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
| | - Andrea Bileck
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
- Joint Metabolome Facility, University of Vienna, Medical University of Vienna, Vienna, Austria
| | - Marc Pignitter
- Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Josef-Holaubek-Platz 2, 1090, Vienna, Austria
| | - Doris Marko
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
| | - Christopher Gerner
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria
- Joint Metabolome Facility, University of Vienna, Medical University of Vienna, Vienna, Austria
| | - Giorgia Del Favero
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria.
- Core Facility Multimodal Imaging, Faculty of Chemistry, University of Vienna, Währingerstr. 38-42, 1090, Vienna, Austria.
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19
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Dey DK, Sharma C, Vadlamudi Y, Kang SC. CopA3 peptide inhibits MDM2-p53 complex stability in colorectal cancers and activates p53 mediated cell death machinery. Life Sci 2023; 318:121476. [PMID: 36758667 DOI: 10.1016/j.lfs.2023.121476] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/23/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
The diverse expression patterns of the tumor suppressor p53 in cancer cells reflect the regulatory efficiency of multiple cellular pathways. By contrast, many human tumors are reported to develop in the presence of wild-type p53. Recently, several oncogene inhibitors have been used clinically to suppress tumor development by functionally reactivating other oncoproteins. On the other hand, p53 reactivation therapies have not been well established, as few of the p53-MDM2 complex inhibitors such as Nutlin-3 induces mutation in p53 gene upon prolonged usage. Therefore, in this study CopA3, a 9-mer dimeric D-type peptide with anticancer activity against the human colorectal cancer cells, was used to explore the efficacy of p53 reactivation in-vitro and in-vivo. The anticancer activity of CopA3 was more selective towards the wild-type p53 expressing cells than the p53 deficient or mutant colorectal cancer cells. In response to this, this study investigated the signaling pathway in vitro and validated its anti-tumor activity in-vivo. The protein-peptide interaction and molecular docking efficiently provided insight into the specific binding affinity of CopA3 to the p53-binding pocket of the MDM2 protein, which efficiently blocked the p53 and MDM2 interaction. CopA3 plays a crucial role in the binding with MDM2 and enhanced the nuclear translocation of the p53 protein, which sequentially activated the downstream targets to trigger the autophagic mediated cell death machinery through the JNK/Beclin-1 mediated pathway. Collectively, CopA3 affected the MDM2-p53 interaction, which suppressed tumor development. This study may provide a novel inhibitor candidate for the MDM2-p53 complex, which could ultimately suppress the growth of colorectal cancer cells without being cytotoxic to the healthy neighboring cells present around the tumor microenvironment.
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Affiliation(s)
- Debasish Kumar Dey
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Chanchal Sharma
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Yellamandayya Vadlamudi
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea
| | - Sun Chul Kang
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea.
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20
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Ozato Y, Kojima Y, Kobayashi Y, Hisamatsu Y, Toshima T, Yonemura Y, Masuda T, Kagawa K, Goto Y, Utou M, Fukunaga M, Gamachi A, Imamura K, Kuze Y, Zenkoh J, Suzuki A, Niida A, Hirose H, Hayashi S, Koseki J, Oki E, Fukuchi S, Murakami K, Tobo T, Nagayama S, Uemura M, Sakamoto T, Oshima M, Doki Y, Eguchi H, Mori M, Iwasaki T, Oda Y, Shibata T, Suzuki Y, Shimamura T, Mimori K. Spatial and single-cell transcriptomics decipher the cellular environment containing HLA-G+ cancer cells and SPP1+ macrophages in colorectal cancer. Cell Rep 2023; 42:111929. [PMID: 36656712 DOI: 10.1016/j.celrep.2022.111929] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/31/2022] [Accepted: 12/14/2022] [Indexed: 01/19/2023] Open
Abstract
The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.
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Affiliation(s)
- Yuki Ozato
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Yasuhiro Kojima
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yuta Kobayashi
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan; Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Yuuichi Hisamatsu
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
| | - Takeo Toshima
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
| | - Yusuke Yonemura
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
| | - Takaaki Masuda
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
| | - Kouichi Kagawa
- Department of Gastroenterology, Shinbeppu Hospital, Beppu 874-8538, Japan
| | - Yasuhiro Goto
- Department of Gastroenterology, Shinbeppu Hospital, Beppu 874-8538, Japan
| | - Mitsuaki Utou
- Department of Pathology, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
| | - Mituko Fukunaga
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
| | - Ayako Gamachi
- Department of Pathology, Almeida Memorial Hospital, Oita 870-1195, Japan
| | - Kiyomi Imamura
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa 277-8561, Japan
| | - Yuta Kuze
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa 277-8561, Japan
| | - Junko Zenkoh
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa 277-8561, Japan
| | - Ayako Suzuki
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa 277-8561, Japan
| | - Atsushi Niida
- Laboratory of Molecular Medicine, the Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan
| | - Haruka Hirose
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Shuto Hayashi
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Jun Koseki
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Satoshi Fukuchi
- Department of Gastroenterological Medicine, Almeida Memorial Hospital, Oita 870-1195, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Oita University Hospital, Yufu 879-5593, Japan
| | - Taro Tobo
- Department of Pathology, Almeida Memorial Hospital, Oita 870-1195, Japan
| | - Satoshi Nagayama
- Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Takeharu Sakamoto
- Department of Cancer Biology, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Japan
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
| | - Masaki Mori
- Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Takeshi Iwasaki
- Department of Pathology, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Pathology, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Tatsuhiro Shibata
- Laboratory of Molecular Medicine, the Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan
| | - Yutaka Suzuki
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa 277-8561, Japan
| | - Teppei Shimamura
- Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
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21
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Damane BP, Mulaudzi TV, Kader SS, Naidoo P, Savkovic SD, Dlamini Z, Mkhize-Kwitshana ZL. Unraveling the Complex Interconnection between Specific Inflammatory Signaling Pathways and Mechanisms Involved in HIV-Associated Colorectal Oncogenesis. Cancers (Basel) 2023; 15:748. [PMID: 36765706 PMCID: PMC9913377 DOI: 10.3390/cancers15030748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/16/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
The advancement of HIV treatment has led to increased life expectancy. However, people living with HIV (PLWH) are at a higher risk of developing colorectal cancers. Chronic inflammation has a key role in oncogenesis, affecting the initiation, promotion, transformation, and advancement of the disease. PLWH are prone to opportunistic infections that trigger inflammation. It has been documented that 15-20% of cancers are triggered by infections, and this percentage is expected to be increased in HIV co-infections. The incidence of parasitic infections such as helminths, with Ascariasis being the most common, is higher in HIV-infected individuals. Cancer cells and opportunistic infections drive a cascade of inflammatory responses which assist in evading immune surveillance, making them survive longer in the affected individuals. Their survival leads to a chronic inflammatory state which further increases the probability of oncogenesis. This review discusses the key inflammatory signaling pathways involved in disease pathogenesis in HIV-positive patients with colorectal cancers. The possibility of the involvement of co-infections in the advancement of the disease, along with highlights on signaling mechanisms that can potentially be utilized as therapeutic strategies to prevent oncogenesis or halt cancer progression, are addressed.
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Affiliation(s)
- Botle Precious Damane
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
- Department of Medical Microbiology, School of Laboratory Medicine & Medical Sciences, Medical School Campus, College of Health Sciences, University of KwaZulu-Natal-Natal, Durban 4041, South Africa
| | - Thanyani Victor Mulaudzi
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
| | - Sayed Shakeel Kader
- Department of Surgery, University of KwaZulu Natal, Congella, Durban 4013, South Africa
| | - Pragalathan Naidoo
- Department of Medical Microbiology, School of Laboratory Medicine & Medical Sciences, Medical School Campus, College of Health Sciences, University of KwaZulu-Natal-Natal, Durban 4041, South Africa
- SAMRC Research Capacity Development Division, South African Medical Research Council, Tygerberg, Cape Town 4091, South Africa
| | - Suzana D. Savkovic
- School of Medicine, Department of Pathology & Laboratory Medicine, 1430 Tulane Ave., SL-79, New Orleans, LA 70112, USA
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
| | - Zilungile Lynette Mkhize-Kwitshana
- Department of Medical Microbiology, School of Laboratory Medicine & Medical Sciences, Medical School Campus, College of Health Sciences, University of KwaZulu-Natal-Natal, Durban 4041, South Africa
- SAMRC Research Capacity Development Division, South African Medical Research Council, Tygerberg, Cape Town 4091, South Africa
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22
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Sawaya K, Abou Najem S, Khawaja G, Khalil M. Proapoptotic and Antiproliferative Effects of the Desert Truffle Terfezia boudieri on Colon Cancer Cell Lines. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:1693332. [PMID: 37064948 PMCID: PMC10104735 DOI: 10.1155/2023/1693332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 04/18/2023]
Abstract
Background Colon cancer is the second leading cause of cancer-related mortality, and ranks third among cancers in terms of prevalence. Despite advances in early detection and treatment with chemotherapy and surgery, colon cancer continues to be associated with high recurrence rates, thereby resulting in a heavy disease burden. Moreover, the effectiveness of currently available treatment modalities is limited by the occurrence of toxic side effects. Hence, there is an urgent need to develop alternative treatments. Extracts from the black desert truffle Terfezia boudieri (T. boudieri) have shown promising anticancer properties. However, the cellular mechanisms underlying this activity remain poorly understood. Methods In this study, the colon cancer cell lines HCT-116 and Caco-2 were treated with either water or ethanolic extract of T. boudieri. Cell viability and the half-maximal inhibitory concentration were determined using MTT assays. Then, the activity of the more potent water extract was further verified using crystal violet assays, and its role in inhibiting colony formation and wound healing was investigated. Protein levels of p53, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), cyclin D1 (CCND1), and c-Myc were measured in cells treated with different doses of the water extract. Results Treatment with the water extract of T. boudieri reduced the capacity of cells for wound healing and colony formation in a dose-dependent manner. The Bax/Bcl-2 ratio and p53 expression were elevated in both cell lines. In contrast, the levels of cyclin D1 and c-Myc were suppressed. Conclusion T. boudieri water extract exerted a cytotoxic effect on colon cancer cells, and blocked colony formation and wound healing potentially through inhibition of proliferation. Mechanistically, these effects are attributed to influence the mitochondrial pathway of apoptosis, proteins involved in cellular proliferation, and the cell cycle.
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Affiliation(s)
- Katia Sawaya
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Sonia Abou Najem
- Health Sciences Division, Abu Dhabi Women's College, Higher Colleges of Technology, Abu Dhabi, UAE
| | - Ghada Khawaja
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Mahmoud Khalil
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
- Molecular Biology Unit, Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
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23
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Shasha T, Gruijs M, van Egmond M. Mechanisms of colorectal liver metastasis development. Cell Mol Life Sci 2022; 79:607. [PMID: 36436127 PMCID: PMC9701652 DOI: 10.1007/s00018-022-04630-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/11/2022] [Accepted: 11/13/2022] [Indexed: 11/28/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, largely due to the development of colorectal liver metastases (CRLM). For the establishment of CRLM, CRC cells must remodel their tumor-microenvironment (TME), avoid the immune system, invade the underlying stroma, survive the hostile environment of the circulation, extravasate into the liver, reprogram the hepatic microenvironment into a permissive pre-metastatic niche, and finally, awake from a dormant state to grow out into clinically detectable CRLM. These steps form part of the invasion-metastasis cascade that relies on reciprocal interactions between the tumor and its ever-changing microenvironment. Such interplay provides a strong rational for therapeutically targeting the TME. In fact, several TME constituents, such as VEGF, TGF-β coreceptor endoglin, and CXCR4, are already targeted in clinical trials. It is, however, of utmost importance to fully understand the complex interactions in the invasion-metastasis cascade to identify novel potential therapeutic targets and prevent the establishment of CRLM, which may ultimately greatly improve patient outcome.
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Affiliation(s)
- Tal Shasha
- Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands
| | - Mandy Gruijs
- Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands
| | - Marjolein van Egmond
- Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.
- Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Surgery, De Boelelaan 1117, Amsterdam, The Netherlands.
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24
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Ascenção K, Lheimeur B, Szabo C. Regulation of CyR61 expression and release by 3-mercaptopyruvate sulfurtransferase in colon cancer cells. Redox Biol 2022; 56:102466. [PMID: 36113340 PMCID: PMC9482125 DOI: 10.1016/j.redox.2022.102466] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/29/2022] [Accepted: 09/02/2022] [Indexed: 10/28/2022] Open
Abstract
Cysteine-rich angiogenic inducer 61 (CYR61, also termed CCN family member 1 or CCN1), is a matricellular protein encoded by the CYR61 gene. This protein has been implicated in the regulation of various cancer-associated processes including tumor growth, angiogenesis, tumor cell adhesion, migration, and invasion as well as the regulation of anticancer drug resistance. Hydrogen sulfide (H2S) is a gaseous endogenous biological mediator, involved in the regulation of cellular bioenergetics, angiogenesis, invasion, and chemotherapeutic resistance in several types of cancer. H2S is produced by three enzymes: cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current studies were set up to investigate if CBS or 3-MST regulates CyR61 in colon cancer cells in the context of the regulation of proliferation, migration, and survival. The study mainly utilized HCT116 cells, in which two of the principal H2S-producing enzymes, CBS and 3-MST, are highly expressed. The H2S donor GYY4137 and the polysulfide donor Na2S3 activated the CyR61 promoter in a concentration-dependent fashion. Aminooxyacetic acid (AOAA), a pharmacological inhibitor of CBS as well as HMPSNE: 2-[(4-hydroxy-6- methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one, a pharmacological inhibitor of 3-MST inhibited CyR61 mRNA expression. This effect was more pronounced in response to HMPSNE than to AOAA and occurred through the modulation of S1PR via ATF1 and CREB. CyR61 was found to play an active, but relatively minor role in maintaining colon cell proliferation. HMPSNE markedly suppressed the secretion/release of CyR61 from the colon cancer cells. Moreover, HMPSNE promoted colon cancer cell apoptosis; endogenously produced CyR61 was found to counteract this effect, at least in part via RhoA activation. Taken together, we conclude that the upregulation of 3-MST in cancer cells exerts cytoprotective effects and confers the cancer cells a more aggressive phenotype - at least in part via the modulation of CyR61 expression and release.
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Affiliation(s)
- Kelly Ascenção
- Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Bassma Lheimeur
- Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Csaba Szabo
- Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
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25
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The Comparative Role of BAMLET and 5-Fluorouracil in Colorectal Cancer Cells by Targeting WNT/& Beta; -Catenin Pathway. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2022. [DOI: 10.5812/ijcm-123140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background: Aberrant activation of the WNT/β-catenin signaling pathway is involved in various types of cancers, particularly colorectal cancer (CRC), which is a prevalent malignancy. Targeting the Wnt signaling pathway has gained a reputation as an attractive therapeutic strategy, mainly because of its potential for regulating cell proliferation, migration, differentiation, angiogenesis, and apoptosis. Objectives: The aim of the current research was to investigate the effects of 5-Fluorouracil (5-FU) and bovine alpha-lactalbumin made lethal to tumor cells (BAMLET), a complex of oleic acid with bovine α-lactalbumin protein, on colon cancer cells focusing on the Wnt signaling pathway. Methods: For this purpose, HT-29 and HCT116 cells were treated with 5-FU and BAMLET, and the expression levels of Wnt signaling-related proteins (β-catenin and E-cadherin) and VEGF as angiogenesis regulators were evaluated by quantitative real-time polymerase chain reaction (RT-qPCR) and Western Blot analysis. Results: Bovine alpha-lactalbumin made lethal to tumor cells (BAMLET) treatment down-regulated the expression of β-catenin and up-regulated the expression of E-cadherin significantly compared to the 5-FU (P < 0.0001). The reduced mRNA levels of VEGF in treated cells revealed the effectiveness of 5-FU and BAMLET on angiogenesis. Conclusions: Bovine alpha-lactalbumin made lethal to tumor cells (BAMLET) can be considered for targeting the Wnt signaling pathway and angiogenesis. It is amenable to further investigation in the development of CRC treatment.
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26
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Lamichhane A, Shahi Thakuri P, Singh S, Rafsanjani Nejad P, Heiss J, Luker GD, Tavana H. Therapeutic Targeting of Cancer Stem Cells Prevents Resistance of Colorectal Cancer Cells to MEK Inhibition. ACS Pharmacol Transl Sci 2022; 5:724-734. [PMID: 36110381 PMCID: PMC9469186 DOI: 10.1021/acsptsci.1c00257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Indexed: 11/30/2022]
Abstract
Drug resistance is a leading cause for the failure of cancer treatments. Plasticity of cancer cells to acquire stem cell-like properties enables them to escape drug toxicity through different adaptive mechanisms. Eliminating cancer stem cells (CSCs) can potentially improve treatment outcomes for patients. To determine the role of CSCs in resistance of colorectal cancer cells to targeted therapies and identify treatment strategies, we treated spheroids of BRAFmut and KRASmut colorectal cancer cells with inhibitors of the mitogen-activated protein kinase pathway and studied resistance mechanisms through gene and protein expression analyses. We found that treatments activated several oncogenic pathways and expression of CSC markers CD166 and ALDH1A3. We identified a specific combination treatment using trametinib and mithramycin A to simultaneously inhibit the CSC phenotype and activities of several pathways in cancer cells. This study demonstrates the feasibility of therapeutic targeting of CSCs as a strategy to block tumorigenic activities of cancer cells.
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Affiliation(s)
- Astha Lamichhane
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Pradip Shahi Thakuri
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Sunil Singh
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Pouria Rafsanjani Nejad
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Jacob Heiss
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
| | - Gary D. Luker
- Department
of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48105, United States
| | - Hossein Tavana
- Department
of Biomedical Engineering, The University
of Akron, Akron, Ohio 44325, United States
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27
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Raeisi M, Saberivand M, Velaei K, Aghaei N, Rahimi-Farsi N, Kharrati-Shishavan H, Hassanzadeh D, Mehdizadeh A. Porcn as a novel therapeutic target in cancer therapy: A review. Cell Biol Int 2022; 46:1979-1991. [PMID: 35971741 DOI: 10.1002/cbin.11882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 06/06/2022] [Accepted: 07/29/2022] [Indexed: 11/11/2022]
Abstract
Wingless-related integration site (Wnt) signaling is one of the main oncogenic pathways in different malignancies. Therefore, targeting this pathway has been considered an exciting strategy in cancer treatment. Porcn is among the central enzymes in this pathway that has recently been considered for cancer-targeted therapy. As a membrane-bound O-acyltransferase, Porcn plays a critical role in wnt ligand palmitoylation and its subsequent secretion. In addition to Porcn's role in stem cell signaling and differentiation, recent findings have shown its role in developing and progressing colorectal, pancreatic, liver, head, and neck cancers. Developed small molecule inhibitors have also opened a promising window toward cancer treatment strategies. In this review, the structure and biological role of Porcn in different cancer-related signaling pathways and inhibitors used for inhibiting this enzyme are discussed.
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Affiliation(s)
- Mortaza Raeisi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Saberivand
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kobra Velaei
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negar Aghaei
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Imam Sajjad Hospital, Tabriz, Iran
| | | | | | - Davoud Hassanzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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28
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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29
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Sokolov D, Sharda N, Giri B, Hassan MS, Singh D, Tarasiewicz A, Lohr C, von Holzen U, Kristian T, Waddell J, Reiter RJ, Ahmed H, Banerjee A. Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling. J Pineal Res 2022; 73:e12808. [PMID: 35619550 PMCID: PMC9288490 DOI: 10.1111/jpi.12808] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 04/19/2022] [Accepted: 05/23/2022] [Indexed: 11/30/2022]
Abstract
β-catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating β-catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT-15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting β-catenin expression and its downregulatory signals, Cyclin D1, c-Myc. MLT + AGP treated cells exhibited translocation of phospho-β-catenin to the nucleus and dephosphorylated-β-catenin. Downregulation of β-catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G-protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and β-catenin found increased apoptosis and downregulation of β-catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/β-catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs.
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Affiliation(s)
- Daniil Sokolov
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Neha Sharda
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Banabihari Giri
- Division of Virology and Immunology, Maryland Department of Health, Baltimore, Maryland, U.S.A
| | - Md Sazzad Hassan
- Department of Surgery, Indiana University School of Medicine, South Bend, IN, U.S.A
- Harper Cancer Research Institute, South Bend, IN, U.S.A
| | - Damandeep Singh
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Agnieszka Tarasiewicz
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Charity Lohr
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Urs von Holzen
- Department of Surgery, Indiana University School of Medicine, South Bend, IN, U.S.A
- Harper Cancer Research Institute, South Bend, IN, U.S.A
- Goshen Center for Cancer Care, Goshen, Goshen, IN, U.S.A
- University of Basel, Basel, Switzerland
| | - Tibor Kristian
- VAMHCS, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
- Department of Anesthesiology and the Center for Shock, Trauma, and Anesthesiology Research (STAR)
| | - Jaylyn Waddell
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, U.S.A
| | | | - Aditi Banerjee
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A
- Corresponding author: Department of Pediatrics, University of Maryland School of Medicine, Bressler Research Building, 13-043, 655 W. Baltimore Street, Baltimore, MD 21201, Voice: (410) 706-1772, Fax: (410) 328-1072,
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Melcher C, Yu J, Duong VHH, Westphal K, Helmi Siasi Farimany N, Shaverskyi A, Zhao B, Strowig T, Glage S, Brand K, Chan AC, Föger N, Lee KH. B cell-mediated regulatory mechanisms control tumor-promoting intestinal inflammation. Cell Rep 2022; 40:111051. [PMID: 35830810 DOI: 10.1016/j.celrep.2022.111051] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2022] [Accepted: 06/14/2022] [Indexed: 11/03/2022] Open
Abstract
Mechanisms underlying tumor-promoting inflammatory processes in colitis-associated colorectal cancer (CAC) remain largely elusive. Here, we provide genetic evidence for distinct B cell-mediated immunoregulatory mechanisms that protect from chronic colitis versus CAC. We demonstrate an inherent capacity of interleukin-10 (IL-10)-producing B cells to differentiate into immunoglobulin A (IgA) plasma cells (PCs) upon Toll-like receptor (TLR) activation. Our data show that B cell-derived IL-10 is essential to limit pathogenic T helper type 1 (Th1)/Th17 T cell responses during chronic colitis, while IgA PCs derived from IL-10+ B cells are being implicated in restraining tumorigenesis during CAC. Formation of a tumor-protective intestinal environment was associated with clonal expansion of specific types of colonic IgA PCs and development of an altered microbiota that attenuated CAC. We thus propose that regulatory B cell-mediated immunomodulation entails temporal release of IL-10, which is superseded by the generation of specific IgA affecting the microbial community, thereby controlling chronic inflammation and tumorigenesis in a distinctive but interrelated manner.
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Affiliation(s)
- Christian Melcher
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Jinbo Yu
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Vu Huy Hoang Duong
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Katrin Westphal
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Noushin Helmi Siasi Farimany
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Anton Shaverskyi
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Bei Zhao
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hannover Medical School, 30625 Hannover, Germany
| | - Till Strowig
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hannover Medical School, 30625 Hannover, Germany
| | - Silke Glage
- Experimental Pathology, Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Korbinian Brand
- Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Andrew C Chan
- Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Niko Föger
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Kyeong-Hee Lee
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany.
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Xiong Q, Zeng Z, Yang Y, Wang Y, Xu Y, Zhou Y, Liu J, Zhang Z, Qiu M, Zhu Q. KRAS Gene Copy Number as a Negative Predictive Biomarker for the Treatment of Metastatic Rectal Cancer With Cetuximab: A Case Report. Front Oncol 2022; 12:872630. [PMID: 35734602 PMCID: PMC9207953 DOI: 10.3389/fonc.2022.872630] [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: 02/15/2022] [Accepted: 04/14/2022] [Indexed: 02/05/2023] Open
Abstract
Background Close to one third of colorectal cancer (CRC) patients are diagnosed with metastatic CRC (mCRC). Patients with wild-type RAS and BRAF usually receive anti-EGFR monoclonal antibody therapy containing cetuximab. Overall, 30–50% of mCRC patients are reported to harbor RAS mutations, and RAS mutation status should be assessed when considering EGFR inhibitor treatment according to mCRC biomarker guidelines. Of note, 0.67–2% of patients with CRC harbored a KRAS amplification. Here we reported a case of advanced rectal cancer with wild-type RAS and BRAF in a male patient who harbored a KRAS amplification during anti-EGFR treatment. Case Presentation A 46-year-old man was diagnosed with rectal adenocarcinoma with liver metastases (cT3NxM1a, stage IVA). After receiving first-line irinotecan- fluorouracil chemotherapy (FOLFIRI) plus cetuximab, second-line capecitabine- oxaliplatin chemotherapy (XELOX) plus bevacizumab, and third-line regorafenib, he rechallenged FOLFIRI and cetuximab for seven cycles, achieving a prolonged survival of at least 5 months. The KRAS copy number of circulating tumor DNA (ctDNA) was assessed during treatment. Notably, apart from serum carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA), the change of plasm Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) copy number appeared to strongly correlate with treatment response. Conclusion Our findings suggest that the dynamic change of KRAS copy number on ctDNA during treatment might be a negative predictive biomarker. Additionally, RAS and BRAF wild-type mCRC patients who are resistant to first-line FOLFIRI plus cetuximab therapy may respond well to the FOLFIRI plus cetuximab “rechallenged” strategy.
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Affiliation(s)
- Qunli Xiong
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhu Zeng
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Yang
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Ya Wang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongfeng Xu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Ying Zhou
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinlu Liu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiwei Zhang
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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Babaker MA, Aljoud FA, Alkhilaiwi F, Algarni A, Ahmed A, Khan MI, Saadeldin IM, Alzahrani FA. The Therapeutic Potential of Milk Extracellular Vesicles on Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23126812. [PMID: 35743255 PMCID: PMC9224713 DOI: 10.3390/ijms23126812] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer remains one of the leading prevalent cancers in the world and is the fourth most common cause of death from cancer. Unfortunately, the currently utilized chemotherapies fail in selectively targeting cancer cells and cause harm to healthy cells, which results in profound side effects. Researchers are focused on developing anti-cancer targeted medications, which is essential to making them safer, more effective, and more selective and to maximizing their therapeutic benefits. Milk-derived extracellular vesicles (EVs) from camels and cows have attracted much attention as a natural substitute product that effectively suppresses a wide range of tumor cells. This review sheds light on the biogenesis, methods of isolation, characterization, and molecular composition of milk EVs as well as the therapeutic potentials of milk EVs on colorectal cancer.
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Affiliation(s)
- Manal A. Babaker
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Department of Chemistry, Faculty of Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Fadwa A. Aljoud
- Regenerative Medicine Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (F.A.A.); (F.A.)
| | - Faris Alkhilaiwi
- Regenerative Medicine Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (F.A.A.); (F.A.)
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdulrahman Algarni
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar 73221, Saudi Arabia;
| | - Asif Ahmed
- MirZyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham B7 4BB, UK;
- School of Health Sciences, University of Southampton, University Road, Southampton SO17 1BJ, UK
| | - Mohammad Imran Khan
- Centre of Artificial Intelligence in Precision Medicines (CAIPM), King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Islam M. Saadeldin
- Research Institute of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
- Correspondence: (I.M.S.); (F.A.A.)
| | - Faisal A. Alzahrani
- MirZyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham B7 4BB, UK;
- Centre of Artificial Intelligence in Precision Medicines (CAIPM), King Abdulaziz University, Jeddah 21589, Saudi Arabia;
- Embryonic Stem Cells Unit, Department of Biochemistry, Faculty of Science, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: (I.M.S.); (F.A.A.)
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Aramini B, Masciale V, Grisendi G, Bertolini F, Maur M, Guaitoli G, Chrystel I, Morandi U, Stella F, Dominici M, Haider KH. Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers (Basel) 2022; 14:cancers14040976. [PMID: 35205721 PMCID: PMC8869911 DOI: 10.3390/cancers14040976] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Cancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process. Abstract Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
- Correspondence:
| | - Valentina Masciale
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Federica Bertolini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Michela Maur
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Giorgia Guaitoli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Isca Chrystel
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Uliano Morandi
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
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Catalano T, D’Amico E, Moscatello C, Di Marcantonio MC, Ferrone A, Bologna G, Selvaggi F, Lanuti P, Cotellese R, Curia MC, Lattanzio R, Aceto GM. Oxidative Distress Induces Wnt/β-Catenin Pathway Modulation in Colorectal Cancer Cells: Perspectives on APC Retained Functions. Cancers (Basel) 2021; 13:6045. [PMID: 34885156 PMCID: PMC8656656 DOI: 10.3390/cancers13236045] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/25/2021] [Accepted: 11/27/2021] [Indexed: 01/10/2023] Open
Abstract
Colorectal cancer (CRC) is a multistep process that arises in the colic tissue microenvironment. Oxidative stress plays a role in mediating CRC cell survival and progression, as well as promoting resistance to therapies. CRC progression is associated with Wnt/β-Catenin signaling dysregulation and loss of proper APC functions. Cancer recurrence/relapse has been attributed to altered ROS levels, produced in a cancerous microenvironment. The effect of oxidative distress on Wnt/β-Catenin signaling in the light of APC functions is unclear. This study evaluated the effect of H2O2-induced short-term oxidative stress in HCT116, SW480 and SW620 cells with different phenotypes of APC and β-Catenin. The modulation and relationship of APC with characteristic molecules of Wnt/β-Catenin were assessed in gene and protein expression. Results indicated that CRC cells, even when deprived of growth factors, under acute oxidative distress conditions by H2O2 promote β-Catenin expression and modulate cytoplasmic APC protein. Furthermore, H2O2 induces differential gene expression depending on the cellular phenotype and leading to favor both Wnt/Catenin-dependent and -independent signaling. The exact mechanism by which oxidative distress can affect Wnt signaling functions will require further investigation to reveal new scenarios for the development of therapeutic approaches for CRC, in the light of the conserved functions of APC.
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Affiliation(s)
- Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Emira D’Amico
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (E.D.); (C.M.); (F.S.); (R.C.); (M.C.C.)
| | - Carmelo Moscatello
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (E.D.); (C.M.); (F.S.); (R.C.); (M.C.C.)
| | - Maria Carmela Di Marcantonio
- Department of Innovative Technologies in Medicine & Dentistry, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (M.C.D.M.); (R.L.)
| | - Alessio Ferrone
- Department of Medicine and Aging Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (A.F.); (G.B.); (P.L.)
| | - Giuseppina Bologna
- Department of Medicine and Aging Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (A.F.); (G.B.); (P.L.)
- Center for Advanced Studies and Technology (C.A.S.T.), University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Federico Selvaggi
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (E.D.); (C.M.); (F.S.); (R.C.); (M.C.C.)
- Unit of General Surgery, Ospedale Floraspe Renzetti, Lanciano, 66034 Chieti, Italy
| | - Paola Lanuti
- Department of Medicine and Aging Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (A.F.); (G.B.); (P.L.)
- Center for Advanced Studies and Technology (C.A.S.T.), University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (E.D.); (C.M.); (F.S.); (R.C.); (M.C.C.)
- Villa Serena Foundation for Research, Via Leonardo Petruzzi, 65013 Città Sant’Angelo, Italy
| | - Maria Cristina Curia
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (E.D.); (C.M.); (F.S.); (R.C.); (M.C.C.)
| | - Rossano Lattanzio
- Department of Innovative Technologies in Medicine & Dentistry, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (M.C.D.M.); (R.L.)
- Center for Advanced Studies and Technology (C.A.S.T.), University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy; (E.D.); (C.M.); (F.S.); (R.C.); (M.C.C.)
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Tong K, Kothari OA, Haro KS, Panda A, Bandari MM, Carrick JN, Hur JJ, Zhang L, Chan CS, Xing J, Gatza ML, Ganesan S, Verzi MP. SMAD4 is critical in suppression of BRAF-V600E serrated tumorigenesis. Oncogene 2021; 40:6034-6048. [PMID: 34453124 PMCID: PMC8559887 DOI: 10.1038/s41388-021-01997-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/04/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023]
Abstract
BRAF-driven colorectal cancer is among the poorest prognosis subtypes of colon cancer. Previous studies suggest that BRAF-mutant serrated cancers frequently exhibit Microsatellite Instability (MSI) and elevated levels of WNT signaling. The loss of tumor-suppressor Smad4 in oncogenic BRAF-V600E mouse models promotes rapid serrated tumor development and progression, and SMAD4 mutations co-occur in human patient tumors with BRAF-V600E mutations. This study assesses the role of SMAD4 in early-stage serrated tumorigenesis. SMAD4 loss promotes microsatellite stable (MSS) serrated tumors in an oncogenic BRAF-V600E context, providing a model for MSS serrated cancers. Inactivation of Msh2 in these mice accelerated tumor formation, and whole-exome sequencing of both MSS and MSI serrated tumors derived from these mouse models revealed that all serrated tumors developed oncogenic WNT mutations, predominantly in the WNT-effector gene Ctnnb1 (β-catenin). Mouse models mimicking the oncogenic β-catenin mutation show that the combination of three oncogenic mutations (Ctnnb1, Braf, and Smad4) are critical to drive rapid serrated dysplasia formation. Re-analysis of human tumor data reveals BRAF-V600E mutations co-occur with oncogenic mutations in both WNT and SMAD4/TGFβ pathways. These findings identify SMAD4 as a critical factor in early-stage serrated cancers and helps broaden the knowledge of this rare but aggressive subset of colorectal cancer.
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Affiliation(s)
- Kevin Tong
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Om A. Kothari
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Katherine S. Haro
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Anshuman Panda
- Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
| | - Manisha M. Bandari
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Jillian N. Carrick
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Joseph J. Hur
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Lanjing Zhang
- Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA,Department of Pathology, Penn Medicine Princeton Medical Center, Plainsboro, NJ, USA
| | - Chang S. Chan
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Jinchuan Xing
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA
| | - Michael L. Gatza
- Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA,Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Shridar Ganesan
- Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA
| | - Michael P. Verzi
- Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, 145 Bevier Road, Piscataway, NJ 08854, USA,Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA,Corresponding Author: Michael P. Verzi,
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Neiheisel A, Kaur M, Ma N, Havard P, Shenoy AK. Wnt pathway modulators in cancer therapeutics: An update on completed and ongoing clinical trials. Int J Cancer 2021; 150:727-740. [PMID: 34536299 DOI: 10.1002/ijc.33811] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/31/2021] [Accepted: 09/06/2021] [Indexed: 01/17/2023]
Abstract
Wnt signaling plays an essential role in the initiation and progression of various types of cancer. Besides, the Wnt pathway components have been established as reliable biomarkers and potential targets for cancer therapy. Wnt signaling is categorized into canonical and noncanonical pathways. The canonical pathway is involved in cell survival, proliferation, differentiation and migration, while the noncanonical pathway regulates cell polarity and migration. Apart from its biological role in development and homeostasis, the Wnt pathway has been implicated in several pathological disorders, including cancer. As a result, inhibiting this pathway has been a focus of cancer research with multiple targetable candidates in development. In this review, our focus will be to summarize information about ongoing and completed clinical trials targeting various Wnt pathway components, along with describing current and emerging Wnt targeted therapies. In addition, we will discuss potential opportunities and associated challenges of inhibiting Wnt signaling for cancer therapy.
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Affiliation(s)
- Ann Neiheisel
- College of Pharmacy, California Health Sciences University, Clovis, California, USA
| | - Manpreet Kaur
- College of Pharmacy, California Health Sciences University, Clovis, California, USA
| | - Nancy Ma
- College of Pharmacy, California Health Sciences University, Clovis, California, USA
| | - Patty Havard
- Kaweah Health Foundation, Kaweah Health, Visalia, California, USA
| | - Anitha K Shenoy
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Health Sciences University, Clovis, California, USA
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LEF1 silencing sensitizes colorectal cancer cells to oxaliplatin, 5-FU, and irinotecan. Biomed Pharmacother 2021; 143:112091. [PMID: 34474344 DOI: 10.1016/j.biopha.2021.112091] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/10/2021] [Accepted: 08/19/2021] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer all around the world. Chemotherapy plays an essential role in the treatment of CRC while Oxaliplatin, Irinotecan, and 5 - fluorouracil (5-FU) are the most commonly used chemotherapeutic drugs. However, chemo-resistance is a major obstacle to successful therapy. It has been shown that inhibition of Wnt signaling pathway can sensitize the cells to chemotherapy. Lymphoid enhancer factor (LEF1) is a member of TCF/LEF transcription family mediating Wnt nuclear responses. The long isoform of LEF1 is highly expressed in colorectal cancer cells compared to the normal intestinal cells, in which expression of the short isoform is dominant. We found that the downregulation of long isoforms of LEF1 makes CRC cell lines more sensitive to the effect of chemotherapeutic drugs. This sensitivity is imposed by reduced proliferation, increased apoptosis, or cell cycle arrest. Our results also demonstrated that there is a balance in the expression of long, and short isoforms of LEF1. In summary, we showed the role of LEF1 in chemo-resistance of colorectal cancer cells to Oxaliplatin, Irinotecan and 5-FU.
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38
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Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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Wu F, Wu B, Zhang X, Yang C, Zhou C, Ren S, Wang J, Yang Y, Wang G. Screening of MicroRNA Related to Irradiation Response and the Regulation Mechanism of miRNA-96-5p in Rectal Cancer Cells. Front Oncol 2021; 11:699475. [PMID: 34458143 PMCID: PMC8386172 DOI: 10.3389/fonc.2021.699475] [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: 04/23/2021] [Accepted: 07/13/2021] [Indexed: 01/03/2023] Open
Abstract
Neoadjuvant chemoradiotherapy has been widely used in the treatment of locally advanced rectal cancer due to the excellent advantages of irradiation in cancer therapy. Unfortunately, not every patient can benefit from this treatment, therefore, it is of great significance to explore biomarkers that can predict irradiation sensitivity. In this study, we screened microRNAs (miRNAs) which were positively correlated with irradiation resistance and found that miRNA-552 and miRNA-183 families were positively correlated with the irradiation resistance of rectal cancer, and found that high expression of miRNA-96-5p enhanced the irradiation resistance of rectal cancer cells through direct regulation of the GPC3 gene and abnormal activation of the canonical Wnt signal transduction pathway. Based on the radioreactivity results of patient-derived xenograft models, this is the first screening report for radio-resistant biomarkers in rectal cancer. Our results suggest that miRNA-96-5p expression is an important factor affecting the radiation response of colorectal cancer cells.
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Affiliation(s)
- Fengpeng Wu
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bingyue Wu
- Department of Oncology, Hebei Provincial People's Hospital, Graduate School of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Zhang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Congrong Yang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chaoxi Zhou
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shuguang Ren
- Laboratory Animal Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Wang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yafan Yang
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guiying Wang
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Department of General Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, China
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40
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Parol-Kulczyk M, Gzil A, Maciejewska J, Bodnar M, Grzanka D. Clinicopathological significance of the EMT-related proteins and their interrelationships in prostate cancer. An immunohistochemical study. PLoS One 2021; 16:e0253112. [PMID: 34157052 PMCID: PMC8219170 DOI: 10.1371/journal.pone.0253112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 05/29/2021] [Indexed: 11/19/2022] Open
Abstract
The chronic inflammation influences a microenvironment, where as a result of losing control over tissue homeostatic mechanisms, the carcinogenesis process may be induced. Inflammatory response cells can secrete a number of factors that support both initiation and progression of cancer and also they may consequently induct an epithelial-mesenchymal transition (EMT), the process responsible for development of distant metastasis. Macrophage migration inhibitory factor (MIF) acts as a pro-inflammatory cytokine that is considered as a link between chronic inflammation and tumor development. MIF can function as a modulator of important cancer-related genes expression, as well as an activator of signaling pathways that promotes the development of prostate cancer. The study was performed on FFPE tissues resected from patients who underwent radical prostatectomy. To investigate the relationship of studied proteins with involvement in tumor progression and initiation of epithelial-to-mesenchymal transition (EMT) process, we selected clinicopathological parameters related to tumor progression. Immunohistochemical analyses of MIF, SOX-4, β-catenin and E-cadherin were performed on TMA slides. We found a statistically significant correlation of overall β-catenin expression with the both lymph node metastasis (p<0.001) and presence of angioinvasion (p = 0.012). Membrane β-catenin expression was associated with distant metastasis (p = 0.021). In turn, nuclear MIF was correlated with lymph node metastasis (p = 0.003). The positive protein-protein correlations have been shown between the total β-catenin protein expression level with level of nuclear SOX-4 protein expression (r = 0.27; p<0.05) as well as negative correlation of β-catenin expression with level of nuclear MIF protein expression (r = -0.23; p<0.05). Our results seem promising and strongly highlight the potential role of MIF in development of nodal metastases as well as may confirm an involvement of β-catenin in disease spread in case of prostate cancer.
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Affiliation(s)
- Martyna Parol-Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Joanna Maciejewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Magdalena Bodnar
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Toruń, Poland
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Xu Z, Zheng J, Chen Z, Guo J, Li X, Wang X, Qu C, Yuan L, Cheng C, Sun X, Yu J. Multilevel regulation of Wnt signaling by Zic2 in colon cancer due to mutation of β-catenin. Cell Death Dis 2021; 12:584. [PMID: 34099631 PMCID: PMC8184991 DOI: 10.1038/s41419-021-03863-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 01/22/2023]
Abstract
Zinc-finger of the cerebellum 2 (Zic2) is widely implicated in cancers, but the role of Zic2 in tumorigenesis is bilateral. A recent study indicated that Zic2 could render colon cancer cells more resistant to low glucose-induced apoptosis. However, the functional roles of Zic2 in colon cancer and the underlying molecular mechanism remain elusive. Herein, we demonstrated that Zic2 was highly expressed in colon cancer tissues and correlated with poor survival. Knockdown of Zic2 inhibited colon cancer cell growth, arrested the cell cycle transition from G0/G1 to S phase, and suppressed tumor sphere formation in vitro; in addition, silencing Zic2 retarded xenograft tumor formation in vivo. Consistently, ectopic expression of Zic2 had the opposite effects. Mechanistically, Zic2 executed its oncogenic role in colon cancer by enhancing Wnt/β-catenin signaling. Zic2 directly binds to the promoter of Axin2 and transcriptionally represses Axin2 expression and subsequently promotes the accumulation and nuclear translocation of β-catenin. Meanwhile, Zic2 could activate Wnt signaling by interacting with β-catenin. Intriguingly, in HCT116 cells with intrinsic Ser45 mutation of β-catenin, which blocks the degradation-related phosphorylation of β-catenin by CK1, modified Zic2 expression did not affect the protein level of β-catenin. Altogether, our findings uncover a novel multilevel mechanism for the oncogenic activity of Zic2 in colon cancer and suggest Zic2 as a potential therapeutic target for colon cancer patients.
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Affiliation(s)
- Zhengshui Xu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Jianbao Zheng
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Zilu Chen
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Jing Guo
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Xiaopeng Li
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Xingjie Wang
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Chao Qu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Liyue Yuan
- Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Chen Cheng
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China
| | - Xuejun Sun
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China.
| | - Junhui Yu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, PR China.
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42
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Zheng XY, Cao MZ, Ba Y, Li YF, Ye JL. LncRNA testis-specific transcript, Y-linked 15 (TTTY15) promotes proliferation, migration and invasion of colorectal cancer cells via regulating miR-29a-3p/DVL3 axis. Cancer Biomark 2021; 31:1-11. [PMID: 33016900 DOI: 10.3233/cbm-201709] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Long non-coding RNA testis-specific transcript, Y-linked 15 (TTTY15) is oncogenic in prostate cancer, however its expression and function in colorectal cancer remain largely unknown. METHODS Paired colorectal cancer samples/normal tissues were collected, and the expression levels of TTTY15, miR-29a-3p and disheveled segment polarity protein 3 (DVL3) were examined by quantitative real-time polymerase chain reaction (qRT-PCR); TTTY15 shRNA and overexpression plasmids were transfected into HT29 and HCT-116 cell lines using lipofectamine reagent, respectively; the proliferation and colony formation were detected by CCK-8 assay and plate colony formation assay; qRT-PCR and Western blot were used to analyze the changes of miR-29a-3p and DVL3; dual-luciferase reporter gene assay was used to determine the regulatory relationships between miR-29a-3p and TTTY15, miR-29a-3p and DVL3. RESULTS TTTY15 was significantly up-regulated in cancerous tissues of colorectal cancer samples, positively correlated with the expression of DVL3, while negatively correlated with the expression of miR-29a-3p. After TTTY15 shRNAs were transfected into colorectal cancer cells, the proliferation and metastasis of cancer cells were significantly inhibited, while TTTY15 overexpression had opposite biological effects. TTTY15 shRNA could reduce the expression of DVL3 on both mRNA and protein levels, and the luciferase activity of TTTY15 sequence was also inhibited by miR-29a-3p. DVL3 was also validated as a target gene of miR-29a-3p, and it could be repressed by miR-29a-3p mimics or TTTY15 shRNA. CONCLUSION TTTY15 is abnormally upregulated in colorectal cancer tissues, and it can modulate the proliferation and metastasis of colorectal cancer cells. It functions as the ceRNA to regulate the expression of DVL3 by sponging miR-29a-3p.
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Affiliation(s)
- Xiao-Ying Zheng
- Department of Pathology, Qinghai University Affiliated Hospital, Xining, Qinghai, China
| | - Ming-Zheng Cao
- Department of General Surgery, Linyi Central Hospital, Linyi, Shandong, China
| | - Ying Ba
- Department of Nursing, Linyi Central Hospital, Linyi, Shandong, China
| | - Yue-Feng Li
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong, China
| | - Jun-Ling Ye
- Department of Pathology, Qinghai University Affiliated Hospital, Xining, Qinghai, China
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43
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Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol Res 2021; 167:105532. [DOI: 10.1016/j.phrs.2021.105532] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/14/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023]
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Deyell M, Garris CS, Laughney AM. Cancer metastasis as a non-healing wound. Br J Cancer 2021; 124:1491-1502. [PMID: 33731858 PMCID: PMC8076293 DOI: 10.1038/s41416-021-01309-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/25/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023] Open
Abstract
Most cancer deaths are caused by metastasis: recurrence of disease by disseminated tumour cells at sites distant from the primary tumour. Large numbers of disseminated tumour cells are released from the primary tumour, even during the early stages of tumour growth. However, only a minority survive as potential seeds for future metastatic outgrowths. These cells must adapt to a relatively inhospitable microenvironment, evade immune surveillance and progress from the micro- to macro-metastatic stage to generate a secondary tumour. A pervasive driver of this transition is chronic inflammatory signalling emanating from tumour cells themselves. These signals can promote migration and engagement of stem and progenitor cell function, events that are also central to a wound healing response. In this review, we revisit the concept of cancer as a non-healing wound, first introduced by Virchow in the 19th century, with a new tumour cell-intrinsic perspective on inflammation and focus on metastasis. Cellular responses to inflammation in both wound healing and metastasis are tightly regulated by crosstalk with the surrounding microenvironment. Targeting or restoring canonical responses to inflammation could represent a novel strategy to prevent the lethal spread of cancer.
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Affiliation(s)
- Matthew Deyell
- grid.5386.8000000041936877XInstitute for Computational Biomedicine, Weill Cornell Medicine, New York, NY USA ,grid.5386.8000000041936877XDepartment of Physiology and Biophysics, Weill Cornell Medicine, New York, NY USA ,grid.5386.8000000041936877XSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY USA ,grid.4444.00000 0001 2112 9282Chimie Biologie et Innovation, ESPCI Paris, Université PSL, CNRS, Paris, France
| | | | - Ashley M. Laughney
- grid.5386.8000000041936877XInstitute for Computational Biomedicine, Weill Cornell Medicine, New York, NY USA ,grid.5386.8000000041936877XDepartment of Physiology and Biophysics, Weill Cornell Medicine, New York, NY USA ,grid.5386.8000000041936877XSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY USA
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45
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Kim J, Choi KW, Lee J, Lee J, Lee S, Sun R, Kim J. Wnt/β-catenin Signaling Inhibitors suppress the Tumor-initiating properties of a CD44 +CD133 + subpopulation of Caco-2 cells. Int J Biol Sci 2021; 17:1644-1659. [PMID: 33994850 PMCID: PMC8120464 DOI: 10.7150/ijbs.58612] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 03/26/2021] [Indexed: 01/15/2023] Open
Abstract
Tumor-initiating cells or cancer stem cells are a subset of cancer cells that have tumorigenic potential in human cancer. Although several markers have been proposed to distinguish tumor-initiating cells from colorectal cancer cells, little is known about how this subpopulation contributes to tumorigenesis. Here, we characterized a tumor-initiating cell subpopulation from Caco-2 colorectal cancer cells. Based on the findings that Caco-2 cell subpopulations express different cell surface markers, we were able to discriminate three main fractions, CD44-CD133-, CD44-CD133+, and CD44+CD133+ subsets, and characterized their biochemical and tumorigenic properties. Our results show that CD44+CD133+ cells possessed an unusual capacity to proliferate and could form tumors when transplanted into NSG mice. Additionally, primary tumors grown from CD44+CD133+ Caco-2 cells contained mixed populations of CD44+CD133+ and non-CD44+CD133+ Caco-2 cells, indicating that the full phenotypic heterogeneity of the parental Caco-2 cells was re-created. Notably, only the CD44+CD133+ subset of Caco-2-derived primary tumors had tumorigenic potential in NSG mice, and the tumor growth of CD44+CD133+ cells was faster in secondary xenografts than in primary transplants. Gene expression analysis revealed that the Wnt/β-catenin pathway was over-activated in CD44+CD133+ cells, and the growth and tumorigenic potential of this subpopulation were significantly suppressed by small-molecule Wnt/β-catenin signaling inhibitors. Our findings suggest that the CD44+CD133+ subpopulation from Caco-2 cells was highly enriched in tumorigenic cells and will be useful for investigating the mechanisms leading to human colorectal cancer development.
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Affiliation(s)
| | | | | | | | | | | | - Jungho Kim
- Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul 04107, Korea
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46
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László L, Kurilla A, Takács T, Kudlik G, Koprivanacz K, Buday L, Vas V. Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology. Cells 2021; 10:667. [PMID: 33802849 PMCID: PMC8002639 DOI: 10.3390/cells10030667] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/03/2021] [Accepted: 03/10/2021] [Indexed: 12/17/2022] Open
Abstract
The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC.
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Affiliation(s)
- Loretta László
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Anita Kurilla
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Tamás Takács
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Gyöngyi Kudlik
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - Kitti Koprivanacz
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
| | - László Buday
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
- Department of Medical Chemistry, Semmelweis University Medical School, 1071 Budapest, Hungary
| | - Virag Vas
- Research Centre for Natural Sciences, Institute of Enzymology, 1051 Budapest, Hungary; (L.L.); (A.K.); (T.T.); (G.K.); (K.K.); (L.B.)
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Preisler L, Habib A, Shapira G, Kuznitsov-Yanovsky L, Mayshar Y, Carmel-Gross I, Malcov M, Azem F, Shomron N, Kariv R, Hershkovitz D, Ben-Yosef D. Heterozygous APC germline mutations impart predisposition to colorectal cancer. Sci Rep 2021; 11:5113. [PMID: 33664379 PMCID: PMC7933349 DOI: 10.1038/s41598-021-84564-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 02/04/2021] [Indexed: 12/24/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.
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Affiliation(s)
- Livia Preisler
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel.,Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
| | - Aline Habib
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel.,Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
| | - Guy Shapira
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
| | - Liron Kuznitsov-Yanovsky
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel.,Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
| | - Yoav Mayshar
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel.,Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ilana Carmel-Gross
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel
| | - Mira Malcov
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel
| | - Foad Azem
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel
| | - Noam Shomron
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
| | - Revital Kariv
- Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Dov Hershkovitz
- Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
| | - Dalit Ben-Yosef
- Wolfe PGD-Stem Cell Laboratory, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 64239, Tel-Aviv, Israel. .,Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel.
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48
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Villota H, Röthlisberger S, Pedroza-Díaz J. Modulation of the Canonical Wnt Signaling Pathway by Dietary Polyphenols, an Opportunity for Colorectal Cancer Chemoprevention and Treatment. Nutr Cancer 2021; 74:384-404. [PMID: 33596716 DOI: 10.1080/01635581.2021.1884730] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In the last few decades there has been a rise in the worldwide incidence of colorectal cancer which can be traced back to the influence of well-known modifiable risk factors such as lifestyle, diet and obesity. Conversely, the consumption of fruits, vegetables and fiber decreases the risk of CRC, which is why dietary polyphenols have aroused interest in recent years as potentially anti-carcinogenic compounds. One of the driving forces of colorectal carcinogenesis, in both sporadic and hereditary CRC, is the aberrant activation/regulation of the Wnt/β-catenin pathway. This review discusses reports of modulation of the Wnt/β-Catenin signaling pathway by dietary polyphenols (resveratrol, avenanthramides, epigallocatechinin, curcumin, quercetin, silibinin, genistein and mangiferin) specifically focusing on CRC, and proposes a model as to how this modulation occurs. There is potential for implementing these dietary polyphenols into preventative and therapeutic therapies for CRC as evidenced by some clinical trials that have been carried out with promising results.
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Affiliation(s)
- Hernan Villota
- Biomedical Innovation and Research Group, Faculty of Applied and Exact Sciences, Instituto Tecnologico Metropolitano, Medellin, Colombia
| | - Sarah Röthlisberger
- Biomedical Innovation and Research Group, Faculty of Applied and Exact Sciences, Instituto Tecnologico Metropolitano, Medellin, Colombia
| | - Johanna Pedroza-Díaz
- Biomedical Innovation and Research Group, Faculty of Applied and Exact Sciences, Instituto Tecnologico Metropolitano, Medellin, Colombia
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49
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Barriuso J, Nagaraju RT, Belgamwar S, Chakrabarty B, Burghel GJ, Schlecht H, Foster L, Kilgour E, Wallace AJ, Braun M, Dive C, Evans DG, Bristow RG, Saunders MP, O'Dwyer ST, Aziz O. Early Adaptation of Colorectal Cancer Cells to the Peritoneal Cavity Is Associated with Activation of "Stemness" Programs and Local Inflammation. Clin Cancer Res 2021; 27:1119-1130. [PMID: 33257424 PMCID: PMC7611320 DOI: 10.1158/1078-0432.ccr-20-3320] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/20/2020] [Accepted: 11/24/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity. EXPERIMENTAL DESIGN We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases. RESULTS We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of "stemness" in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69-3.19; P < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50-2.91; P < 0.0001)]. CONCLUSIONS Our findings indicated that the activation of "stemness" pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The in silico analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting.
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Affiliation(s)
- Jorge Barriuso
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom.
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, United Kingdom
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
| | - Raghavendar T Nagaraju
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, United Kingdom
| | - Shreya Belgamwar
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
| | - Bipasha Chakrabarty
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
- Department of Pathology, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
| | - George J Burghel
- NW GLH (Manchester), Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, England, United Kingdom
| | - Helene Schlecht
- NW GLH (Manchester), Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, England, United Kingdom
| | - Lucy Foster
- Department of Pathology, Manchester University NHS Foundation Trust, Manchester, England, United Kingdom
| | - Elaine Kilgour
- Cancer Research UK Manchester Institute, Cancer Biomarker Centre, University of Manchester, Manchester, England, United Kingdom
| | - Andrew J Wallace
- NW GLH (Manchester), Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, England, United Kingdom
| | - Michael Braun
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, United Kingdom
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
| | - Caroline Dive
- Cancer Research UK Manchester Institute, Cancer Biomarker Centre, University of Manchester, Manchester, England, United Kingdom
| | - D Gareth Evans
- Department of Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, England, United Kingdom
| | - Robert G Bristow
- Manchester Cancer Research Centre, CRUK Manchester Institute, University of Manchester, Manchester, England, United Kingdom
| | - Mark P Saunders
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
- Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
| | - Sarah T O'Dwyer
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, United Kingdom
| | - Omer Aziz
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, England, United Kingdom.
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, United Kingdom
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50
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FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells. Int J Mol Sci 2021; 22:ijms22020753. [PMID: 33451103 PMCID: PMC7828641 DOI: 10.3390/ijms22020753] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.
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