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Kayacik N, Kurter H, Sever T, Basbinar Y, Calibasi-Kocal G. Picropodophyllin, an IGF‑1 receptor inhibitor, enhances oxaliplatin efficacy in chemoresistant colorectal cancer HCT116 cells by reducing metastatic potential. Oncol Lett 2025; 29:220. [PMID: 40103601 PMCID: PMC11916648 DOI: 10.3892/ol.2025.14966] [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: 07/24/2024] [Accepted: 02/05/2025] [Indexed: 03/20/2025] Open
Abstract
The insulin-like growth factor receptor (IGF-1R) axis drives cellular growth, survival and chemoresistance in colorectal cancer (CRC) by promoting proliferative signaling, anti-apoptotic effects and epithelial-mesenchymal transition (EMT). Targeting the IGF-1R pathway is therefore a promising strategy, not only for overcoming drug resistance, but also for reducing migration and metastatic behavior related to EMT. The present study aimed to evaluate the potential of picropodophyllin (PPP), a selective IGF-1R inhibitor, to enhance the effects of oxaliplatin (OX) in HCT116 and OX-resistant HCT116-R cells. Cell viability was evaluated using a resazurin-based assay following 48-h combination treatment with OX at its IC50 concentrations (HCT116 cells, 53 µM and HCT116-R cells, 324 µM) and PPP (1 µM). Migration was assessed using wound healing assays, with images captured and analyzed at 0 and 48 h. Additionally, immunofluorescence staining was performed to assess E-cadherin and vimentin expression, evaluating epithelial and mesenchymal characteristics. In HCT116-R cells, the combination of OX (53 µM) and PPP significantly reduced cell viability by 0.65-fold compared with OX alone (P=0.0286). Wound healing assays demonstrated that combining PPP with OX (53 and 324 µM) significantly decreased migration, with 0.34-fold and 0.22-fold reductions, respectively (P<0.05). Immunofluorescence staining revealed that this combination also significantly increased E-cadherin expression, by 1.37- and 1.63-fold, respectively (P<0.05), indicating the role of PPP in enhancing epithelial characteristics and reducing EMT-related drug resistance. These findings highlight the potential for combining PPP with OX to enhance the cytotoxic and anti-metastatic effects of OX in chemo-resistant CRC cells, thus offering a promising strategy for overcoming drug resistance and improving patient outcomes in CRC treatment.
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Affiliation(s)
- Nurcin Kayacik
- Department of Oncology, Institute of Health Sciences, Dokuz Eylul University, 35340 Izmir, Turkey
| | - Hasan Kurter
- Department of Oncology, Institute of Health Sciences, Dokuz Eylul University, 35340 Izmir, Turkey
| | - Tolga Sever
- Department of Oncology, Institute of Health Sciences, Dokuz Eylul University, 35340 Izmir, Turkey
| | - Yasemin Basbinar
- Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, 35340 Izmir, Turkey
| | - Gizem Calibasi-Kocal
- Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, 35340 Izmir, Turkey
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Shaham SH, Vij P, Tripathi MK. Advances in Targeted and Chemotherapeutic Strategies for Colorectal Cancer: Current Insights and Future Directions. Biomedicines 2025; 13:642. [PMID: 40149618 PMCID: PMC11940796 DOI: 10.3390/biomedicines13030642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, necessitating the continuous evolution of therapeutic approaches. Despite advancements in early detection and localized treatments, metastatic colorectal cancer (mCRC) poses significant challenges due to low survival rates and resistance to conventional therapies. This review highlights the current landscape of CRC treatment, focusing on chemotherapy and targeted therapies. Chemotherapeutic agents, including 5-fluorouracil, irinotecan, and oxaliplatin, have significantly improved survival but face limitations such as systemic toxicity and resistance. Targeted therapies, leveraging mechanisms like VEGF, EGFR, and Hedgehog pathway inhibition, offer promising alternatives, minimizing damage to healthy tissues while enhancing therapeutic precision. Furthermore, future directions in CRC treatment include exploring innovative targets such as Wnt/β-catenin, Notch, and TGF-β pathways, alongside IGF/IGF1R inhibition. These emerging strategies aim to address drug resistance and improve patient outcomes. This review emphasizes the importance of integrating molecular insights into drug development, advocating for a more personalized approach to combat CRC's complexity and heterogeneity.
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Affiliation(s)
- Salique H. Shaham
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA;
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Puneet Vij
- Department of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Queens, New York, NY 11439, USA;
| | - Manish K. Tripathi
- Medicine and Oncology ISU, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA;
- South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
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Shadnoush M, Momenan M, Seidel V, Tierling S, Fatemi N, Nazemalhosseini-Mojarad E, Norooz MT, Cheraghpour M. A comprehensive update on the potential of curcumin to enhance chemosensitivity in colorectal cancer. Pharmacol Rep 2025; 77:103-123. [PMID: 39304638 DOI: 10.1007/s43440-024-00652-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 09/07/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.
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Affiliation(s)
- Mahdi Shadnoush
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, P.O.Box, Tehran, 16635-148, Iran
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Momenan
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Science and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Veronique Seidel
- Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Sascha Tierling
- Department of Genetics/Epigenetics, Faculty NT, Life Sciences, Saarland University, Saarbrücken, Germany
| | - Nayeralsadat Fatemi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, P.O.Box, Tehran, 16635-148, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Tayefeh Norooz
- General Surgery Department, Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, P.O.Box, Tehran, 16635-148, Iran.
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4
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Chen YL, Chu CA, Wang JY, Chen WL, Wang YW, Ho CL, Lee CT, Chow NH. Nuclear translocation of RON receptor tyrosine kinase. New mechanistic and functional insights. Cytokine Growth Factor Rev 2025; 81:9-15. [PMID: 39794156 DOI: 10.1016/j.cytogfr.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025]
Abstract
Receptor tyrosine kinases (RTKs) are membrane sensors that monitor alterations in the extracellular milieu and translate this information into appropriate cellular responses. Epidermal growth factor receptor (EGFR) is the most well-known model in which gene expression is upregulated by mitogenic signals through the activation of multiple signaling cascades or by nuclear translocation of the full-length EGFR protein. RON (Receptuer d'Origine Nantatise, also known as macrophage stimulating 1 receptor, MST1R) has recently gained attention as a therapeutic target for human cancer. This review summarizes the recent understanding of the unusual nuclear translocation of uncleaved RON receptor proteins in response to cellular stresses, such as serum starvation, hormonal deprivation, hypoxia, and genotoxicity. This nonligand mechanism, achieved by RON per se or by interaction with EGFR, may directly activate the transcriptional machinery necessary for cancer cells to survive. In vitro experiments have demonstrated the importance of tyrosine kinase of RON in binding to and activating the c-JUN promoter, HIF-1α, DNA helicase 2, DNA-dependent protein kinase catalytic subunit, and other stress-responsive networks. Nuclear RON-activated nonhomologous end joining repair confers chemoresistance to drugs that induce double-strand breaks (DSBs) in cancer cells. Tyrosine kinase inhibitors or monoclonal antibodies targeting RON kinase may therefore be useful treatments for patients with RON-overexpressing tumors. DSB-inducing anticancer drugs are not recommended for these cancer patients. Moreover, multi-RTK inhibition is a more rational strategy for patients with RON- and RTK-coexpressing human cancer.
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Affiliation(s)
- Yi-Lin Chen
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Chien-An Chu
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Jiu-Yao Wang
- Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan; Department of Allergy, Immunology, and Rheumatology (AIR), China Medical University Children's Hospital, Taichung, Taiwan
| | - Wan-Li Chen
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yi-Wen Wang
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Ta Lee
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Nan-Haw Chow
- Center for Precision Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Pathology, College of Medicine, China Medical University, Taichung, Taiwan.
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Deng J, Zhou J, Jiang B. Advances in the role of membrane-bound transcription factors in carcinogenesis and therapy. Discov Oncol 2024; 15:559. [PMID: 39404930 PMCID: PMC11480308 DOI: 10.1007/s12672-024-01414-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024] Open
Abstract
Protein shuttling between the cytoplasm and nucleus is a unique phenomenon in eukaryotic organisms, integral to various cellular functions. Membrane-bound transcription factors (MTFs), a specialized class of nucleocytoplasmic shuttling proteins, are anchored to the cell membrane and enter the nucleus upon ligand binding to exert their transcriptional regulatory functions. MTFs are crucial in cellular signal transduction, and aberrant nucleocytoplasmic shuttling of MTFs is closely associated with tumor initiation, progression, and resistance to anticancer therapies. Studies have demonstrated that MTFs, such as human epidermal growth factor receptor (HER), fibroblast growth factor receptor (FGFR), β-catenin, Notch, insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor (IR), play critical roles in tumorigenesis and cancer progression. Targeted therapies developed against HERs and FGFRs, among these MTFs, have yielded significant success in cancer treatment. However, the development of drug resistance remains a major challenge. As research on MTFs progress, it is anticipated that additional MTF-targeted therapies will be developed to enhance cancer treatment. In this review, we summarized recent advancements in the study of MTFs and their roles in carcinogenesis and therapy, aiming to provide valuable insights into the potential of targeting MTF pathways for the reseach of therapeutic strategies.
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Affiliation(s)
- JiaLi Deng
- Medical Research Center, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
- Department of Clinical Laboratory, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - Jie Zhou
- Medical Research Center, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
- Department of Clinical Laboratory, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China
| | - BinYuan Jiang
- Medical Research Center, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China.
- Department of Clinical Laboratory, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China.
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Chen YC, Gowda K, Amin S, Schell TD, Sharma AK, Robertson GP. Pharmacological agents targeting drug-tolerant persister cells in cancer. Pharmacol Res 2024; 203:107163. [PMID: 38569982 PMCID: PMC11734664 DOI: 10.1016/j.phrs.2024.107163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/05/2024] [Accepted: 03/29/2024] [Indexed: 04/05/2024]
Abstract
Current cancer therapy can be effective, but the development of drug resistant disease is the usual outcome. These drugs can eliminate most of the tumor burden but often fail to eliminate the rare, "Drug Tolerant Persister" (DTP) cell subpopulations in residual tumors, which can be referred to as "Persister" cells. Therefore, novel therapeutic agents specifically targeting or preventing the development of drug-resistant tumors mediated by the remaining persister cells subpopulations are needed. Since approximately ninety percent of cancer-related deaths occur because of the eventual development of drug resistance, identifying, and dissecting the biology of the persister cells is essential for the creation of drugs to target them. While there remains uncertainty surrounding all the markers identifying DTP cells in the literature, this review summarizes the drugs and therapeutic approaches that are available to target the persister cell subpopulations expressing the cellular markers ATP-binding cassette sub-family B member 5 (ABCB5), CD133, CD271, Lysine-specific histone demethylase 5 (KDM5), and aldehyde dehydrogenase (ALDH). Persister cells expressing these markers were selected as the focus of this review because they have been found on cells surviving following drug treatments that promote recurrent drug resistant cancer and are associated with stem cell-like properties, including self-renewal, differentiation, and resistance to therapy. The limitations and obstacles facing the development of agents targeting these DTP cell subpopulations are detailed, with discussion of potential solutions and current research areas needing further exploration.
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Affiliation(s)
- Yu-Chi Chen
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Krishne Gowda
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Shantu Amin
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Todd D Schell
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Arun K Sharma
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Gavin P Robertson
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA; The Pennsylvania State University Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
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7
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Soni UK, Jenny L, Hegde RS. IGF-1R targeting in cancer - does sub-cellular localization matter? J Exp Clin Cancer Res 2023; 42:273. [PMID: 37858153 PMCID: PMC10588251 DOI: 10.1186/s13046-023-02850-7] [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: 09/09/2023] [Accepted: 10/03/2023] [Indexed: 10/21/2023] Open
Abstract
The insulin-like growth factor receptor (IGF-1R) was among the most intensively pursued kinase targets in oncology. However, even after a slew of small-molecule and antibody therapeutics reached clinical trials for a range of solid tumors, the initial promise remains unfulfilled. Mechanisms of resistance to, and toxicities resulting from, IGF-1R-targeted drugs are well-catalogued, and there is general appreciation of the fact that a lack of biomarker-based patient stratification was a limitation of previous clinical trials. But no next-generation therapeutic strategies have yet successfully exploited this understanding in the clinic.Currently there is emerging interest in re-visiting IGF-1R targeted therapeutics in combination-treatment protocols with predictive biomarker-driven patient-stratification. One such biomarker that emerged from early clinical trials is the sub-cellular localization of IGF-1R. After providing some background on IGF-1R, its drugging history, and the trials that led to the termination of drug development for this target, we look more deeply into the correlation between sub-cellular localization of IGF-1R and susceptibility to various classes of IGF-1R - targeted agents.
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Affiliation(s)
- Upendra K Soni
- Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Liam Jenny
- Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rashmi S Hegde
- Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Werner H. The IGF1 Signaling Pathway: From Basic Concepts to Therapeutic Opportunities. Int J Mol Sci 2023; 24:14882. [PMID: 37834331 PMCID: PMC10573540 DOI: 10.3390/ijms241914882] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/02/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface protein that is evolutionarily related to the insulin receptor (InsR). The effects of IGF1 are moderated by a group of binding proteins (IGFBPs) that bind and transport the ligand in the circulation and extracellular fluids. In mechanistic terms, IGF1R function is linked to the MAPK and PI3K signaling pathways. Furthermore, IGF1R has been shown to migrate to cell nucleus, where it functions as a transcriptional activator. The co-localization of IGF1R and MAPK in the nucleus is of major interest as it suggests novel mechanistic paradigms for the IGF1R-MAPK network. Given its potent anti-apoptotic and pro-survival roles, and in view of its almost universal pattern of expression in most types of cancer, IGF1R has emerged as a promising molecular target in oncology. The present review article provides a concise overview of key scientific developments in the research area of IGF and highlights a number of more recent findings, including its nuclear migration and its interaction with oncogenes and tumor suppressors.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
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Zheng K, Sha N, Hou G, Leng Z, Zhao Q, Zhang L, He L, Xu M, Jiang Y, Chen T. IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. Nat Commun 2023; 14:6117. [PMID: 37777542 PMCID: PMC10542766 DOI: 10.1038/s41467-023-41658-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: 01/10/2023] [Accepted: 09/14/2023] [Indexed: 10/02/2023] Open
Abstract
The proline synthesis is importantly involved in tumor growth under hypoxia, while the underlying mechanism remains to be further investigated. Here we show that pyrroline-5-carpoxylate reductase-1 (PYCR1), displaying a constant nuclear localization, is phosphorylated by nuclear IGF1R at Tyrosine 135 under hypoxia; this phosphorylation promotes the binding of PYCR1 to ELK4 and thus PYCR1 recruitment to ELK4-targeted genes promoter. Under hypoxia, ELK4-binding ability and enzymatic activity of PYCR1 are both required for ELK4-Sirt7-mediated transcriptional repression and cell growth maintenance, in which PYCR1-catalyzed NAD+ production stimulates the deacetylation activity of Sirt7 on H3K18ac that restrains genes transcription. Functionally, PYCR1 Tyr-135 phosphorylation exerts supportive effect on tumor growth under hypoxia, and the level of PYCR1 Tyr-135 phosphorylation is associated with malignancy of colorectal cancer (CRC). These data uncover the relationship between the compartmentally metabolic activity of PYCR1 and genes transcription regulation, and highlight the oncogenic role of PYCR1 during CRC development.
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Affiliation(s)
- Ke Zheng
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nannan Sha
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guofang Hou
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuyun Leng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qin Zhao
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhang
- Department of Pathology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lingnan He
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Meidong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Yuhui Jiang
- Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
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Shulman DS, Merriam P, Choy E, Guenther LM, Cavanaugh KL, Kao P, Posner A, Bhushan K, Fairchild G, Barker E, Klega K, Stegmaier K, Crompton BD, London WB, DuBois SG. Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma. Cancer Med 2023; 12:15207-15216. [PMID: 37306107 PMCID: PMC10417097 DOI: 10.1002/cam4.6208] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 05/08/2023] [Accepted: 05/23/2023] [Indexed: 06/13/2023] Open
Abstract
BACKGROUND Ewing sarcoma (EWS) is an aggressive sarcoma with few treatment options for patients with relapsed disease. Cyclin-dependent kinase 4 (CDK4) is a genomic vulnerability in EWS that is synergistic with IGF-1R inhibition in preclinical studies. We present the results of a phase 2 study combining palbociclib (CDK4/6 inhibitor) with ganitumab (IGF-1R monoclonal antibody) for patients with relapsed EWS. PATIENTS AND METHODS This open-label, non-randomized, phase 2 trial enrolled patients ≥12 years with relapsed EWS. All patients had molecular confirmation of EWS and RECIST measurable disease. Patients initially received palbociclib 125 mg orally on Days 1-21 and ganitumab 18 mg/kg intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoints were objective response (complete or partial) per RECIST and toxicity by CTCAE. An exact one-stage design required ≥4 responders out of 15 to evaluate an alternative hypothesis of 40% response rate against a null of 10%. The study was closed following enrollment of the 10th patient due to discontinuation of ganitumab supply. RESULTS Ten evaluable patients enrolled [median age 25.7 years (range 12.3-40.1)]. The median duration of therapy was 2.5 months (range 0.9-10.8). There were no complete or partial responders. Three of 10 patients had stable disease for >4 cycles and 2 had stable disease at completion of planned therapy or study closure. Six-month progression-free survival was 30% (95% CI 1.6%-58.4%). Two patients had cycle 1 hematologic dose-limiting toxicities (DLTs) triggering palbociclib dose reduction to 100 mg daily for 21 days. Two subsequent patients had cycle 1 hematologic DLTs at the reduced dose. Eighty percent of patients had grade 3/4 AEs, including neutropenia (n = 8), white blood cell decreased (n = 7), and thrombocytopenia (n = 5). Serum total IGF-1 significantly increased (p = 0.013) and ctDNA decreased during the first cycle. CONCLUSIONS This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease.
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Affiliation(s)
- David S. Shulman
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Priscilla Merriam
- Dana‐Farber Cancer Institute and Harvard Medical SchoolBostonMassachusettsUSA
| | - Edwin Choy
- Massachusetts General HospitalMassachusetts General Hospital Cancer CenterBostonMassachusettsUSA
| | | | - Kerri L. Cavanaugh
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Pei‐Chi Kao
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Andrew Posner
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Ketki Bhushan
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Grace Fairchild
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Emma Barker
- Dana‐Farber Cancer Institute and Harvard Medical SchoolBostonMassachusettsUSA
| | - Kelly Klega
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Kimberly Stegmaier
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Brian D. Crompton
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Wendy B. London
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Steven G. DuBois
- Dana‐Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical SchoolBostonMassachusettsUSA
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Wang D, Tang X, Ruan J, Zhu Z, Wang R, Weng Y, Zhang Y, Wang T, Huang Y, Wang H, Su Z, Wu X, Tao G, Wang Y. HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:9335440. [PMID: 37180757 PMCID: PMC10169247 DOI: 10.1155/2023/9335440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/22/2023] [Accepted: 03/30/2023] [Indexed: 05/16/2023]
Abstract
Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells-A2780/CDDP and SKOV3/CDDP-were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.
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Affiliation(s)
- Daojuan Wang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Xun Tang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
- Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, China
| | - Jianguo Ruan
- Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China
| | - Zhengquan Zhu
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Rong Wang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Yajing Weng
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Yaling Zhang
- School of Medicine, Jiaxing University, Jiaxing 314001, China
| | - Tingyu Wang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Ying Huang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Hongwei Wang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Zhenzi Su
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Xiaoke Wu
- Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
| | - Gaojian Tao
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
| | - Yong Wang
- The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
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12
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Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer. World J Gastroenterol 2023; 29:1911-1941. [PMID: 37155531 PMCID: PMC10122790 DOI: 10.3748/wjg.v29.i13.1911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/02/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.
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Affiliation(s)
- Sheng-Nan Ren
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Zhan-Yi Zhang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Jie Guo
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Ren Wang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Fang-Fang Chen
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Bo Chen
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Dong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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13
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Kasprzak A. Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia. Int J Mol Sci 2023; 24:ijms24043665. [PMID: 36835075 PMCID: PMC9959216 DOI: 10.3390/ijms24043665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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14
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Insulin‑like growth factor axis: A potential nanotherapy target for resistant cervical cancer tumors (Review). Oncol Lett 2023; 25:128. [PMID: 36844628 PMCID: PMC9950333 DOI: 10.3892/ol.2023.13714] [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: 12/09/2021] [Accepted: 09/07/2022] [Indexed: 02/12/2023] Open
Abstract
Cervical cancer is among the most frequently occurring neoplasms worldwide, and it particularly affects individuals in developing countries. Factors such as the low quality of screening tests, the high incidence of locally advanced cancer stages and the intrinsic resistance of certain tumors are the main causes of failure in the treatment of this neoplasm. Due to advances in the understanding of carcinogenic mechanisms and bioengineering research, advanced biological nanomaterials have been manufactured. The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including IGF receptor 1. These receptors are activated by binding to their respective growth factor ligands, IGF-1 and IGF-2, and insulin, and play an important role in the development, maintenance, progression, survival and treatment resistance of cervical cancer. In the present review, the role of the IGF system in cervical cancer and three nanotechnological applications that use elements of this system are described, namely Trap decoys, magnetic iron oxide nanoparticles and protein nanotubes. Their use in the treatment of resistant cervical cancer tumors is also discussed.
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15
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Niu L, Liu L, Cai J. A novel strategy for precise prognosis management and treatment option in colon adenocarcinoma with TP53 mutations. Front Surg 2023; 10:1079129. [PMID: 36843983 PMCID: PMC9947352 DOI: 10.3389/fsurg.2023.1079129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/10/2023] [Indexed: 02/11/2023] Open
Abstract
Background TP53 is one of the most frequent mutated genes in colon cancer. Although colon cancer with TP53 mutations has a high risk of metastasis and worse prognosis generally, it showed high heterogeneity clinically. Methods A total of 1,412 colon adenocarcinoma (COAD) samples were obtained from two RNA-seq cohorts and three microarray cohorts, including the TCGA-COAD (N = 408), the CPTAC-COAD (N = 106), GSE39582 (N = 541), GSE17536 (N = 171) and GSE41258 (N = 186). The LASSO-Cox method was used to establish the prognostic signature based on the expression data. The patients were divided into high-risk and low-risk groups based on the median risk score. The efficiency of the prognostic signature was validated in various cohorts, including TP53-mutant and TP53 wild-type. The exploration of potential therapeutic targets and agents was performed by using the expression data of TP53-mutant COAD cell lines obtained from the CCLE database and the corresponding drug sensitivity data obtained from the GDSC database. Results A 16-gene prognostic signature was established in TP53-mutant COAD. The high-risk group had significantly inferior survival time compared to the low-risk group in all TP53-mutant datasets, while the prognostic signature failed to classify the prognosis of COAD with TP53 wild-type properly. Besides, the risk score was the independent poor factor for the prognosis in TP53-mutant COAD and the nomogram based on the risk score was also shown good predictive efficiency in TP53-mutant COAD. Moreover, we identified SGPP1, RHOQ, and PDGFRB as potential targets for TP53-mutant COAD, and illuminated that the high-risk patients might benefit from IGFR-3801, Staurosporine, and Sabutoclax. Conclusion A novel prognostic signature with great efficiency was established especially for COAD patients with TP53 mutations. Besides, we identified novel therapeutic targets and potential sensitive agents for TP53-mutant COAD with high risk. Our findings provided not only a new strategy for prognosis management but also new clues for drug application and precision treatment in COAD with TP53 mutations.
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Yoshihiro T, Ariyama H, Yamaguchi K, Imajima T, Yamaga S, Tsuchihashi K, Isobe T, Kusaba H, Akashi K, Baba E. Inhibition of insulin-like growth factor-1 receptor enhances eribulin-induced DNA damage in colorectal cancer. Cancer Sci 2022; 113:4207-4218. [PMID: 36053154 PMCID: PMC9746063 DOI: 10.1111/cas.15558] [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: 02/24/2022] [Revised: 08/21/2022] [Accepted: 08/25/2022] [Indexed: 12/15/2022] Open
Abstract
Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G2 /M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.
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Affiliation(s)
- Tomoyasu Yoshihiro
- Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
| | - Hiroshi Ariyama
- Department of Hematology, Oncology and Cardiovascular MedicineKyushu University HospitalFukuokaJapan
| | - Kyoko Yamaguchi
- Department of Hematology, Oncology and Cardiovascular MedicineKyushu University HospitalFukuokaJapan
| | - Takashi Imajima
- Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
| | - Satoru Yamaga
- Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
| | - Kenji Tsuchihashi
- Department of Hematology, Oncology and Cardiovascular MedicineKyushu University HospitalFukuokaJapan
| | - Taichi Isobe
- Department of Oncology and Social Medicine, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Hitoshi Kusaba
- Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
| | - Koichi Akashi
- Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
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17
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Werner H, LeRoith D. Hallmarks of cancer: The insulin-like growth factors perspective. Front Oncol 2022; 12:1055589. [PMID: 36479090 PMCID: PMC9720135 DOI: 10.3389/fonc.2022.1055589] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/07/2022] [Indexed: 08/30/2023] Open
Abstract
The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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18
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Layos L, Martínez-Balibrea E, Ruiz de Porras V. Curcumin: A Novel Way to Improve Quality of Life for Colorectal Cancer Patients? Int J Mol Sci 2022; 23:ijms232214058. [PMID: 36430537 PMCID: PMC9695864 DOI: 10.3390/ijms232214058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women. Treatment of metastatic CRC consists of highly toxic chemotherapeutic drug combinations that often negatively affect patient quality of life (QoL). Moreover, chemotherapy-induced toxicity and chemotherapy resistance are among the most important factors limiting cancer treatment and can lead to the interruption or discontinuation of potentially effective therapy. Several preclinical studies have demonstrated that curcumin acts through multiple cellular pathways and possesses both anti-cancer properties against CRC and the capacity to mitigate chemotherapy-related side effects and overcome drug resistance. In this review article, we suggest that the addition of curcumin to the standard chemotherapeutic treatment for metastatic CRC could reduce associated side-effects and overcome chemotherapy resistance, thereby improving patient QoL.
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Affiliation(s)
- Laura Layos
- Medical Oncology Department, Catalan Institute of Oncology, Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
- Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain
| | - Eva Martínez-Balibrea
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain
- ProCURE Program, Catalan Institute of Oncology, Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain
| | - Vicenç Ruiz de Porras
- Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain
- Correspondence: ; Tel.: +34-(93)-5546301
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Wang P, Mak VCY, Cheung LWT. Drugging IGF-1R in cancer: New insights and emerging opportunities. Genes Dis 2022; 10:199-211. [PMID: 37013053 PMCID: PMC10066341 DOI: 10.1016/j.gendis.2022.03.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 03/02/2022] [Indexed: 11/19/2022] Open
Abstract
The insulin-like growth factor (IGF) axis plays important roles in cancer development and metastasis. The type 1 IGF receptor (IGF-1R) is a key member in the IGF axis and has long been recognized for its oncogenic role in multiple cancer lineages. Here we review the occurrence of IGF-1R aberrations and activation mechanisms in cancers, which justify the development of anti-IGF-1R therapies. We describe the therapeutic agents available for IGF-1R inhibition, with focuses on the recent or ongoing pre-clinical and clinical studies. These include antisense oligonucleotide, tyrosine kinase inhibitors and monoclonal antibodies which may be conjugated with cytotoxic drug. Remarkably, simultaneous targeting of IGF-1R and several other oncogenic vulnerabilities has shown early promise, highlighting the potential benefits of combination therapy. Further, we discuss the challenges in targeting IGF-1R so far and new concepts to improve therapeutic efficacy such as blockage of the nuclear translocation of IGF-1R.
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20
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IGF2BP2 promotes gastric cancer progression by regulating the IGF1R-RhoA-ROCK signaling pathway. Cell Signal 2022; 94:110313. [DOI: 10.1016/j.cellsig.2022.110313] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 12/12/2022]
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Biglycan Interacts with Type I Insulin-like Receptor (IGF-IR) Signaling Pathway to Regulate Osteosarcoma Cell Growth and Response to Chemotherapy. Cancers (Basel) 2022; 14:cancers14051196. [PMID: 35267503 PMCID: PMC8909324 DOI: 10.3390/cancers14051196] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Osteosarcoma (OS) is an aggressive, primary bone cancer. OS cells produce altered osteoid whose components participate in signaling correlated to the development of this cancer. Biglycan (BGN), a proteoglycan, is correlated to aggressive OS type and resistance to chemotherapy. A constitutive signaling of insulin-like growth factor receptor I (IGF-IR) signaling in sarcoma progression was established. We showed that biglycan binds IGF-IR resulting in prolonged IGF-IR activation, nuclear translocation, and growth response of the poorly-differentiated MG63 cells correlated to increased aggressiveness markers expression and enhanced chemoresistance. This mechanism is not valid in moderately and well-differentiated, biglycan non-expressing U-2OS and Saos-2 OS cells. Abstract Osteosarcoma (OS) is a mesenchymally derived, aggressive bone cancer. OS cells produce an aberrant nonmineralized or partly mineralized extracellular matrix (ECM) whose components participate in signaling pathways connected to specific pathogenic phenotypes of this bone cancer. The expression of biglycan (BGN), a secreted small leucine-rich proteoglycan (SLRP), is correlated to aggressive OS phenotype and resistance to chemotherapy. A constitutive signaling of IGF-IR signaling input in sarcoma progression has been established. Here, we show that biglycan activates the IGF-IR signaling pathway to promote MG63 biglycan-secreting OS cell growth by forming a complex with the receptor. Computational models of IGF-IR and biglycan docking suggest that biglycan binds IGF-IR dimer via its concave surface. Our binding free energy calculations indicate the formation of a stable complex. Biglycan binding results in prolonged IGF-IR activation leading to protracted IGF-IR-dependent cell growth response of the poorly-differentiated MG63 cells. Moreover, biglycan facilitates the internalization (p ≤ 0.01, p ≤ 0.001) and sumoylation-enhanced nuclear translocation of IGF-IR (p ≤ 0.05) and its DNA binding in MG63 cells (p ≤ 0.001). The tyrosine kinase activity of the receptor mediates this mechanism. Furthermore, biglycan downregulates the expression of the tumor-suppressor gene, PTEN (p ≤ 0.01), and increases the expression of endothelial–mesenchymal transition (EMT) and aggressiveness markers vimentin (p ≤ 0.01) and fibronectin (p ≤ 0.01) in MG63 cells. Interestingly, this mechanism is not valid in moderately and well-differentiated, biglycan non-expressing U-2OS and Saos-2 OS cells. Furthermore, biglycan exhibits protective effects against the chemotherapeutic drug, doxorubicin, in MG63 OS cells (p ≤ 0.01). In conclusion, these data indicate a potential direct and adjunct therapeutical role of biglycan in osteosarcoma.
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22
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Ionica E, Gaina G, Tica M, Chifiriuc MC, Gradisteanu-Pircalabioru G. Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients' Stratification. Front Oncol 2022; 11:811486. [PMID: 35198435 PMCID: PMC8859258 DOI: 10.3389/fonc.2021.811486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
In order to ensure that primary endpoints of clinical studies are attained, the patients' stratification is an important aspect. Selection criteria include age, gender, and also specific biomarkers, such as inflammation scores. These criteria are not sufficient to achieve a straightforward selection, however, in case of multifactorial diseases, with unknown or partially identified mechanisms, occasionally including host factors, and the microbiome. In these cases, the efficacy of interventions is difficult to predict, and as a result, the selection of subjects is often random. Colorectal cancer (CRC) is a highly heterogeneous disease, with variable clinical features, outcomes, and response to therapy; the CRC onset and progress involves multiple sequential steps with accumulation of genetic alterations, namely, mutations, gene amplification, and epigenetic changes. The gut microbes, either eubiotic or dysbiotic, could influence the CRC evolution through a complex and versatile crosstalk with the intestinal and immune cells, permanently changing the tumor microenvironment. There have been significant advances in the development of personalized approaches for CRC screening, treatment, and potential prevention. Advances in molecular techniques bring new criteria for patients' stratification-mutational analysis at the time of diagnosis to guide treatment, for example. Gut microbiome has emerged as the main trigger of gut mucosal homeostasis. This may impact cancer susceptibility through maintenance of the epithelial/mucus barrier and production of protective metabolites, such as short-chain fatty acids (SCFAs) via interactions with the hosts' diet and metabolism. Microbiome dysbiosis leads to the enrichment of cancer-promoting bacterial populations, loss of protective populations or maintaining an inflammatory chronic state, all of which contribute to the development and progression of CRC. Meanwhile, variations in patient responses to anti-cancer immuno- and chemotherapies were also linked to inter-individual differences in intestine microbiomes. The authors aim to highlight the contribution of epithelial and gut microbiome inflammatory biomarkers in the improvement of CRC patients' stratification towards a personalized approach of early diagnosis and treatment.
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Affiliation(s)
- Elena Ionica
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Gisela Gaina
- Laboratory of Cell Biology, Neuroscience and Experimental Miology, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Mihaela Tica
- Bucharest Emergency University Hospital, Bucharest, Romania
| | - Mariana-Carmen Chifiriuc
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
- Biological Science Division, Romanian Academy of Sciences, Bucharest, Romania
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23
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Ottaiano A, Circelli L, Santorsola M, Savarese G, Fontanella D, Gigantino V, Di Mauro A, Capuozzo M, Zappavigna S, Lombardi A, Perri F, Cascella M, Granata V, Capuozzo M, Nasti G, Caraglia M. Metastatic colorectal cancer and type 2 diabetes: prognostic and genetic interactions. Mol Oncol 2021; 16:319-332. [PMID: 34668636 PMCID: PMC8763648 DOI: 10.1002/1878-0261.13122] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/04/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
The present study was undertaken to analyze prognostic and genetic interactions between type 2 diabetes and metastatic colorectal cancer. Patients’ survival was depicted through the Kaplan–Meier product limit method. Prognostic factors were examined through the Cox proportional‐hazards regression model, and associations between diabetes and clinical‐pathologic variables were evaluated by the χ2 test. In total, 203 metastatic colorectal cancer patients were enrolled. Lymph nodes (P = 0.0004) and distant organs (> 2 distant sites, P = 0.0451) were more frequently involved in diabetic patients compared with those without diabetes. Diabetes had an independent statistically significant negative prognostic value for survival. Highly selected patients with cancer and/or diabetes as their only illness(es) were divided into three groups: (a) seven oligo‐metastatic patients without diabetes, (b) 10 poly‐metastatic patients without diabetes, and (c) 12 poly‐metastatic diabetic patients. These groups of patients were genetically characterized through the Illumina NovaSeq 6000 (San Diego, CA, USA) platform and TruSigt™Oncology 500 kit, focusing on genes involved in diabetes and colorectal cancer. Gene variants associated with diabetes and cancer were more frequent in patients in group 3. We found that type 2 diabetes is a negative prognostic factor for survival in colorectal cancer. Diabetes‐associated gene variants could concur with malignancy, providing a rational basis for innovative models of tumor progression and therapy.
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Affiliation(s)
| | - Luisa Circelli
- AMES, Centro Polidiagnostico Strumentale srl, Naples, Italy
| | | | | | | | | | | | | | - Silvia Zappavigna
- Department of Precision Medicine, University "L. Vanvitelli" of Naples, Italy.,Cytometric and Mutational Diagnostics, Azienda Universitaria Policlinico "L. Vanvitelli,", Naples, Italy
| | - Angela Lombardi
- Department of Precision Medicine, University "L. Vanvitelli" of Naples, Italy.,Cytometric and Mutational Diagnostics, Azienda Universitaria Policlinico "L. Vanvitelli,", Naples, Italy
| | - Francesco Perri
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale,", Naples, Italy
| | - Marco Cascella
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale,", Naples, Italy
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale,", Naples, Italy
| | | | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale,", Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University "L. Vanvitelli" of Naples, Italy.,Cytometric and Mutational Diagnostics, Azienda Universitaria Policlinico "L. Vanvitelli,", Naples, Italy.,Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Ariano Irpino, Italy
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24
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Jiang R, Wang M, Shen X, Huang S, Han J, Li L, Xu Z, Jiang C, Zhou Q, Feng X. SUMO1 modification of IGF-1R combining with SNAI2 inhibited osteogenic differentiation of PDLSCs stimulated by high glucose. Stem Cell Res Ther 2021; 12:543. [PMID: 34663464 PMCID: PMC8522165 DOI: 10.1186/s13287-021-02618-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/15/2021] [Indexed: 01/09/2023] Open
Abstract
Background Periodontal disease, an oral disease characterized by loss of alveolar bone and progressive teeth loss, is the sixth major complication of diabetes. It is spreading worldwide as it is difficult to be cured. The insulin-like growth factor 1 receptor (IGF-1R) plays an important role in regulating functional impairment associated with diabetes. However, it is unclear whether IGF-1R expression in periodontal tissue is related to alveolar bone destruction in diabetic patients. SUMO modification has been reported in various diseases and is associated with an increasing number of biological processes, but previous studies have not focused on diabetic periodontitis. This study aimed to explore the role of IGF-1R in osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in high glucose and control the multiple downstream damage signal factors. Methods PDLSCs were isolated and cultured after extraction of impacted teeth from healthy donors or subtractive orthodontic extraction in adolescents. PDLSCs were cultured in the osteogenic medium with different glucose concentrations prepared by medical 5% sterile glucose solution. The effects of different glucose concentrations on the osteogenic differentiation ability of PDLSCs were studied at the genetic and cellular levels by staining assay, Western Blot, RT-PCR, Co-IP and cytofluorescence. Results We found that SNAI2, RUNX2 expression decreased in PDLSCs cultured in high glucose osteogenic medium compared with that in normal glucose osteogenic medium, which were osteogenesis-related marker. In addition, the IGF-1R expression, sumoylation of IGF-1R and osteogenic differentiation in PDLSCs cultured in high glucose osteogenic medium were not consistent with those cultured in normal glucose osteogenic medium. However, osteogenic differentiation of PDLCSs enhanced after adding IGF-1R inhibitors to high glucose osteogenic medium. Conclusion Our data demonstrated that SUMO1 modification of IGF-1R inhibited osteogenic differentiation of PDLSCs by binding to SNAI2 in high glucose environment, a key factor leading to alveolar bone loss in diabetic patients. Thus we could maximize the control of multiple downstream damage signaling factors and bring new hope for alveolar bone regeneration in diabetic patients.
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Affiliation(s)
- Rongrong Jiang
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Miao Wang
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Xiaobo Shen
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Shuai Huang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, 226001, Jiangsu, China
| | - Jianpeng Han
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Lei Li
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Zhiliang Xu
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Chengfeng Jiang
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Qiao Zhou
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.
| | - Xingmei Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.
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25
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Stefani C, Miricescu D, Stanescu-Spinu II, Nica RI, Greabu M, Totan AR, Jinga M. Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now? Int J Mol Sci 2021; 22:ijms221910260. [PMID: 34638601 PMCID: PMC8508474 DOI: 10.3390/ijms221910260] [Citation(s) in RCA: 174] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC.
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Affiliation(s)
- Constantin Stefani
- Department of Family Medicine and Clinical Base, ‘‘Dr. Carol Davila’ Central Military Emergency University Hospital, 051075 Bucharest, Romania;
| | - Daniela Miricescu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
- Correspondence: (D.M.); (M.G.)
| | - Iulia-Ioana Stanescu-Spinu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
| | - Remus Iulian Nica
- Surgery 2, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 051075 Bucharest, Romania;
| | - Maria Greabu
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
- Correspondence: (D.M.); (M.G.)
| | - Alexandra Ripszky Totan
- Department of Biochemistry, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania; (I.-I.S.-S.); (A.R.T.)
| | - Mariana Jinga
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 051075 Bucharest, Romania;
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26
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Liu B, Jiang HY, Yuan T, Zhou WD, Xiang ZD, Jiang QQ, Wu DL. Long non-coding RNA AFAP1-AS1 facilitates prostate cancer progression by regulating miR-15b/IGF1R axis. Curr Pharm Des 2021; 27:4261-4269. [PMID: 34126893 DOI: 10.2174/1381612827666210612052317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 04/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Prostate cancer (PCa) is a commonly diagnosed malignant cancer and is the second highest cause of cancer related death in men worldwide. Enzalutamide is the second-generation inhibitor of androgen receptor signaling and is the fundamental drug for the treatment of advanced PCa. However, the disease will eventually progress to metastatic castration-resistant prostate cancer (CRPC) and aggressive neuroendocrine prostate cancer (NEPC) because of androgen-deprivation therapy (ADT) resistance. The aim of the study was to investigate the role of long non-coding RNA (lncRNA) AFAP1-AS1 in ADT resistance. METHODS Quantitative real-time PCR analysis (qPCR) was used to assess the expression of AFAP1-AS1 in PCa cell lines and tissues. Cell proliferation and invasion were assessed after AFAP1-AS1 knockdown using Cell Counting Kit (CCK)-8 and Transwell assay, respectively. A dual-luciferase reporter gene assay was carried out to validate the regulatory relationship among AFAP1-AS1, microRNA (miR)-15b, and insulin-like growth factor1 receptor (IGF1R). RESULTS AFAP1-AS1 level was markedly increased in castration-resistant C4-2 cells and NE-like cells (PC3, DU145, and NCI-H660), compared with androgen-sensitive LNCaP cells. Enzalutamide treatment increased the expression of AFAP1-AS1 in vitro and in vivo. Functionally, AFAP1-AS1 knockdown repressed tumor cell proliferation and invasion. Mechanistically, AFAP1-AS1 functioned as an oncogene in PCa through binding to miR-15b and destroying its tumor suppressor function. Finally, we identified that AFAP1-AS1 up-regulated IGF1R expression by competitively binding to miR-15b to de-repress IGF1R. CONCLUSION AFAP1-AS1 facilitates PCa progression by regulating miR-15b/IGF1R axis, indicating that AFAP1-AS1 may serve as a diagnostic biomarker and therapeutic target for PCa.
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Affiliation(s)
- Bo Liu
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
| | - Hui-Yang Jiang
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
| | - Tao Yuan
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
| | - Wei-Dong Zhou
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
| | - Zhen-Dong Xiang
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
| | - Qi-Quan Jiang
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
| | - Deng-Long Wu
- Department of Urology, Tongji Hospital, Tongji University of Medicine, 389 Xincun Road, Putuo, Shanghai, 200065, China
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27
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Xiu M, Huan X, Ou Y, Ying S, Wang J. The basic route of nuclear-targeted transport of IGF-1/IGF-1R and potential biological functions in intestinal epithelial cells. Cell Prolif 2021; 54:e13030. [PMID: 33932050 PMCID: PMC8168413 DOI: 10.1111/cpr.13030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 02/08/2021] [Accepted: 02/20/2021] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES Insulin-like growth factor (IGF-1) plays an important role in many biological processes in the intestinal tract. However, the cellular behaviour and characteristics of IGF-1/IGF-1R in intestinal cells remain unclear. MATERIALS AND METHODS A series of techniques (such as indirect immunofluorescence, co-localization and Western blot) have been used to systematically study the cellular behaviour of IGF-1/IGF-1R on intestinal cells. RESULTS We found that IGF-1 can not only internalize into the cytoplasm, but also transport into the cell nuclei. We systematically studied the detailed molecular pathways of IGF-1/IGF-1R's nuclear translocation. We found that IGF-1R underwent clathrin-mediated endocytosis into cells and then entered into Rab-5-positive endosomes. Dynein/dynactin were used as motors to drive Rab-5-positive endosomes carrying IGF-1R (cargo molecule) to Golgi apparatus (transit station) along the surface of the microtubule. IGF-1 and/or IGF-1R entered the cell nuclei through NPC (nuclear pore complex), a process mediated by NUP358. Further study indicated that nuclear localization of IGF-1 and/or IGF-1R promoted cell proliferation and increased the nuclear residence time of signalling molecules activated by IGF-1. Further experiments showed that IGF-1R may regulate the transcription of genes in the cell nuclei, indicating that nuclear-localized IGF-1R plays an important in cell proliferation. CONCLUSIONS In short, we revealed the molecular mechanism by which IGF-1/IGF-1R transports into the cell nuclei of intestinal cells. More importantly, the current work showed that the nuclear-localized IGF-1R has important biological functions.
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Affiliation(s)
- Ming Xiu
- Department of Intensive care unit, The first hospital of Jilin University, Changchun, China
| | - Xia Huan
- Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yang Ou
- The department of Geriatris, The first hospital of Jilin University, Changchun, China
| | - Sha Ying
- The department of Geriatris, The first hospital of Jilin University, Changchun, China
| | - Jianmeng Wang
- Department of Intensive care unit, The first hospital of Jilin University, Changchun, China.,The department of Geriatris, The first hospital of Jilin University, Changchun, China
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Werner H, Sarfstein R, Laron Z. The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer. Biomolecules 2021; 11:biom11040531. [PMID: 33918477 PMCID: PMC8065599 DOI: 10.3390/biom11040531] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology.
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Affiliation(s)
- Haim Werner
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
- Shalom and Varda Yoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv 69978, Israel
- Correspondence:
| | - Rive Sarfstein
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
| | - Zvi Laron
- Endocrine and Diabetes Research Unit, Schneider Children’s Medical Center, Petah Tikva 49292, Israel;
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29
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Ghafouri-Fard S, Abak A, Mohaqiq M, Shoorei H, Taheri M. The Interplay Between Non-coding RNAs and Insulin-Like Growth Factor Signaling in the Pathogenesis of Neoplasia. Front Cell Dev Biol 2021; 9:634512. [PMID: 33768092 PMCID: PMC7985092 DOI: 10.3389/fcell.2021.634512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/02/2021] [Indexed: 12/11/2022] Open
Abstract
The insulin-like growth factors (IGFs) are polypeptides with similar sequences with insulin. These factors regulate cell growth, development, maturation, and aging via different processes including the interplay with MAPK, Akt, and PI3K. IGF signaling participates in the pathogenesis of neoplasia, insulin resistance, diabetes mellitus, polycystic ovarian syndrome, cerebral ischemic injury, fatty liver disease, and several other conditions. Recent investigations have demonstrated the interplay between non-coding RNAs and IGF signaling. This interplay has fundamental roles in the development of the mentioned disorders. We designed the current study to search the available data about the role of IGF-associated non-coding RNAs in the evolution of neoplasia and other conditions. As novel therapeutic strategies have been designed for modification of IGF signaling, identification of the impact of non-coding RNAs in this pathway is necessary for the prediction of response to these modalities.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Mohaqiq
- School of Advancement, Centennial College, Ashtonbee Campus, Toronto, ON, Canada
- Wake Forest Institute for Regenerative Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, United States
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Biranjd University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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30
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Chen X, Liu Y, Zhang Q, Liu B, Cheng Y, Zhang Y, Sun Y, Liu J, Gen H. Exosomal Long Non-coding RNA HOTTIP Increases Resistance of Colorectal Cancer Cells to Mitomycin via Impairing MiR-214-Mediated Degradation of KPNA3. Front Cell Dev Biol 2021; 8:582723. [PMID: 33585440 PMCID: PMC7876302 DOI: 10.3389/fcell.2020.582723] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/12/2020] [Indexed: 12/15/2022] Open
Abstract
It has been reported that long non-coding RNA HOXA distal transcript antisense RNA (lncRNA HOTTIP) functions as a tumor promoter in colorectal cancer (CRC). Hence, we paid attention to exploring whether exosomes could carry lncRNA HOTTIP to affect the mitomycin resistance in CRC and to identify the underlying mechanisms. High expression of HOTTIP was detected in mitomycin-resistant CRC cells. Inhibition of HOTTIP reduced the mitomycin resistance. In the co-culture system of mitomycin-resistant cells or their derived exosomes with CRC cells, the HOTTIP was found to be transferred into the parental cells via extracellular vesicles (EVs) secreted from mitomycin-resistant cells and to contribute to the mitomycin resistance. Based on the bioinformatics databases, possible interaction network of HOTTIP, microRNA-214 (miR-214) and Karyopherin subunit alpha 3 (KPNA3) in CRC was predicted, which was further analyzed by dual-luciferase reporter, RNA binding protein immunoprecipitation and RNA pull-down assays. As HOTTIP down-regulated miR-214 to elevate the KPNA3 expression, HOTTIP enhanced the mitomycin resistance through impairing miR-214-dependent inhibition of KPNA3. Finally, HOTTIP was suggested as an independent factor predicting mitomycin response in patients with CRC. Those data together confirmed the promotive effects of EV-carried HOTTIP on the mitomycin resistance, while targeting HOTTIP might be a promising strategy overcoming drug resistance in CRC.
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Affiliation(s)
- Xijuan Chen
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingqiang Liu
- Department of General Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Qinglan Zhang
- Department of Hematology, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Baoxing Liu
- Department of Chest Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Cheng
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yonglei Zhang
- Department of General Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Sun
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hong Gen
- Department of Radiation Oncology, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
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Chen PC, Kuo YC, Chuong CM, Huang YH. Niche Modulation of IGF-1R Signaling: Its Role in Stem Cell Pluripotency, Cancer Reprogramming, and Therapeutic Applications. Front Cell Dev Biol 2021; 8:625943. [PMID: 33511137 PMCID: PMC7835526 DOI: 10.3389/fcell.2020.625943] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Stem cells work with their niches harmoniously during development. This concept has been extended to cancer pathology for cancer stem cells (CSCs) or cancer reprogramming. IGF-1R, a classical survival signaling, has been shown to regulate stem cell pluripotency, CSCs, or cancer reprogramming. The mechanism underlying such cell fate determination is unclear. We propose the determination is due to different niches in embryo development and tumor malignancy which modulate the consequences of IGF-1R signaling. Here we highlight the modulations of these niche parameters (hypoxia, inflammation, extracellular matrix), and the targeted stem cells (embryonic stem cells, germline stem cells, and mesenchymal stem cells) and CSCs, with relevance to cancer reprogramming. We organize known interaction between IGF-1R signaling and distinct niches in the double-sided cell fate with emerging trends highlighted. Based on these new insights, we propose that, through targeting IGF-1R signaling modulation, stem cell therapy and cancer stemness treatment can be further explored.
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Affiliation(s)
- Pei-Chin Chen
- Department of Education, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yung-Che Kuo
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Ming Chuong
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.,International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan.,PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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Fu X, Zhang Y, Chang L, Hui D, Jia R, Liu N, Zhang H, Han G, Han Z, Li Y, Liu H, Zhu H, Li Q. The JPJDF has Synergistic Effect with Fluoropyrimidine in the Maintenance Therapy for Metastatic Colorectal Cancer. Recent Pat Anticancer Drug Discov 2020; 15:257-269. [PMID: 32679021 DOI: 10.2174/1574892815666200717141205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/20/2020] [Accepted: 06/24/2020] [Indexed: 02/07/2023]
Abstract
Background:
Maintenance chemotherapeutic regimen with low toxicity is needed for
metastatic colorectal cancer. A recent patent has been issued on the spleen-strengthening and detoxification
prescription (JPJDF), a traditional Chinese herbal medicinal formula with anti-angiogenesis
effect. The clinical effect of JPJDF on the maintenance treatment of advanced colorectal cancer
has not been evaluated.
Objective:
This study aims to evaluate the effectiveness and safety of JPJDF in combination with
fluoropyrimidine compared to fluoropyrimidine alone as maintenance therapy for metastatic colorectal
cancer.
Methods:
We applied a prospective, randomized, double-blinded, single center clinical study design.
A total of 137 patients with advanced colorectal cancer were recruited. Patients received either
Fluoropyrimidine (Flu-treated group, n = 68), or Fluoropyrimidine plus JPJDF (Flu-F-treated
group, n = 69) as maintenance treatment after 6-cycle of FOLFOX4 or FOLFORI induction treatment.
The primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS).
The secondary endpoints were safety, Performance Status (PS) score and other symptoms.
Results:
The endpoint of disease progression was observed in 91.7% of patients. The PFS was 5.0
months and 3.0 months in the Flu-F-treated and Flu-treated groups, respectively. The OS was 15.0
months and 9.0 months in the Flu-F-treated and Flu-treated groups, respectively. Some common
symptoms, such as hypodynamia, anepithymia, dizziness and tinnitus and shortness of breath, were
improved in the Flu-F-treated group. There was no significant difference in the common adverse reactions
between the two groups.
Conclusion:
JPJDF and fluoropyrimidine have synergistic effect in the maintenance treatment of
mCRC.
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Affiliation(s)
- Xiaoling Fu
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110, Ganhe Road, Shanghai 200437, China
| | - Yanbo Zhang
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Lisheng Chang
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Dengcheng Hui
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Ru Jia
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Ningning Liu
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Huayue Zhang
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110, Ganhe Road, Shanghai 200437, China
| | - Gang Han
- Department of Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Zhifen Han
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Yuan Li
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110, Ganhe Road, Shanghai 200437, China
| | - Hui Liu
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Huirong Zhu
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
| | - Qi Li
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai 201203, China
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Ruiz de Porras V, Layos L, Martínez-Balibrea E. Curcumin: A therapeutic strategy for colorectal cancer? Semin Cancer Biol 2020; 73:321-330. [PMID: 32942023 DOI: 10.1016/j.semcancer.2020.09.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/26/2020] [Accepted: 09/05/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the second cause of cancer death worldwide. The metastatic disease is mainly treated with aggressive therapies consisting on combinations of cytotoxic chemotherapy plus anti-EGFR or anti-VEGF drugs. In spite of the improvements in clinical outcomes achieved in the last decade, these are the result of multiple new combinations using the existing therapeutic options and the introduction of regorafenib and TAS-102 in second or later lines of treatment. As immunotherapies are limited to less than 5% of CRC patients harboring tumors with deficient mismatch repair, there is an urgent need of finding new drugs to increase our patients' survival opportunities. Among all the natural products that are candidates to be used for the treatment of CRC cancer, curcumin (the golden spice) is in the spotlight. Used for centuries in the Ayurveda medicine, its demonstrated anticancer properties and low toxicity profile made it the focus of hundreds of preclinical and clinical investigations. So far we know that it can be combined with most of the aforementioned drugs in a safe and synergistic way. Regretfully, its poor bioavailability has been one of the main issues for its successful introduction in the clinic. Nevertheless, a plethora of new formulations with a huge increase in bioavailability are under study with promising results. In this review we discuss the possibility of incorporating curcumin in the treatment of CRC; specifically, we review preclinical and clinical data supporting its possible combination with current therapies as well as new formulations under clinical study. It is time for the golden spice revolution.
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Affiliation(s)
- Vicenç Ruiz de Porras
- B-ARGO Group, Medical Oncology Service, Catalan Institute of Oncology, Ctra. Del Canyet s/n, 08916, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Ctra. De Can Ruti, camí de les escoles s/n, 08916, Badalona, Spain.
| | - Laura Layos
- B-ARGO Group, Medical Oncology Service, Catalan Institute of Oncology, Ctra. Del Canyet s/n, 08916, Badalona, Spain; Germans Trias i Pujol Research Institute (IGTP), Ctra. De Can Ruti, camí de les escoles s/n, 08916, Badalona, Spain; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. De Can Ruti, camí de les escoles s/n, 08916, Badalona, Spain.
| | - Eva Martínez-Balibrea
- Germans Trias i Pujol Research Institute (IGTP), Ctra. De Can Ruti, camí de les escoles s/n, 08916, Badalona, Spain; Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Ctra. De Can Ruti, camí de les escoles s/n, 08916, Badalona, Spain; Program of Predictive and Personalized Cancer Medicine (PMPPC), IGTP, Ctra. De Can Ruti, camí de les escoles s/n, 08916, Badalona, Spain.
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Ciulei G, Orasan OH, Coste SC, Cozma A, Negrean V, Procopciuc LM. Vitamin D and the insulin-like growth factor system: Implications for colorectal neoplasia. Eur J Clin Invest 2020; 50:e13265. [PMID: 32379895 DOI: 10.1111/eci.13265] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/30/2020] [Accepted: 05/03/2020] [Indexed: 12/17/2022]
Abstract
Epidemiological studies have strongly associated lower levels of vitamin D and its metabolites with an increased risk of colorectal cancer (CRC). The action of calcitriol, the active metabolite of vitamin D, is mediated by the vitamin D receptor (VDR) that is present in most tissues. In advanced CRC, VDR expression is lowered. Calcitriol has several antineoplastic effects in CRC: it promotes the G1-phase cycle arrest, lowers vascular endothelial growth factor (VEGF) synthesis and acts on tumour stromal fibroblasts to limit cell migration and angiogenesis. Hyperinsulinemia and insulin-like growth factors (IGFs) have been implicated in the pathophysiology of CRC. IGF-1 and IGFBP-3 have been the most studied components of the IGF system. Only 1% of the total serum IGF-1 is free and bioactive, and 80% of it binds to IGFBP-3. IGF-1 and its receptor IGF-1R are known to induce cell proliferation. Both IGF-1 and IGFBP-3 can favour angiogenesis by increasing the transcription of the VEGF gene. A high serum IGF-1/IGFBP-3 ratio is associated with increased risk for CRC. VDR is a transcription factor for the IGFBP-3 gene, and IGF-1 can increase calcitriol synthesis. Studies examining the effect of vitamin D treatment on serum IGF-1 and IGFBP-3 have not been in agreement since different populations, dosages and intervention periods have been used. New vitamin D treatment studies that examine CRC should take in account confounding factors such as obesity or VDR genotypes.
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Affiliation(s)
- George Ciulei
- Department 5 Internal Medicine, 4th Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Olga Hilda Orasan
- Department 5 Internal Medicine, 4th Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Sorina Cezara Coste
- Department 5 Internal Medicine, 4th Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Angela Cozma
- Department 5 Internal Medicine, 4th Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Vasile Negrean
- Department 5 Internal Medicine, 4th Medical Clinic, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lucia Maria Procopciuc
- Department 3 Molecular Sciences, Medical Biochemistry, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Yang C, Zhang Y, Chen Y, Ragaller F, Liu M, Corvigno S, Dahlstrand H, Carlson J, Chen Z, Näsman A, Waraky A, Lin Y, Larsson O, Haglund F. Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers. PLoS One 2020; 15:e0236291. [PMID: 32701997 PMCID: PMC7377393 DOI: 10.1371/journal.pone.0236291] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 07/01/2020] [Indexed: 12/18/2022] Open
Abstract
Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.
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Affiliation(s)
- Chen Yang
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Changsha, Hunan, China
| | - Yifan Zhang
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Yi Chen
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Franziska Ragaller
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mingzhi Liu
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Sara Corvigno
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Hanna Dahlstrand
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Joseph Carlson
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Zihua Chen
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Changsha, Hunan, China
| | - Anders Näsman
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Ahmed Waraky
- Department of Laboratory Medicine, Gothenburg University, Gothenburg, Sweden
| | - Yingbo Lin
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Olle Larsson
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Felix Haglund
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
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Zhang H, Yang K, Ren T, Huang Y, Liang X, Yu Y, Wang W, Niu J, Lou J, Tang X, Guo W. miR-100-5p Inhibits Malignant Behavior of Chordoma Cells by Targeting IGF1R. Cancer Manag Res 2020; 12:4129-4137. [PMID: 32606920 PMCID: PMC7293400 DOI: 10.2147/cmar.s252185] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/13/2020] [Indexed: 12/27/2022] Open
Abstract
Purpose Our research aimed to illuminate the role of miR-100-5p in chordoma and potential mechanism. Materials and Methods We used microRNA array analysis to explore differentially expressed miRNAs in chordoma tissue and then verified by qRT-PCR. Cell proliferation and transwell assay were used to evaluate the function of miR-100-5p. Cell apoptosis was analyzed by flow cytometry, and using biological software, we predicted that the insulin-like growth factor 1 receptor (IGF1R) could be the target gene of miR-100-5p, which was then validated by dual luciferase assays and Western blot. Results miR-100-5p was downregulated in chordoma tissues. Overexpression of miR-100-5p could suppress the growth of chordoma both in vitro and in vivo, and miR-100-5p could inhibit the migration and invasion of chordoma cells partially by suppressing epithelial–mesenchymal transition (EMT). Furthermore, IGF1R was validated as the target gene of miR-100-5p and expressed in most chordoma tissues. Conclusion In conclusion, our results showed that miR-100-5p was lowly expressed in chordoma and inhibited tumor malignant progression by targeting IGF1R.
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Affiliation(s)
- Hongliang Zhang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Kang Yang
- Department of Orthopedics, Yangzhou University Affiliated Hospital, Yangzhou, People's Republic of China
| | - Tingting Ren
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Yi Huang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Xin Liang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Yiyang Yu
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Wei Wang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Jianfang Niu
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Jingbing Lou
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Xiaodong Tang
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
| | - Wei Guo
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China
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Fadaka AO, Bakare OO, Pretorius A, Klein A. Genomic profiling of microRNA target genes in colorectal cancer. Tumour Biol 2020; 42:1010428320933512. [PMID: 32552466 DOI: 10.1177/1010428320933512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer is the second and third most common cancer in men and women, respectively, worldwide. Alterations such as genetic and epigenetic are common in colorectal cancer and are the basis of tumor formation. The exploration of the molecular basis of colorectal cancer can drive a better understanding of the disease as well as guide the prognosis, therapeutics, and disease management. This study is aimed at investigating the genetic mutation profile of five candidate microRNAs (hsa-miR-513b-3p, hsa-miR-500b-3p, hsa-miR-500a-3p, hsa-miR-450b-3p, hsa-miR-193a-5p) targeted by seven genes (APC, KRAS, TCF7L2, EGFR, IGF1R, CASP8, and GNAS)) using in silico approaches. Two datasets (dataset 1 from our previous study and dataset two (The Cancer Genome Atlas, Nature 2012) were considered for this study. Protein-protein interaction, expression analysis, and genetic profiling were carried out using STRING, FireBrowse, and cBioPortal, respectively. Protein-protein interaction network showed that epidermal growth factor receptor has the highest connection among the target genes and this can be considered as the hub gene. Relative to other solid tumors, in colorectal cancer, six of the target genes were downregulated and only CASP8 was upregulated. Genes with protein tyrosine kinases domain were frequently altered in colorectal cancer and the most common alteration in these genes/domain are missense mutation. These results could serve as a lead in the identification of driver genes responsible for colorectal cancer initiation and progression. However, the intense mechanism of these results remains unclear and further experimental validation and molecular approaches are the focal points in the nearest future.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Science and Technology/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa.,Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Olalekan Olanrewaju Bakare
- Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashley Pretorius
- Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashwil Klein
- Plant Omics Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
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38
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Chen MK, Hsu JL, Hung MC. Nuclear receptor tyrosine kinase transport and functions in cancer. Adv Cancer Res 2020; 147:59-107. [PMID: 32593407 DOI: 10.1016/bs.acr.2020.04.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Signaling functions of plasma membrane-localized receptor tyrosine kinases (RTKs) have been extensively studied after they were first described in the mid-1980s. Plasma membrane RTKs are activated by extracellular ligands and cellular stress stimuli, and regulate cellular responses by activating the downstream effector proteins to initiate a wide range of signaling cascades in the cells. However, increasing evidence indicates that RTKs can also be transported into the intracellular compartments where they phosphorylate traditional effector proteins and non-canonical substrate proteins. In general, internalization that retains the RTK's transmembrane domain begins with endocytosis, and endosomal RTK remains active before being recycled or degraded. Further RTK retrograde transport from endosome-Golgi-ER to the nucleus is primarily dependent on membranes vesicles and relies on the interaction with the COP-I vesicle complex, Sec61 translocon complex, and importin. Internalized RTKs have non-canonical substrates that include transcriptional co-factors and DNA damage response proteins, and many nuclear RTKs harbor oncogenic properties and can enhance cancer progression. Indeed, nuclear-localized RTKs have been shown to positively correlate with cancer recurrence, therapeutic resistance, and poor prognosis of cancer patients. Therefore, understanding the functions of nuclear RTKs and the mechanisms of nuclear RTK transport will further improve our knowledge to evaluate the potential of targeting nuclear RTKs or the proteins involved in their transport as new cancer therapeutic strategies.
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Affiliation(s)
- Mei-Kuang Chen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Jennifer L Hsu
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
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39
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Hua H, Kong Q, Yin J, Zhang J, Jiang Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. J Hematol Oncol 2020; 13:64. [PMID: 32493414 PMCID: PMC7268628 DOI: 10.1186/s13045-020-00904-3] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Insulin-like growth factors (IGFs) play important roles in mammalian growth, development, aging, and diseases. Aberrant IGFs signaling may lead to malignant transformation and tumor progression, thus providing the rationale for targeting IGF axis in cancer. However, clinical trials of the type I IGF receptor (IGF-IR)-targeted agents have been largely disappointing. Accumulating evidence demonstrates that the IGF axis not only promotes tumorigenesis, but also confers resistance to standard treatments. Furthermore, there are diverse pathways leading to the resistance to IGF-IR-targeted therapy. Recent studies characterizing the complex IGFs signaling in cancer have raised hope to refine the strategies for targeting the IGF axis. This review highlights the biological activities of IGF-IR signaling in cancer and the contribution of IGF-IR to cytotoxic, endocrine, and molecular targeted therapies resistance. Moreover, we update the diverse mechanisms underlying resistance to IGF-IR-targeted agents and discuss the strategies for future development of the IGF axis-targeted agents.
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Affiliation(s)
- Hui Hua
- State Key Laboratory of Biotherapy, Laboratory of Stem Cell Biology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qingbin Kong
- State Key Laboratory of Biotherapy, Laboratory of Oncogene, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jie Yin
- State Key Laboratory of Biotherapy, Laboratory of Oncogene, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jin Zhang
- State Key Laboratory of Biotherapy, Laboratory of Oncogene, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yangfu Jiang
- State Key Laboratory of Biotherapy, Laboratory of Oncogene, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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40
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Gasser M, Lissner R, Nawalaniec K, Hsiao LL, Waaga-Gasser AM. KMP01D Demonstrates Beneficial Anti-inflammatory Effects on Immune Cells: An ex vivo Preclinical Study of Patients With Colorectal Cancer. Front Immunol 2020; 11:684. [PMID: 32425932 PMCID: PMC7205007 DOI: 10.3389/fimmu.2020.00684] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 03/26/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Colorectal cancer (CRC) is frequently associated with dysbiosis of the gut microbiome which, together with a compromised gut barrier, can result in perioperative endotoxin leakage into the circulation. Constant local and systemic inflammatory activity is suggested to facilitate metastases formation. Previous studies have pointed to the capacity of a colostrum preparation to neutralize endotoxins within the gastrointestinal tract which could ameliorate associated inflammatory responses and tumor recurrence in affected patients. This study aimed to examine the effects of the colostrum preparation, KMP01D, on the inflammatory activity of patient-derived immune cells. Methods: The effects of KMP01D on pro-/anti-inflammatory cytokine responses and apoptosis were examined ex vivo using immune cells from CRC patients (stages I-IV, n = 48). The expression of CD14, CD68, Toll-like receptor (TLR)4, and insulin-like growth factor (IGF)-1 was also analyzed. Results: KMP01D increased interleukin (IL)-10 and IL-13 anti-inflammatory cytokine expression in patient-derived peripheral blood mononuclear cells (PBMCs). Interestingly, KMP01D also decreased the secretion of IL-1β, IL-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-12 inflammatory cytokines, and IGF-1 in these cells. Moreover, CD14 and TLR4 expression involved in endotoxin signaling was downregulated in PBMCs and tumor-derived cells. Apoptosis of immune cells and tumor-derived cells was likewise enhanced with KMP01D. Addition of vitamin D3 as a cofactor demonstrated enhanced anti-inflammatory effects. Conclusions: KMP01D demonstrated beneficial ex vivo effects on inflammatory cytokine responses in PBMCs and enhanced apoptosis of immune cells from CRC patients. In line with previous clinical trials, we present new evidence endorsing KMP01D as a treatment strategy to regulate stage-dependent local and systemic inflammation in CRC patients.
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Affiliation(s)
- Martin Gasser
- Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany
| | - Reinhard Lissner
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany
| | - Karol Nawalaniec
- Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Li-Li Hsiao
- Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Ana Maria Waaga-Gasser
- Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.,Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
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41
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Chen YM, Qi S, Perrino S, Hashimoto M, Brodt P. Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug. Cells 2020; 9:cells9051098. [PMID: 32365498 PMCID: PMC7290707 DOI: 10.3390/cells9051098] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 12/13/2022] Open
Abstract
The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap—a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.
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Affiliation(s)
- Yinhsuan Michely Chen
- Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
| | - Shu Qi
- The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
| | - Stephanie Perrino
- The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
| | - Masakazu Hashimoto
- The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Surgery, McGill University, Montreal, QC H3A 0G4, Canada
| | - Pnina Brodt
- Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Surgery, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
- Correspondence: ; Tel.: +1-514-934-1934
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Wu YZ, Lin HY, Zhang Y, Chen WF. miR-200b-3p mitigates oxaliplatin resistance via targeting TUBB3 in colorectal cancer. J Gene Med 2020; 22:e3178. [PMID: 32092782 DOI: 10.1002/jgm.3178] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/17/2020] [Accepted: 02/21/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Numerous abnormally expressed miRs have been reported involved in oxaliplatin (L-OHP) resistance of colorectal cancer (CRC). The present study aimed to investigate whether miR-200b-3p could regulate L-OHP resistance via targeting TUBB3 in CRC cells. METHODS L-OHP resistant HT29 and HCT116 cells were exposed to escalating concentrations of L-OHP up to 30 μm. The effect of miR-200b-3p on L-OHP resistant CRC cells was then evaluated using the cell counting kit-8 (CCK-8) assay. CRC cell apoptosis was detected using Annexin V-FITC/PI double staining. Bioinformatics algorithms and luciferase reporter assays were also performed to investigate whether TUBB3 was a direct target of miR-200b-3p. RESULTS miR-200b-3p declined in L-OHP resistant CRC tissues and cell lines, and the overexpression of miR-200b-3p elevated the L-OHP sensitivity in L-OHP resistant HT29 and HCT116 cells. In addition, we determined the potential mechanisms underlying miR-200b-3p-mediated reversal of L-OHP resistance by mediating its downstream target TUBB3, and the overexpression of miR-200b-3p could induce migration and growth inhibition and apoptosis in L-OHP resistant HT29 and HCT116 cells by silencing βIII-tubulin protein expression. However, the overexpression of TUBB3 reversed miR-200b-3p mimic-induced migration, as well as growth inhibition and apoptosis, in L-OHP resistant CRC cells. CONCLUSIONS miR-200b-3p improved L-OHP resistance and induced growth inhibition and cell apoptosis in L-OHP resistant CRC cells, and the underlying mechanism was mediated, at least partially, through the suppression of βIII-tubulin protein expression.
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Affiliation(s)
- Yu-Zhu Wu
- Department of Pharmacy, Second Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Hong-Yue Lin
- Department of Gastrointestinal Surgery, Affiliated Quanzhou First Hospital to Fujian Medical University, Quanzhou, China
| | - Yin Zhang
- Department of Pharmacy, Second Hospital Affiliated to Fujian Medical University, Quanzhou, China
| | - Wen-Fa Chen
- Department of Pharmacy, Second Hospital Affiliated to Fujian Medical University, Quanzhou, China
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43
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Iida M, Harari PM, Wheeler DL, Toulany M. Targeting AKT/PKB to improve treatment outcomes for solid tumors. Mutat Res 2020; 819-820:111690. [PMID: 32120136 DOI: 10.1016/j.mrfmmm.2020.111690] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/31/2020] [Accepted: 02/11/2020] [Indexed: 12/16/2022]
Abstract
The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBβ) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA, RAS, PDPK1, and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy.
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Affiliation(s)
- M Iida
- Department of Human Oncology, University of Wisconsin in Madison, Madison, WI, USA.
| | - P M Harari
- Department of Human Oncology, University of Wisconsin in Madison, Madison, WI, USA
| | - D L Wheeler
- Department of Human Oncology, University of Wisconsin in Madison, Madison, WI, USA
| | - M Toulany
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany; German Cancer Consortium (DKTK), Partner Site Tuebingen, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
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44
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Buraschi S, Morcavallo A, Neill T, Stefanello M, Palladino C, Xu SQ, Belfiore A, Iozzo RV, Morrione A. Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer. Matrix Biol Plus 2020; 6-7:100022. [PMID: 33543020 PMCID: PMC7852334 DOI: 10.1016/j.mbplus.2020.100022] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/06/2020] [Accepted: 01/08/2020] [Indexed: 12/11/2022] Open
Abstract
Bladder cancer is one of the most common and aggressive cancers and, regardless of the treatment, often recurs and metastasizes. Thus, a better understanding of the mechanisms regulating urothelial tumorigenesis is critical for the design and implementation of rational therapeutic strategies. We previously discovered that the IGF-IR axis is critical for bladder cancer cell motility and invasion, suggesting a possible role in bladder cancer progression. However, IGF-IR depletion in metastatic bladder cancer cells only partially inhibited anchorage-independent growth. Significantly, metastatic bladder cancer cells have decreased IGF-IR levels but overexpressed the insulin receptor isoform A (IR-A), suggesting that the latter may play a more prevalent role than the IGF-IR in bladder tumor progression. The collagen receptor DDR1 cross-talks with both the IGF-IR and IR in breast cancer, and previous data suggest a role of DDR1 in bladder cancer. Here, we show that DDR1 is expressed in invasive and metastatic, but not in papillary, non-invasive bladder cancer cells. DDR1 is phosphorylated upon stimulation with IGF-I, IGF-II, and insulin, co-precipitates with the IGF-IR, and the IR-A and transient DDR1 depletion severely inhibits IGF-I-induced motility. We further demonstrate that DDR1 interacts with Pyk2 and non-muscle myosin IIA in ligands-dependent fashion, suggesting that it may link the IGF-IR and IR-A to the regulation of F-actin cytoskeleton dynamics. Similarly to the IGF-IR, DDR1 is upregulated in bladder cancer tissues compared to healthy tissue controls. Thus, our findings provide the first characterization of the molecular cross-talk between DDR1 and the IGF-I system and could lead to the identification of novel targets for therapeutic intervention in bladder cancer. Moreover, the expression profiles of IGF-IR, IR-A, DDR1, and downstream effectors could serve as a novel biomarker signature with diagnostic and prognostic significance.
We discovered that the collagen receptor DDR1 cross-talks with insulin growth factor I (IGF-I) signaling in bladder cancer DDR1 co-precipitates with the IGF-IR and the insulin receptor (IR), and is phosphorylated upon stimulation with IGF ligands This collagen receptor modulates IGF-I-evoked motility and anchorage-independent growth DDR1 complexes with Pyk2, myosin IIA, IGF-IR and/or IR and regulates actin dynamics
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Affiliation(s)
- Simone Buraschi
- Department of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Alaide Morcavallo
- Department of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Thomas Neill
- Department of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Manuela Stefanello
- Department of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Chiara Palladino
- Department of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Shi-Qiong Xu
- Department of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Renato V Iozzo
- Department of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Andrea Morrione
- Department of Pathology, Anatomy and Cell Biology, and Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.,Department of Urology, and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.,Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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Matsuoka T, Yashiro M. Precision medicine for gastrointestinal cancer: Recent progress and future perspective. World J Gastrointest Oncol 2020; 12:1-20. [PMID: 31966910 PMCID: PMC6960076 DOI: 10.4251/wjgo.v12.i1.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 10/12/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
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Rieger L, O’Connor R. Controlled Signaling-Insulin-Like Growth Factor Receptor Endocytosis and Presence at Intracellular Compartments. Front Endocrinol (Lausanne) 2020; 11:620013. [PMID: 33584548 PMCID: PMC7878670 DOI: 10.3389/fendo.2020.620013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/02/2020] [Indexed: 12/16/2022] Open
Abstract
Ligand-induced activation of the IGF-1 receptor triggers plasma-membrane-derived signal transduction but also triggers receptor endocytosis, which was previously thought to limit signaling. However, it is becoming ever more clear that IGF-1R endocytosis and trafficking to specific subcellular locations can define specific signaling responses that are important for key biological processes in normal cells and cancer cells. In different cell types, specific cell adhesion receptors and associated proteins can regulate IGF-1R endocytosis and trafficking. Once internalized, the IGF-1R may be recycled, degraded or translocated to the intracellular membrane compartments of the Golgi apparatus or the nucleus. The IGF-1R is present in the Golgi apparatus of migratory cancer cells where its signaling contributes to aggressive cancer behaviors including cell migration. The IGF-1R is also found in the nucleus of certain cancer cells where it can regulate gene expression. Nuclear IGF-1R is associated with poor clinical outcomes. IGF-1R signaling has also been shown to support mitochondrial biogenesis and function, and IGF-1R inhibition causes mitochondrial dysfunction. How IGF-1R intracellular trafficking and compartmentalized signaling is controlled is still unknown. This is an important area for further study, particularly in cancer.
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47
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Powell MK, Cempirkova D, Dundr P, Grimmichova T, Trebicky F, E Brown R, Gregorova J, Litschmannova M, Janurova K, Pesta M, Heneberg P. Metformin Treatment for Diabetes Mellitus Correlates with Progression and Survival in Colorectal Carcinoma. Transl Oncol 2019; 13:383-392. [PMID: 31896527 PMCID: PMC6940647 DOI: 10.1016/j.tranon.2019.10.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 10/24/2019] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND: Diabetes mellitus is unfavorably associated with cancer risk. The purpose of this multidisciplinary project was to evaluate a possible association of diabetes mellitus and other comorbidities and their treatment with progression of colorectal cancer. PATIENTS AND METHODS: We investigated the correlation between pathological characteristics and clinical course, including comorbidities in 1004 Czech patients diagnosed and surgically treated for colorectal adenocarcinoma (CRC) between 1999 and 2016. RESULTS: In our data set, CRC patients treated with metformin due to coexisting diabetes mellitus type 2 (T2DM) developed fewer distant metastases which clinically correlates with slower CRC progression. Survival in metformin subgroup was longer, particularly in men with CRC. Osteoporosis may be a negative factor of survival in CRC patients. CONCLUSIONS: Our findings also indicate that aging, higher tumor grade and TNM stage, coexistence of selected endocrine disorders, and metabolic abnormalities may change the tumor microenvironment and impact survival in colorectal cancer, although mechanism of these observations yet to be explained. Patients with diabetes mellitus type 2 treated with metformin may represent the altered microenvironment with specifically tuned metabolic molecular responses and with various epigenetic characteristics. More awareness and increased understanding of the mechanisms underlying the positive effect of metformin on patients' survival could offer insight into new treatment methods and permit more individualized treatment plans.
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Affiliation(s)
- Marta K Powell
- Third Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Pathology, Hospital Jablonec Nad Nisou, Jablonec Nad Nisou, Czech Republic; Department of Neurology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
| | - Dana Cempirkova
- Department of Pathology, Hospital Jindrichuv Hradec, Jindrichuv Hradec, Czech Republic
| | - Pavel Dundr
- Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Tereza Grimmichova
- Third Faculty of Medicine, Charles University, Prague, Czech Republic; Medicine Department, University Hospital Kralovske Vinohrady, Prague, Czech Republic; Institute of Endocrinology, Prague, Czech Republic
| | | | - Robert E Brown
- Morphoproteomic Laboratory, UT Health McGovern Medical School, Houston, Texas, USA
| | - Jana Gregorova
- Clinical Pharmacy Department, Na Bulovce Hospital, Prague, Czech Republic
| | - Martina Litschmannova
- Department of Applied Mathematics, Faculty of Electrical Engineering and Computer Science, VSB - Technical University of Ostrava, Ostrava, Czech Republic
| | - Katerina Janurova
- IT4Innovations, VSB - Technical University of Ostrava, Ostrava, Czech Republic
| | - Michal Pesta
- Charles University, Faculty of Mathematics and Physics, Department of Probability and Mathematical Statistics, Prague, Czech Republic
| | - Petr Heneberg
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
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48
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High IGF1R protein expression correlates with disease-free survival of patients with stage III colon cancer. Cell Oncol (Dordr) 2019; 43:237-247. [PMID: 31823290 DOI: 10.1007/s13402-019-00484-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2019] [Indexed: 10/25/2022] Open
Abstract
PURPOSE The aim of this study was to investigate the association between expression of insulin-like growth factor-1 receptor (IGF1R) and its ligand, IGF-II, and disease-free survival (DFS) in patients with stage III colon cancer (CC). METHODS In this retrospective study we included consecutive patients who underwent curative surgery for stage III CC. IGF1R and IGF-II/IGF2 status were evaluated in tumour samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Associations of markers with DFS were analysed using Cox proportional hazards models. RESULTS Hundred and fifty-one CC patients were included (median age, 66.6 years; female, 54.3%). Low levels of IGF1R and IGF-II protein expression were observed in 16.1% and 10.7% of the cases, respectively. No significant differences in clinicopathological characteristics between patients with tumours expressing low IGF1R or IGF-II protein levels and those with high levels were observed. A low IGF1R protein expression was found to be significantly associated with a shorter DFS (HR 3.32; 95% CI, 1.7-6.31; p = 0.0003), while no association was observed between IGF-II protein expression and DFS (HR 0.91; 95% CI, 0.28-2.96; p = 0.87). In a multivariate analysis, IGF1R protein status remained an independent prognostic factor for DFS (HR 2.73; 95% CI, 1.40-5.31; p = 0.003). Furthermore, we found that neither IGF1R nor IGF2 mRNA expression levels as measured by qRT-PCR correlated with the respective protein expression levels as assessed by immunohistochemistry. Neither of the mRNA expression levels was significantly associated with DFS. CONCLUSIONS From our data we conclude that low IGF1R protein expression represents a poor prognostic biomarker in stage III colon cancer.
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Abstract
Introduction: The HGF/MET axis is a key therapeutic pathway in cancer; it is aberrantly activated because of mutations, fusions, amplification or aberrant ligand production. Extensive efforts have been made to discover predictive factors of anti-MET therapeutic efficacy, but they have mostly unsuccessful. An understanding of the intrinsic and acquired mechanism of MET resistance will be fundamental for the development of new therapeutic interventions.Areas covered: This article provides a systematic review of phase II randomized and phase III clinical trials investigating the use of MET inhibitors in the treatment of cancer. We discuss preliminary findings on efficacy and methodologic design flaws in these trials.Expert opinion: MET inhibitors showed poor activity in unselected patients or patients selected by MET expression, p-MET or high HGF basal levels. The efficacy in advanced solid tumors is very modest and in phase III clinical trials, survival differences did not fulfill the stringent requirements of ESMO-Magnitude Clinical Benefit Score (MCBS). Prospective novel liquid biomarker-driven studies and novel trial designs such as Umbrella and Basket trials are necessary to progress MET inhibitor development.
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Affiliation(s)
- Helena Oliveres
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.,Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Department of Medical Oncology, University of Barcelona, Barcelona, Spain
| | - Estela Pineda
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.,Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Department of Medical Oncology, University of Barcelona, Barcelona, Spain
| | - Joan Maurel
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.,Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Department of Medical Oncology, University of Barcelona, Barcelona, Spain
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50
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Liu Z, Qin Y, Dong S, Chen X, Huo Z, Zhen Z. Overexpression of miR-106a enhances oxaliplatin sensitivity of colorectal cancer through regulation of FOXQ1. Oncol Lett 2019; 19:663-670. [PMID: 31897182 PMCID: PMC6924180 DOI: 10.3892/ol.2019.11151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 09/06/2019] [Indexed: 12/27/2022] Open
Abstract
Chemotherapy resistance poses a major challenge for the clinical treatment of colorectal cancer, therefore, the aim of the present study was to examine its underlying mechanisms. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to determine the microRNA (miRNA)/mRNA and protein expression levels, respectively. A dual luciferase assay was conducted for verification of the interaction between miR-106a and 3′untranslated region (UTR) of Forkhead box Q1 (FOXQ1). Cell viability was assessed using an MTT assay. In the present study, it was demonstrated that miR-106a is involved in regulating oxaliplatin sensitivity of colorectal cancer. Transfection of miR-106a mimics slightly inhibited colorectal cancer cell growth and sensitized colorectal cancer cells to oxaliplatin exposure. In addition, miR-106a overexpression induced a decrease of FOXQ1 at mRNA and protein levels in colorectal cancer cells. The enhanced expression of miR-106a also increased the expression of Wnt target genes, including vascular endothelial growth factor-A and matrix metallopeptidase 2, which were reported to be regulated by FOXQ1. It was predicted and validated that miR-106a could repress FOXQ1 expression via direct binding to 3′UTR. Elevation of miR-106a and a decrease of FOXQ1 expression levels were detected in tumor tissues from patients with oxaliplatin-sensitive colorectal cancer, compared with patients with oxaliplatin-resistant colorectal cancer. Furthermore, there was a significant association between miR-106a and FOXQ1 mRNA levels. In conclusion, the present study demonstrated that miR-106a increased oxaliplatin sensitivity of colorectal cancer cells through direct repression of FOXQ1 expression.
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Affiliation(s)
- Zhihu Liu
- Department of Hepatobiliary Surgery, Xingtai People's Hospital, Xingtai, Hebei 054000, P.R. China
| | - Yan Qin
- Surgical Department of Gastrointestinal Neoplasms, Xingtai People's Hospital, Xingtai, Hebei 054000, P.R. China
| | - Shuxiao Dong
- Obstetrical Department, Xingtai Third Hospital, Xingtai, Hebei 054000, P.R. China
| | - Xiao Chen
- Department of Anesthesiology, Xingtai People's Hospital, Xingtai, Hebei 054000, P.R. China
| | - Zhibin Huo
- Surgical Department of Gastrointestinal Neoplasms, Xingtai People's Hospital, Xingtai, Hebei 054000, P.R. China
| | - Zhongguang Zhen
- Department of Hepatobiliary Surgery, Xingtai People's Hospital, Xingtai, Hebei 054000, P.R. China
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