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1
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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2
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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3
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Sane S, Srinivasan R, Potts RA, Eikanger M, Zagirova D, Freeling J, Reihe CA, Antony RM, Gupta BK, Lynch D, Bleeker J, Turaihi H, Pillatzki A, Zhou W, Luo X, Linnebacher M, Agany D, Zohim EG, Humphrey LE, Black AR, Rezvani K. UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer. Oncogene 2023; 42:1763-1776. [PMID: 37037900 DOI: 10.1038/s41388-023-02686-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 04/12/2023]
Abstract
The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic, pharmacological, and rescue experiments showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. A high level of UBXN2A in patient-derived xenografts and tumor organoids decreases Rictor protein and suppresses the mTORC2 pathway. These findings provide new insights into the functions of an ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.
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Affiliation(s)
- Sanam Sane
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Rekha Srinivasan
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Rashaun A Potts
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Morgan Eikanger
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Diana Zagirova
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Jessica Freeling
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Casey A Reihe
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Ryan M Antony
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Brij K Gupta
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA
| | - Douglas Lynch
- Laboratory Medicine and Pathology, Sanford School of Medicine, Sioux Falls, SD, USA
| | | | | | - Angela Pillatzki
- Veterinary and Biomedical Sciences Department, Animal Disease Research and Diagnostic Laboratory, South Dakota State University, Brookings, SD, USA
| | - Wei Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, The University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael Linnebacher
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, Rostock, Germany
| | - Diing Agany
- Biomedical Engineering Department, GEAR Center, Sioux Falls, SD, USA
| | | | - Lisa E Humphrey
- Tissue Sciences, Eppley Institute for Cancer Research, The University of Nebraska Medical Center, Omaha, NE, USA
| | - Adrian R Black
- Tissue Sciences, Eppley Institute for Cancer Research, The University of Nebraska Medical Center, Omaha, NE, USA
| | - Khosrow Rezvani
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
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4
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Zhang Y, Li H, Lv L, Lu K, Li H, Zhang W, Cui T. Autophagy: Dual roles and perspective for clinical treatment of colorectal cancer. Biochimie 2023; 206:49-60. [PMID: 36244578 DOI: 10.1016/j.biochi.2022.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/29/2022] [Accepted: 10/09/2022] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) raises concerns to people because of its high recurrence and metastasis rate, diagnosis challenges, and poor prognosis. Various studies have shown the association of altered autophagy with tumorigenesis, tumor-stroma interactions, and resistance to cancer therapy in CRC. Autophagy is a highly conserved cytosolic catabolic process in eukaryotes that plays distinct roles in CRC occurrence and progression. In early tumorigenesis, autophagy may inhibit tumor growth through diverse mechanisms, whereas it exhibits a tumor promoting function in CRC progression. This different functions of autophagy in CRC occurrence and progression make developing therapies targeting autophagy complicated. In this review, we discuss the classification and process of autophagy as well as its dual roles in CRC, functions in the tumor microenvironment, cross-talk with apoptosis, and potential usefulness as a CRC therapeutic target.
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Affiliation(s)
- Yabin Zhang
- West China Second University Hospital, State Key Laboratory of Biotherapy, Laboratory of Metabolomics and Gynecological Disease Research and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 610041, Chengdu, China
| | - Haiyan Li
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Liang Lv
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Kefeng Lu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Huihui Li
- West China Second University Hospital, State Key Laboratory of Biotherapy, Laboratory of Metabolomics and Gynecological Disease Research and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 610041, Chengdu, China
| | - Wenli Zhang
- Department of Orthopedics, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Tao Cui
- West China Second University Hospital, State Key Laboratory of Biotherapy, Laboratory of Metabolomics and Gynecological Disease Research and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 610041, Chengdu, China.
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5
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Hou T, Dan W, Liu T, Liu B, Wei Y, Yue C, Que T, Ma B, Lei Y, Wang Z, Zeng J, Fan Y, Li L. Deubiquitinase OTUD5 modulates mTORC1 signaling to promote bladder cancer progression. Cell Death Dis 2022; 13:778. [PMID: 36085200 PMCID: PMC9463452 DOI: 10.1038/s41419-022-05128-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/21/2023]
Abstract
The mechanistic (formally "mammalian") target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer. In our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of sestrin2, which is an inhibitor of the mTOR signaling pathway. Together, we provide novel insights into the pathogenesis of bladder cancer and first prove that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis, which may be exploited in the future for the diagnosis and treatment of this malignancy.
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Affiliation(s)
- Tao Hou
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Weichao Dan
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Tianjie Liu
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Bo Liu
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Yi Wei
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Chenyang Yue
- grid.21100.320000 0004 1936 9430Department of Biology, York University, Toronto, ON M3J1P3 Canada
| | - Taotao Que
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Bohan Ma
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Yuzeshi Lei
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Zixi Wang
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Jin Zeng
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Yizeng Fan
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
| | - Lei Li
- grid.452438.c0000 0004 1760 8119Department of Urology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061 P.R. China ,grid.43169.390000 0001 0599 1243Xi’an Jiaotong university, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China ,grid.452438.c0000 0004 1760 8119The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi China
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6
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Deng J, Tian AL, Pan H, Sauvat A, Leduc M, Liu P, Zhao L, Zhang S, Chen H, Taly V, Laurent-Puig P, Senovilla L, Li Y, Kroemer G, Kepp O. Everolimus and plicamycin specifically target chemoresistant colorectal cancer cells of the CMS4 subtype. Cell Death Dis 2021; 12:978. [PMID: 34675191 PMCID: PMC8531384 DOI: 10.1038/s41419-021-04270-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/19/2021] [Accepted: 10/05/2021] [Indexed: 12/24/2022]
Abstract
Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger cytostatic and cytotoxic effects, increased signs of apoptosis and autophagy, as well as a more pronounced inhibition of DNA-to-RNA transcription and RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing effects on LoVo tumors. Altogether, these results suggest that EVE and PLI should be evaluated for their clinical activity against CMS4 CRC.
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Affiliation(s)
- Jiayin Deng
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Ai-Ling Tian
- Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Hui Pan
- Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Allan Sauvat
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Marion Leduc
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Peng Liu
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Liwei Zhao
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Shuai Zhang
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Hui Chen
- Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin Bicêtre, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Valérie Taly
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain
| | - Laura Senovilla
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain
| | - Yingqiu Li
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France.
- Pôle de Biologie, Institut du Cancer Paris Carpem, APHP, Hôpital Européen Georges Pompidou, Paris, France.
- Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, Jiangsu, China.
- Karolinska Institutet, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France.
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7
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Schmidt S, Denk S, Wiegering A. Targeting Protein Synthesis in Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12051298. [PMID: 32455578 PMCID: PMC7281195 DOI: 10.3390/cancers12051298] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022] Open
Abstract
Under physiological conditions, protein synthesis controls cell growth and survival and is strictly regulated. Deregulation of protein synthesis is a frequent event in cancer. The majority of mutations found in colorectal cancer (CRC), including alterations in the WNT pathway as well as activation of RAS/MAPK and PI3K/AKT and, subsequently, mTOR signaling, lead to deregulation of the translational machinery. Besides mutations in upstream signaling pathways, deregulation of global protein synthesis occurs through additional mechanisms including altered expression or activity of initiation and elongation factors (e.g., eIF4F, eIF2α/eIF2B, eEF2) as well as upregulation of components involved in ribosome biogenesis and factors that control the adaptation of translation in response to stress (e.g., GCN2). Therefore, influencing mechanisms that control mRNA translation may open a therapeutic window for CRC. Over the last decade, several potential therapeutic strategies targeting these alterations have been investigated and have shown promising results in cell lines, intestinal organoids, and mouse models. Despite these encouraging in vitro results, patients have not clinically benefited from those advances so far. In this review, we outline the mechanisms that lead to deregulated mRNA translation in CRC and highlight recent progress that has been made in developing therapeutic strategies that target these mechanisms for tumor therapy.
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Affiliation(s)
- Stefanie Schmidt
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, 97074 Würzburg, Germany; (S.S.); (S.D.)
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, 97074 Würzburg, Germany
| | - Sarah Denk
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, 97074 Würzburg, Germany; (S.S.); (S.D.)
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, 97074 Würzburg, Germany
| | - Armin Wiegering
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, 97074 Würzburg, Germany; (S.S.); (S.D.)
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, 97074 Würzburg, Germany
- Department of Biochemistry and Molecular Biology, Comprehensive Cancer Center Mainfranken, University of Würzburg, 97074 Würzburg, Germany
- Correspondence: ; Tel.: +49-931-20138714
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Allam RM, El-Halawany AM, Al-Abd AM. Chemo-sensitizing agents from natural origin for colorectal cancer: Pharmacodynamic and cellular pharmacokinetics approaches. DRUG RESISTANCE IN COLORECTAL CANCER: MOLECULAR MECHANISMS AND THERAPEUTIC STRATEGIES 2020:93-116. [DOI: 10.1016/b978-0-12-819937-4.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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9
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Synergistic Anti-Tumor Effect of mTOR Inhibitors with Irinotecan on Colon Cancer Cells. Cancers (Basel) 2019; 11:cancers11101581. [PMID: 31627299 PMCID: PMC6826690 DOI: 10.3390/cancers11101581] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 10/02/2019] [Accepted: 10/11/2019] [Indexed: 12/22/2022] Open
Abstract
Advanced colorectal cancer has a poor prognosis because of metastasis formation and resistance to combined therapies. Downstream of PI3K/Akt and Ras/MAPK pathways, the mTOR kinase plays a decisive role in treatment failure. We previously established that irinotecan has antiangiogenic properties and it is known that new mammalian target of rapamycin (mTOR) catalytic AZD inhibitors, unlike rapamycin, target both mTORC1 and mTORC2. Thus, we hypothesized that the complete inhibition of the PI3K/AKT/mTOR/HIF-1α axis with mTOR catalytic inhibitors and low doses of irinotecan may have antitumor effects. We showed that the AZD8055 and AZD2014 inhibitors were much more potent than rapamycin to reduce cell viability of four colon cell lines. On the other hand, whereas AZD2014 alone inhibits migration by 40%, the drug combination led to 70% inhibition. Similarly, neither irinotecan nor AZD2014 significantly reduced cell invasion, whereas a combination of the two inhibits invasion by 70%. In vivo, irinotecan and AZD2014 combination drastically reduced ectopic patient-derived colon tumor growth and this combination was more potent than Folfox or Folfiri. Finally, the combination totally inhibited liver and lung metastases developed from orthotopic implantation of SW480 cells. Thus, the use of mTOR catalytic inhibitors, in association with other chemotherapeutic agents like irinotecan at low doses, is potentially a hope for colon cancer treatment.
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10
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Huang XM, Yang ZJ, Xie Q, Zhang ZK, Zhang H, Ma JY. Natural products for treating colorectal cancer: A mechanistic review. Biomed Pharmacother 2019; 117:109142. [DOI: 10.1016/j.biopha.2019.109142] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/14/2019] [Accepted: 06/14/2019] [Indexed: 12/17/2022] Open
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11
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Bolourian A, Mojtahedi Z. Immunosuppressants produced by Streptomyces: evolution, hygiene hypothesis, tumour rapalog resistance and probiotics. ENVIRONMENTAL MICROBIOLOGY REPORTS 2018; 10:123-126. [PMID: 29377607 DOI: 10.1111/1758-2229.12617] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 01/15/2018] [Indexed: 06/07/2023]
Abstract
Resistance to a drug and the suppression of inflammatory disorders with immunosuppressive drugs might have happened upon exposure to natural compounds during evolution. Streptomycetes are soil bacteria, but they produce therapeutic drugs. They have been reported to be the low-abundant members of mucosal microbiomes with a higher prevalence in nonhumans ingesting soil compared with humans. Their lower abundance in the human microbiome might be the representations of our current hygienic lifestyle. We suggest that the Streptomyces bacteria producing antiproliferative/immunosuppressive compounds (e.g., rapamycin and tacrolimus) contribute to the rapalog resistance of certain mucosal tumours (e.g., colon cancer) and the 'hygiene hypothesis'. If so, the shortage of exposure to these compounds in the current lifestyle might be an underlying reason for the increase of inflammatory diseases, such as inflammatory bowel diseases (IBD). An investigation on adding certain Streptomycetes (e.g., S. hygroscopicus and S. tubercidicus) to the list of probiotics against inflammatory diseases would be an interesting research area in the future.
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Affiliation(s)
- Alireza Bolourian
- School of Life Sciences, University of Nevada, Las Vegas, NV 89154, USA
| | - Zahra Mojtahedi
- Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
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12
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Carrasco-Garcia E, Lopez L, Aldaz P, Arevalo S, Aldaregia J, Egaña L, Bujanda L, Cheung M, Sampron N, Garcia I, Matheu A. SOX9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin. Sci Rep 2016; 6:32350. [PMID: 27571710 PMCID: PMC5004104 DOI: 10.1038/srep32350] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 08/08/2016] [Indexed: 12/31/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9-dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.
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Affiliation(s)
| | - Lidia Lopez
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
| | - Paula Aldaz
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
| | - Sara Arevalo
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
| | - Juncal Aldaregia
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
| | - Larraitz Egaña
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
| | - Luis Bujanda
- Department of Gastroenterology, Hospital Donostia and Instituto Biodonostia, University of the Basque Country, Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), San Sebastian, Spain
| | - Martin Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Nicolas Sampron
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
| | - Idoia Garcia
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
- IKERBASQUE, Basque Foundation, Bilbao, Spain
| | - Ander Matheu
- Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain
- IKERBASQUE, Basque Foundation, Bilbao, Spain
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13
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Erstad DJ, Tumusiime G, Cusack JC. Prognostic and Predictive Biomarkers in Colorectal Cancer: Implications for the Clinical Surgeon. Ann Surg Oncol 2015. [DOI: 10.1245/s10434-015-4706-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Bizama C, García P, Espinoza JA, Weber H, Leal P, Nervi B, Roa JC. Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat Rev 2015; 41:222-34. [PMID: 25639632 DOI: 10.1016/j.ctrv.2015.01.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 01/12/2015] [Accepted: 01/13/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer is the most common and aggressive malignancy of the biliary tract. The complete surgical resection is the only potentially curative approach in early stage; however, most cases are diagnosed in advanced stages and the response to traditional chemotherapy and radiotherapy is extremely limited, with modest impact in overall survival. The recent progress in understanding the molecular alterations of gallbladder cancer has shown great promise for the development of more effective treatment strategies. This has mainly resulted from the identification of molecular alterations in relevant intracellular signaling pathways-Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK and angiogenesis-which are potential tailored targets for gallbladder cancer patients. This review discusses the recent remarkable progress in understanding the molecular alterations that represent novel prognosis molecular markers and therapeutic targets for gallbladder cancer, which will provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy, or eventually modify the fatal natural history of this orphan disease.
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Affiliation(s)
- Carolina Bizama
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Patricia García
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Jaime A Espinoza
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Pamela Leal
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 26767000, Chile
| | - Juan Carlos Roa
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
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15
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Papadatos-Pastos D, Rabbie R, Ross P, Sarker D. The role of the PI3K pathway in colorectal cancer. Crit Rev Oncol Hematol 2014; 94:18-30. [PMID: 25591826 DOI: 10.1016/j.critrevonc.2014.12.006] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 10/07/2014] [Accepted: 12/10/2014] [Indexed: 01/10/2023] Open
Abstract
In the last decade treatment for colorectal cancer (CRC) has evolved with the addition of contemporary chemotherapy drugs and targeted therapies. Despite this progress, our drug armamentarium is by no means complete and modern molecular biology techniques have led to the identification of a number of 'druggable' targets. One of the most important current drug targets is the phosphatidyl-inositol 3-kinase (PI3K) pathway, which is frequently deregulated in patients with CRC. In vitro and in vivo data strongly support the clinical development of compounds affecting signal transduction via the PI3K pathway. In this review we outline the role of PI3K in the development and progression of CRC and discuss data from current and ongoing clinical trials targeting this pathway. In addition we make suggestions toward the optimization of future research in order to derive the maximum benefit for patients with CRC.
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Affiliation(s)
| | - Roy Rabbie
- Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, UK
| | - Paul Ross
- Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, UK
| | - Debashis Sarker
- Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, UK; Department of Research Oncology, Division of Cancer Studies, King's College London, UK.
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16
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A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors. Cancer Chemother Pharmacol 2014; 74:117-23. [PMID: 24819684 DOI: 10.1007/s00280-014-2474-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Accepted: 04/23/2014] [Indexed: 12/22/2022]
Abstract
PURPOSE This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors. METHODS Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B. RESULTS Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months. CONCLUSIONS While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.
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17
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Leto SM, Trusolino L. Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies. J Mol Med (Berl) 2014; 92:709-22. [PMID: 24811491 PMCID: PMC4055851 DOI: 10.1007/s00109-014-1161-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 04/28/2014] [Accepted: 04/29/2014] [Indexed: 12/23/2022]
Abstract
Only approximately 10 % of genetically unselected patients with chemorefractory metastatic colorectal cancer experience tumor regression when treated with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab (“primary” or “de novo” resistance). Moreover, nearly all patients whose tumors initially respond inevitably become refractory (“secondary” or “acquired” resistance). An ever-increasing number of predictors of both primary and acquired resistance to anti-EGFR antibodies have been described, and it is now evident that most of the underlying mechanisms significantly overlap. By trying to extrapolate a unifying perspective out of many idiosyncratic details, here, we discuss the molecular underpinnings of therapeutic resistance, summarize research efforts aimed to improve patient selection, and present alternative therapeutic strategies that are now under development to increase response and combat relapse.
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Affiliation(s)
- Simonetta M Leto
- Department of Oncology, University of Torino Medical School, 10060, Candiolo, Torino, Italy
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18
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Wang XW, Zhang YJ. Targeting mTOR network in colorectal cancer therapy. World J Gastroenterol 2014; 20:4178-88. [PMID: 24764656 PMCID: PMC3989954 DOI: 10.3748/wjg.v20.i15.4178] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/28/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.
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19
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Koehler BC, Jäger D, Schulze-Bergkamen H. Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives. World J Gastroenterol 2014; 20:1923-1934. [PMID: 24587670 PMCID: PMC3934462 DOI: 10.3748/wjg.v20.i8.1923] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/06/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. However, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.
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20
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Nielsen DL, Palshof JA, Larsen FO, Jensen BV, Pfeiffer P. A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan +/- targeted therapy. Cancer Treat Rev 2014; 40:701-15. [PMID: 24731471 DOI: 10.1016/j.ctrv.2014.02.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 02/18/2014] [Accepted: 02/20/2014] [Indexed: 12/12/2022]
Abstract
UNLABELLED Oxaliplatin, irinotecan and 5-fluorouracil in combination with or without targeted therapies are well-documented treatment options for first- and second-line treatments of metastatic colorectal cancer. However, there are much less data on the beneficial effect on systemic therapy in the third-line setting. We therefore performed a systematic review of the current literature on third or later lines of treatment to patients with metastatic colorectal cancer after the use of approved drugs or combinations. METHODS A computer-based literature search was carried out using Pubmed and data reported at international meetings. Original studies reporting ≥15 patients who had previously received 5-fluorouracil, oxaliplatin and irinotecan were included. Furthermore, patients with KRAS wild type tumours should had received EGFR-directed therapy. RESULTS Conventional chemotherapeutic agents as capecitabine, mitomycin C, and gemcitabine have limited or no activity. Retreatment with oxaliplatin might be an option in selected patients. In addition, rechallenge with EGFR-directed therapy might be a valuable strategy. Data also suggest that angiogenetic drugs may postpone further progression and prolong survival. Lately, regorafinib has been approved. In conclusion, our current knowledge is based on many retrospective studies, some phase II studies and very few randomized clinical trials. Further prospective phase III trials comparing an investigational drug or combination with best supportive care in third- or later lines of treatment in metastatic colorectal cancer are highly warranted. Identification of predictive biomarkers and improvement of our understanding of molecular mechanisms is crucial.
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Affiliation(s)
| | | | - Finn Ole Larsen
- Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark.
| | | | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, Odense, Denmark.
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Combination of mTOR and EGFR kinase inhibitors blocks mTORC1 and mTORC2 kinase activity and suppresses the progression of colorectal carcinoma. PLoS One 2013; 8:e73175. [PMID: 23991179 PMCID: PMC3750018 DOI: 10.1371/journal.pone.0073175] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 07/17/2013] [Indexed: 12/21/2022] Open
Abstract
Mammalian target of rapamycin complex 1 and 2 (mTORC1/2) are overactive in colorectal carcinomas; however, the first generation of mTOR inhibitors such as rapamycin have failed to show clinical benefits in treating colorectal carcinoma in part due to their effects only on mTORC1. The second generation of mTOR inhibitors such as PP242 targets mTOR kinase; thus, they are capable of inhibiting both mTORC1 and mTORC2. To examine the therapeutic potential of the mTOR kinase inhibitors, we treated a panel of colorectal carcinoma cell lines with PP242. Western blotting showed that the PP242 inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKTS473) was transient only in the first few hours of the PP242 treatment. Receptor tyrosine kinase arrays further revealed that PP242 treatment increased the phosphorylated epidermal growth factor receptor (EGFR) at Tyr 1068 (EGFRT1068). The parallel increase of AKTS473 and EGFRT1068 in the cells following PP242 treatment raised the possibility that EGFR phosphorylation might contribute to the PP242 incomplete inhibition of mTORC2. To test this notion, we showed that the combination of PP242 with erlotinib, an EGFR small molecule inhibitor, blocked both mTORC1 and mTORC2 kinase activity. In addition, we showed that the combination treatment inhibited colony formation, blocked cell growth and induced apoptotic cell death. A systemic administration of PP242 and erlotinib resulted in the progression suppression of colorectal carcinoma xenografts in mice. This study suggests that the combination of mTOR kinase and EGFR inhibitors may provide an effective treatment of colorectal carcinoma.
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Haines DD, Juhasz B, Tosaki A. Management of multicellular senescence and oxidative stress. J Cell Mol Med 2013; 17:936-57. [PMID: 23789967 PMCID: PMC3780549 DOI: 10.1111/jcmm.12074] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 04/18/2013] [Indexed: 12/15/2022] Open
Abstract
Progressively sophisticated understanding of cellular and molecular processes that contribute to age-related physical deterioration is being gained from ongoing research into cancer, chronic inflammatory syndromes and other serious disorders that increase with age. Particularly valuable insight has resulted from characterization of how senescent cells affect the tissues in which they form in ways that decrease an organism's overall viability. Increasingly, the underlying pathophysiology of ageing is recognized as a consequence of oxidative damage. This leads to hyperactivity of cell growth pathways, prominently including mTOR (mammalian target of rapamycin), that contribute to a build-up in cells of toxic aggregates such as progerin (a mutant nuclear cytoskeletal protein), lipofuscin and other cellular debris, triggering formation of senescent cellular phenotypes, which interact destructively with surrounding tissue. Indeed, senescent cell ablation dramatically inhibits physical deterioration in progeroid (age-accelerated) mice. This review explores ways in which oxidative stress creates ageing-associated cellular damage and triggers induction of the cell death/survival programs' apoptosis, necrosis, autophagy and 'necroapoptophagy'. The concept of 'necroapoptophagy' is presented here as a strategy for varying tissue oxidative stress intensity in ways that induce differential activation of death versus survival programs, resulting in enhanced and sustained representation of healthy functional cells. These strategies are discussed in the context of specialized mesenchymal stromal cells with the potential to synergize with telocytes in stabilizing engrafted progenitor cells, thereby extending periods of healthy life. Information and concepts are summarized in a hypothetical approach to suppressing whole-organism senescence, with methods drawn from emerging understandings of ageing, gained from Cnidarians (jellyfish, corals and anemones) that undergo a unique form of cellular regeneration, potentially conferring open-ended lifespans.
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Affiliation(s)
- David D Haines
- Department of Pharmacology, Faculty of Pharmacy, Health and Science Center, University of Debrecen, Debrecen, Hungary
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