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Guérin C, Vinchent A, Fernandes M, Damour I, Laratte A, Tellier R, Estevam GO, Meneboo JP, Villenet C, Descarpentries C, Fraser JS, Figeac M, Cortot AB, Rouleau E, Tulasne D. MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.11.03.565283. [PMID: 37965202 PMCID: PMC10635098 DOI: 10.1101/2023.11.03.565283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2023]
Abstract
In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: in this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed ten uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.
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Guérin C, Vinchent A, Fernandes M, Damour I, Laratte A, Tellier R, Estevam GO, Meneboo JP, Villenet C, Descarpentries C, Fraser JS, Figeac M, Cortot AB, Rouleau E, Tulasne D. MET variants with activating N-lobe mutations identified in hereditary papillary renal cell carcinomas still require ligand stimulation. Mol Oncol 2025. [PMID: 39980226 DOI: 10.1002/1878-0261.13806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 10/16/2024] [Accepted: 01/15/2025] [Indexed: 02/22/2025] Open
Abstract
In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small-cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: In this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed 10 uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser, and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.
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Affiliation(s)
- Célia Guérin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Audrey Vinchent
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Marie Fernandes
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Isabelle Damour
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Agathe Laratte
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Rémi Tellier
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Gabriella O Estevam
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Jean-Pascal Meneboo
- Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, France
| | - Céline Villenet
- Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, France
| | - Clotilde Descarpentries
- Department of Biochemistry and Molecular Biology, Hormonology Metabolism Nutrition Oncology, CHU Lille, France
| | - James S Fraser
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Martin Figeac
- Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, France
| | - Alexis B Cortot
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
- Thoracic Oncology Department, Univ. Lille, CHU Lille, France
| | - Etienne Rouleau
- Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, Villejuif, France
| | - David Tulasne
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
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Guérin C, Tulasne D. Recording and classifying MET receptor mutations in cancers. eLife 2024; 13:e92762. [PMID: 38652103 PMCID: PMC11042802 DOI: 10.7554/elife.92762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 04/04/2024] [Indexed: 04/25/2024] Open
Abstract
Tyrosine kinase inhibitors (TKI) directed against MET have been recently approved to treat advanced non-small cell lung cancer (NSCLC) harbouring activating MET mutations. This success is the consequence of a long characterization of MET mutations in cancers, which we propose to outline in this review. MET, a receptor tyrosine kinase (RTK), displays in a broad panel of cancers many deregulations liable to promote tumour progression. The first MET mutation was discovered in 1997, in hereditary papillary renal cancer (HPRC), providing the first direct link between MET mutations and cancer development. As in other RTKs, these mutations are located in the kinase domain, leading in most cases to ligand-independent MET activation. In 2014, novel MET mutations were identified in several advanced cancers, including lung cancers. These mutations alter splice sites of exon 14, causing in-frame exon 14 skipping and deletion of a regulatory domain. Because these mutations are not located in the kinase domain, they are original and their mode of action has yet to be fully elucidated. Less than five years after the discovery of such mutations, the efficacy of a MET TKI was evidenced in NSCLC patients displaying MET exon 14 skipping. Yet its use led to a resistance mechanism involving acquisition of novel and already characterized MET mutations. Furthermore, novel somatic MET mutations are constantly being discovered. The challenge is no longer to identify them but to characterize them in order to predict their transforming activity and their sensitivity or resistance to MET TKIs, in order to adapt treatment.
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Affiliation(s)
- Célia Guérin
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesLilleFrance
| | - David Tulasne
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to TherapiesLilleFrance
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Altintas DM, Comoglio PM. An Observatory for the MET Oncogene: A Guide for Targeted Therapies. Cancers (Basel) 2023; 15:4672. [PMID: 37760640 PMCID: PMC10526818 DOI: 10.3390/cancers15184672] [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: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET's functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study's purpose, this work navigates MET biology's intricacies in cancer, offering a comprehensive perspective.
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Affiliation(s)
| | - Paolo M. Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milano, Italy;
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Sun Y, Yang J, Li Y, Luo J, Sun J, Li D, Wang Y, Wang K, Yang L, Wu L, Sun X. Single low-dose INC280-loaded theranostic nanoparticles achieve multirooted delivery for MET-targeted primary and liver metastatic NSCLC. Mol Cancer 2022; 21:212. [PMID: 36457016 PMCID: PMC9717478 DOI: 10.1186/s12943-022-01681-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/11/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) patients with primary tumors and liver metastases have substantially reduced survival. Since mesenchymal-epithelial transition factor (MET) plays a significant role in the molecular mechanisms of advanced NSCLC, small molecule MET inhibitor capmatinib (INC280) hold promise for clinically NSCLC treatment. However, the major obstacles of MET-targeted therapy are poor drug solubility and off-tumor effects, even oral high-dosing regimens cannot significantly increase the therapeutic drug concentration in primary and metastatic NSCLC. METHODS We developed a multirooted delivery system INC280-PFCE nanoparticles (NPs) by loading INC280 into perfluoro-15-crown-5-ether for improving MET-targeted therapy. Biodistribution and anti-MET/antimetastatic effects of NPs were validated in orthotopic NSCLC and NSCLC liver metastasis models in a single low-dose. The efficacy of INC280-PFCE NPs was also explored in human NSCLC specimens. RESULTS INC280-PFCE NPs exhibited excellent antitumor ability in vitro. In orthotopic NSCLC models, sustained release and prolonged retention behaviors of INC280-PFCE NPs within tumors could be visualized in real-time by 19F magnetic resonance imaging (19F-MRI), and single pulmonary administration of NPs showed more significant tumor growth inhibition than oral administration of free INC280 at a tenfold higher dose. Furthermore, a single low-dose INC280-PFCE NPs administered intravenously suppressed widespread dissemination of liver metastasis without systemic toxicity. Finally, we verified the clinical translation potential of INC280-PFCE NPs in human NSCLC specimens. CONCLUSIONS These results demonstrated high anti-MET/antimetastatic efficacies, real-time MRI visualization and high biocompatibility of NPs after a single low-dose.
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Affiliation(s)
- Yige Sun
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Jie Yang
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Yingbo Li
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Jing Luo
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Jiemei Sun
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Daoshuang Li
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Yuchen Wang
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Kai Wang
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Lili Yang
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Lina Wu
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
| | - Xilin Sun
- grid.410736.70000 0001 2204 9268 Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, 150028 Heilongjiang China ,grid.410736.70000 0001 2204 9268NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, 150028 Heilongjiang China
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Regua AT, Arrigo A, Doheny D, Wong GL, Lo HW. Transgenic mouse models of breast cancer. Cancer Lett 2021; 516:73-83. [PMID: 34090924 DOI: 10.1016/j.canlet.2021.05.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 11/26/2022]
Abstract
Transgenic breast cancer mouse models are critical tools for preclinical studies of human breast cancer. Genetic editing of the murine mammary gland allows for modeling of abnormal genetic events frequently found in human breast cancers. Genetically engineered mouse models (GEMMs) of breast cancer employ tissue-specific genetic manipulation for tumorigenic induction within the mammary tissue. Under the transcriptional control of mammary-specific promoters, transgenic mouse models can simulate spontaneous mammary tumorigenesis by expressing one or more putative oncogenes, such as MYC, HRAS, and PIK3CA. Alternatively, the Cre-Lox system allows for tissue-specific deletion of tumor suppressors, such as p53, Rb1, and Brca1, or specific knock-in of putative oncogenes. Thus, GEMMs can be designed to implement one or more genetic events to induce mammary tumorigenesis. Features of GEMMs, such as age of transgene expression, breeding quality, tumor latency, histopathological characteristics, and propensity for local and distant metastasis, are variable and strain-dependent. This review aims to summarize currently available transgenic breast cancer mouse models that undergo spontaneous mammary tumorigenesis upon genetic manipulation, their varying characteristics, and their individual genetic manipulations that model aberrant signaling events observed in human breast cancers.
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Affiliation(s)
- Angelina T Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, USA.
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7
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When the MET receptor kicks in to resist targeted therapies. Oncogene 2021; 40:4061-4078. [PMID: 34031544 DOI: 10.1038/s41388-021-01835-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/26/2021] [Accepted: 05/07/2021] [Indexed: 02/04/2023]
Abstract
Although targeted therapies have increased the life expectancy of patients with druggable molecular alterations directly involved in tumor development, the efficacy of these therapies is limited by acquired resistances leading to treatment failure. Most targeted therapies, including ones exploiting therapeutic antibodies and kinase inhibitors, are directed against receptor tyrosine kinases (RTKs) or major signaling hubs. Resistances to these therapies arise when inhibition of these targets is bypassed through activation of alternative signaling pathways. In recent years, activation of the receptor tyrosine kinase MET has been shown to promote resistance to various targeted therapies. This casts MET as important actor in resistance. In this review, we describe how the MET receptor triggers resistance to targeted therapies against RTKs such as EGFR, VEGFR, and HER2 and against signaling hubs such as BRAF. We also describe how MET can be its own resistance factor, as illustrated by on-target resistance of lung tumors harboring activating mutations causing MET exon 14 skipping. Interestingly, investigation of all these situations reveals functional physiological relationships between MET and the target of the therapy to which the cancer becomes resistant, suggesting that resistance stems from preexisting mechanisms. Identification of MET as a resistance factor opens the way to co-treatment strategies that are being tested in current clinical trials.
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Khater AR, Abou-Antoun T. Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment. Front Cell Dev Biol 2021; 9:654103. [PMID: 34055785 PMCID: PMC8155369 DOI: 10.3389/fcell.2021.654103] [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: 01/15/2021] [Accepted: 03/31/2021] [Indexed: 12/16/2022] Open
Abstract
Malignant nervous system cancers in children are the most devastating and worrisome diseases, specifically due to their aggressive nature and, in some cases, inoperable location in critical regions of the brain and spinal cord, and the impermeable blood-brain barrier that hinders delivery of pharmaco-therapeutic compounds into the tumor site. Moreover, the delicate developmental processes of the nervous system throughout the childhood years adds another limitation to the therapeutic modalities and doses used to treat these malignant cancers. Therefore, pediatric oncologists are charged with the daunting responsibility of attempting to deliver effective cures to these children, yet with limited doses of the currently available therapeutic options in order to mitigate the imminent neurotoxicity of radio- and chemotherapy on the developing nervous system. Various studies reported that c-Met/HGF signaling is affiliated with increased malignancy and stem cell enrichment in various cancers such as high-grade gliomas, high-risk medulloblastomas, and MYCN-amplified, high-risk neuroblastomas. Therapeutic interventions that are utilized to target c-Met signaling in these malignant nervous system cancers have shown benefits in basic translational studies and preclinical trials, but failed to yield significant clinical benefits in patients. While numerous pre-clinical data reported promising results with the use of combinatorial therapy that targets c-Met with other tumorigenic pathways, therapeutic resistance remains a problem, and long-term cures are rare. The possible mechanisms, including the overexpression and activation of compensatory tumorigenic mechanisms within the tumors or ineffective drug delivery methods that may contribute to therapeutic resistance observed in clinical trials are elaborated in this review.
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Affiliation(s)
- Amanda Rose Khater
- Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Tamara Abou-Antoun
- Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon
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Malik R, Mambetsariev I, Fricke J, Chawla N, Nam A, Pharaon R, Salgia R. MET receptor in oncology: From biomarker to therapeutic target. Adv Cancer Res 2020; 147:259-301. [PMID: 32593403 DOI: 10.1016/bs.acr.2020.04.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
First discovered in the 1984, the MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factor or HGF (also known as scatter factor or SF) are implicated as key players in tumor cell migration, proliferation, and invasion in a variety of cancers. This pathway also plays a key role during embryogenesis in the development of muscular and nervous structures. High expression of the MET receptor has been shown to correlate with poor prognosis and resistance to therapy. MET exon 14 splicing variants, initially identified by us in lung cancer, is actionable through various tyrosine kinase inhibitors (TKIs). For this reason, this pathway is of interest as a therapeutic target. In this chapter we will be discussing the history of MET, the genetics of this RTK, and give some background on the receptor biology. Furthermore, we will discuss directed therapeutics, mechanisms of resistance, and the future of MET as a therapeutic target.
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Affiliation(s)
- Raeva Malik
- George Washington University Hospital, Washington, DC, United States
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Jeremy Fricke
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Neal Chawla
- Department of Medicine, Advocate Illinois Masonic Medical Center, Chicago, IL, United States
| | - Arin Nam
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Rebecca Pharaon
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States.
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10
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Swiatnicki MR, Andrechek ER. How to Choose a Mouse Model of Breast Cancer, a Genomic Perspective. J Mammary Gland Biol Neoplasia 2019; 24:231-243. [PMID: 31227983 DOI: 10.1007/s10911-019-09433-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 06/06/2019] [Indexed: 12/20/2022] Open
Abstract
Human breast cancer is a heterogeneous disease with numerous subtypes that have been defined through immunohistological, histological, and gene expression patterns. The diversity of breast cancer has made the study of its various underlying causes complex. To facilitate the examination of particular facets of breast cancer, mouse models have been generated, ranging from carcinogen induced models to genetically engineered mice. While mouse models have been generated to mimic the initiating event, including p53 loss, BRCA loss, or overexpression of HER2 / Neu / erbB2, other genomic events are often not well characterized. However, these secondary genetic events are often critical to the mouse tumor evolution, subtype, and outcome, just as they are in human breast cancer. As such, these other genomic events are a critical component of what models are chosen to study specific subtypes of human breast cancer. Here we review the genomic analyses that have been completed for various genetically engineered mouse models, how they compare to human breast cancer, and detail how this information can be used in choosing a mouse model for analysis.
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Affiliation(s)
- Matthew R Swiatnicki
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Eran R Andrechek
- Department of Physiology, Michigan State University, 2194 BPS Building, 567 Wilson Road, East Lansing, MI, 48824, USA.
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11
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Hervieu A, Kermorgant S. The Role of PI3K in Met Driven Cancer: A Recap. Front Mol Biosci 2018; 5:86. [PMID: 30406111 PMCID: PMC6207648 DOI: 10.3389/fmolb.2018.00086] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/10/2018] [Indexed: 12/27/2022] Open
Abstract
The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and "mechanistic Target of Rapamycin" (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer.
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Affiliation(s)
- Alexia Hervieu
- Signal Transduction and Molecular Pharmacology Team, Cancer Therapeutics Division, Institute of Cancer Research, Sutton, United Kingdom
- Spatial Signalling Team, Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stéphanie Kermorgant
- Spatial Signalling Team, Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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García-Vilas JA, Medina MÁ. Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications. World J Gastroenterol 2018; 24:3695-3708. [PMID: 30197476 PMCID: PMC6127652 DOI: 10.3748/wjg.v24.i33.3695] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/28/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.
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Affiliation(s)
| | - Miguel Ángel Medina
- Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Andalucía Tech, Universidad de Málaga, Málaga 29071, Spain
- Unidad 741 de CIBER “de Enfermedades Raras” (CIBERER), Málaga 29071, Spain
- Institute of Biomedical Research in Málaga, Málaga 29071, Spain
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Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer 2018; 18:341-358. [PMID: 29674709 DOI: 10.1038/s41568-018-0002-y] [Citation(s) in RCA: 245] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered ('oncogene addiction') and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions ('oncogene expedience'). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells ('oncogene inherence'). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.
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Affiliation(s)
- Paolo M Comoglio
- Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
| | - Livio Trusolino
- Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino Medical School, Candiolo, Italy
| | - Carla Boccaccio
- Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino Medical School, Candiolo, Italy
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14
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Fischer T, Wilharm N, Hayn A, Mierke CT. Matrix and cellular mechanical properties are the driving factors for facilitating human cancer cell motility into 3D engineered matrices. CONVERGENT SCIENCE PHYSICAL ONCOLOGY 2017. [DOI: 10.1088/2057-1739/aa8bbb] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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15
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Tovar EA, Graveel CR. MET in human cancer: germline and somatic mutations. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:205. [PMID: 28603720 DOI: 10.21037/atm.2017.03.64] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.
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Affiliation(s)
- Elizabeth A Tovar
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Carrie R Graveel
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
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16
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Liu WT, Jing YY, Yu GF, Chen H, Han ZP, Yu DD, Fan QM, Ye F, Li R, Gao L, Zhao QD, Wu MC, Wei LX. Hepatic stellate cell promoted hepatoma cell invasion via the HGF/c-Met signaling pathway regulated by p53. Cell Cycle 2017; 15:886-94. [PMID: 27077227 DOI: 10.1080/15384101.2016.1152428] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
The biological behaviors of hepatocellular carcinoma (HCC) are complex mainly due to heterogeneity of progressive genetic and epigenetic mutations as well as tumor environment. Hepatocyte growth factor (HGF)/c-Met signaling pathway is regarded to be a prototypical example for stromal-epithelial interactions during developmental morphogenesis, wound healing, organ regeneration and cancer progression. And p53 plays as an important regulator of Met-dependent cell motility and invasion. Present study showed that 2 HCC cell lines, Hep3B and HepG2, displayed different invasive capacity when treated with HGF which was secreted by hepatic stellate cells (HSCs). We found that HGF promoted Hep3B cells invasion and migration as well as epithelial-mesenchymal transition (EMT) occurrence because Hep3B was p53 deficient, which leaded to the c-Met over-expression. Then we found that HGF/c-Met promoted Hep3B cells invasion and migration by upregulating Snail expression. In conclusion, HGF/c-Met signaling is enhanced by loss of p53 expression, resulting in increased ability of invasion and migration by upregulating the expression of Snail.
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Affiliation(s)
- Wen-Ting Liu
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Ying-Ying Jing
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Guo-feng Yu
- c Oncology Department , Ji'an Hospital, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China
| | - Hong Chen
- d Pathology Department , Funing Hospital of Traditional Chinese Medicine , Qinghuangdao , Hebei Province , China
| | - Zhi-peng Han
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Dan-Dan Yu
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Qing-Min Fan
- e Ultrasonography Department , The First Affiliated Hospital of Soochow University , Jiangsu , China
| | - Fei Ye
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Rong Li
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Lu Gao
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Qiu-Dong Zhao
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Meng-Chao Wu
- b Department of Comprehensive Treatment , Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
| | - Li-Xin Wei
- a Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University , Shanghai , China
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17
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Couto JP, Bentires-Alj M. Mouse Models of Breast Cancer: Deceptions that Reveal the Truth. Breast Cancer 2017. [DOI: 10.1007/978-3-319-48848-6_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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18
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Jia YX, Li TF, Zhang DD, Fan ZM, Fan HJ, Yan J, Chen LJ, Tang H, Qin YR, Li XY. The coexpression and prognostic significance of c-MET, fibroblast growth factor receptor 2, and human epidermal growth factor receptor 2 in resected gastric cancer: a retrospective study. Onco Targets Ther 2016; 9:5919-5929. [PMID: 27729801 PMCID: PMC5045911 DOI: 10.2147/ott.s111778] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Molecular-targeted therapy against tyrosine kinase receptors (RTKs) plays an important role in gastric cancer (GC) treatment. Understanding the correlation between RTK coexpression could better guide clinical drug use. In the present study, the coexpression status of c-MET, fibroblast growth factor receptor 2 (FGFR2), and human epidermal growth factor receptor 2 (HER2) in human GC and their clinical significance in clinical therapy were explored. Immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction and fluorescent in situ hybridization were performed in 143 cases of GC who had undergone gastrectomy without preoperative chemoradiotherapy. Their association with clinicopathological features and clinical prognosis was analyzed. The frequencies of c-MET, FGFR2, and HER2 overexpression were 47.6% (68/143), 34.3% (49/143), and 10.5% (15/143), respectively. In the RTK coexpression study, 30.1% of patients (43/143) were positive for only one RTK, 25.8% (37/143) were positive for two RTKs, 3.5% (5/143) had triple-positive status, and 40.6% (58/143) had triple-negative status. In survival analysis, the overexpression of c-MET, FGFR2, and HER2 were significantly associated with overall survival (OS) (P=0.018, 0.004, and 0.049, respectively). In coexpression analysis, patients with triple-positive GC had the poorest OS (P=0.013). In conclusion, RTK coexpression is significantly associated with poor clinical outcome in GC.
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Affiliation(s)
- Yong-Xu Jia
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | | | | | - Zong-Min Fan
- Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University
| | - Hui-Jie Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | - Jie Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | - Li-Juan Chen
- Department of Oncology, Tumor Hospital of Henan Province, Zhengzhou, Henan, People's Republic of China
| | - Hong Tang
- Department of Oncology, Tumor Hospital of Henan Province, Zhengzhou, Henan, People's Republic of China
| | - Yan-Ru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University; Esophageal and Gastric Cancer Center of Henan Province
| | - Xing-Ya Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University
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19
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Hirsch MS, Signoretti S, Dal Cin P. Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics. Surg Pathol Clin 2016; 8:587-621. [PMID: 26612217 DOI: 10.1016/j.path.2015.09.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
According to the current World Health Organization (WHO), renal cell carcinomas (RCCs) that primarily affect adults are classified into 8 major subtypes. Additional emerging entities in renal neoplasia have also been recently recognized and these are discussed in further detail by Mehra et al (Emerging Entities in Renal Neoplasia, Surgical Pathology Clinics, 2015, Volume 8, Issue 4). In most cases, the diagnosis of a RCC subtype can be based on morphologic criteria, but in some circumstances the use of ancillary studies can aid in the diagnosis. This review discusses the morphologic, genetic, and molecular findings in RCCs previously recognized by the WHO, and provides clues to distinction from each other and some of the newer subtypes of RCC. As prognosis and therapeutic options vary for the different subtypes of RCC, accurate pathologic distinction is critical for patient care.
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Affiliation(s)
- Michelle S Hirsch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Paola Dal Cin
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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20
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van Marion DM, Domanska UM, Timmer-Bosscha H, Walenkamp AM. Studying cancer metastasis: Existing models, challenges and future perspectives. Crit Rev Oncol Hematol 2016; 97:107-17. [DOI: 10.1016/j.critrevonc.2015.08.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 08/05/2015] [Indexed: 02/03/2023] Open
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21
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Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia. Am J Hum Genet 2015; 97:837-47. [PMID: 26637977 DOI: 10.1016/j.ajhg.2015.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 11/03/2015] [Indexed: 12/12/2022] Open
Abstract
The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease. Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (MET(Δ14)) lacking a cytoplasmic juxtamembrane domain. Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization. In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the MET(Δ14) mutations, had a stabilizing effect on the mature protein. Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone.
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22
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Zhang SY, Zhang SQ, Nagaraju GP, El-Rayes BF. Biomarkers for personalized medicine in GI cancers. Mol Aspects Med 2015; 45:14-27. [DOI: 10.1016/j.mam.2015.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 06/02/2015] [Indexed: 02/06/2023]
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23
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Li Y, Wang X, Yao L. Directional migration and transcriptional analysis of oligodendrocyte precursors subjected to stimulation of electrical signal. Am J Physiol Cell Physiol 2015; 309:C532-40. [PMID: 26269459 DOI: 10.1152/ajpcell.00175.2015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/05/2015] [Indexed: 12/28/2022]
Abstract
Loss of oligodendrocytes as the result of central nervous system disease causes demyelination that impairs axon function. Effective directional migration of endogenous or grafted oligodendrocyte precursor cells (OPCs) to a lesion is crucial in the neural remyelination process. In this study, the migration of OPCs in electric fields (EFs) was investigated. We found that OPCs migrated anodally in applied EFs, and the directedness and displacement of anodal migration increased significantly when the EF strength increased from 50 to 200 mV/mm. However, EFs did not significantly affect the cell migration speed. The transcriptome of OPCs subjected to EF stimulation (100 and 200 mV/mm) was analyzed using RNA sequencing (RNA-Seq), and results were verified by the reverse transcription quantitative polymerase chain reaction. A Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the mitogen-activated protein kinase pathway that signals cell migration was significantly upregulated in cells treated with an EF of 200 mV/mm compared with control cells. Gene ontology enrichment analysis showed the downregulation of differentially expressed genes in chemotaxis. This study suggests that an applied EF is an effective cue to guiding OPC migration in neural regeneration and that transcriptional analysis contributes to the understanding of the mechanism of EF-guided cell migration.
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Affiliation(s)
- Yongchao Li
- Department of Biological Sciences, Wichita State University, Wichita, Kansas; and
| | - Xinkun Wang
- Genome Sequencing Core and Genomics Facility, University of Kansas, Lawrence, Kansas
| | - Li Yao
- Department of Biological Sciences, Wichita State University, Wichita, Kansas; and
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24
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Teng H, Yang Y, Wei H, Liu Z, Liu Z, Ma Y, Gao Z, Hou L, Zou X. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma. Mar Drugs 2015; 13:3514-30. [PMID: 26047481 PMCID: PMC4483642 DOI: 10.3390/md13063514] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 05/19/2015] [Indexed: 12/30/2022] Open
Abstract
Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.
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Affiliation(s)
- Hongming Teng
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Yazong Yang
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Hengyun Wei
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Zundong Liu
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Zhichao Liu
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Yanhong Ma
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Zixiang Gao
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
| | - Lin Hou
- College of Life Sciences, Liaoning Normal University, Dalian 116081, China
| | - Xiangyang Zou
- Department of Biotechnology, Dalian Medical University, Dalian 116044, China; E-Mails: (H.T.); yangyazong123.@126.com (Y.Y.); (H.W.); (Z.L.); (Z.L.); (Y.M.); (Z.G.)
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25
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Yao L, Li Y, Knapp J, Smith P. Exploration of molecular pathways mediating electric field-directed Schwann cell migration by RNA-seq. J Cell Physiol 2015; 230:1515-24. [PMID: 25557037 DOI: 10.1002/jcp.24897] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 12/15/2014] [Indexed: 01/03/2023]
Abstract
In peripheral nervous systems, Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. Following spinal cord injury, Schwann cells regenerate and migrate to the lesion and are involved in the spinal cord regeneration process. Transplantation of Schwann cells into injured neural tissue results in enhanced spinal axonal regeneration. Effective directional migration of Schwann cells is critical in the neural regeneration process. In this study, we report that Schwann cells migrate anodally in an applied electric field (EF). The directedness and displacement of anodal migration increased significantly when the strength of the EF increased from 50 mV/mm to 200 mV/mm. The EF did not significantly affect the cell migration speed. To explore the genes and signaling pathways that regulate cell migration in EFs, we performed a comparative analysis of differential gene expression between cells stimulated with an EF (100 mV/mm) and those without using next-generation RNA sequencing, verified by RT-qPCR. Based on the cut-off criteria (FC > 1.2, q < 0.05), we identified 1,045 up-regulated and 1,636 down-regulated genes in control cells versus EF-stimulated cells. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found that compared to the control group, 21 pathways are down-regulated, while 10 pathways are up-regulated. Differentially expressed genes participate in multiple cellular signaling pathways involved in the regulation of cell migration, including pathways of regulation of actin cytoskeleton, focal adhesion, and PI3K-Akt.
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Affiliation(s)
- Li Yao
- Department of Biological Sciences, Wichita State University, Wichita, Kansas
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Petrini I. Biology of MET: a double life between normal tissue repair and tumor progression. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:82. [PMID: 25992381 DOI: 10.3978/j.issn.2305-5839.2015.03.58] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 01/28/2015] [Indexed: 01/30/2023]
Abstract
MNNG HOS transforming gene (MET) is a class IV receptor tyrosine kinase, expressed on the surface of epithelial cells. The interaction with the hepatocyte grow factor (HGF) induces MET dimerization and the activation of multiple intracellular pathways leading to cell proliferation, anti-apoptosis, morphogenic differentiation, motility, invasion, and angiogenesis. Knock out mice have demonstrated that MET is necessary for normal embryogenesis including the formation of striate muscles, liver and trophoblastic structures. The overexpression of MET and HGF are common in solid tumors and contribute to determine their growth. Indeed, MET has been cloned as a transforming gene from a chemically induced human osteosarcoma cell line and therefore is considered a proto-oncogene. Germline MET mutations are characteristic of hereditary papillary kidney cancers and MET amplification is observed in tumors including lung and gastric adenocarcinomas. The inhibition of MET signaling is the target for specific drugs that are raising exciting expectation for medical treatment of cancer.
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MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus. J Neurosci 2015; 34:16166-79. [PMID: 25471559 DOI: 10.1523/jneurosci.2580-14.2014] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk.
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Ning L, Yu Y, Liu X, Ai L, Zhang X, Rao W, Shi J, Sun H, Yu Q. Association Analysis of MET Gene Polymorphism with Papillary Thyroid Carcinoma in a Chinese Population. Int J Endocrinol 2015; 2015:405217. [PMID: 26649038 PMCID: PMC4662967 DOI: 10.1155/2015/405217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 10/16/2015] [Accepted: 10/27/2015] [Indexed: 01/22/2023] Open
Abstract
To investigate the association of MET SNPs with gender disparity in thyroid tumors, as well as the metastasis and prognosis of patients, 858 patients with papillary thyroid carcinoma (PTC), 556 patients with nodular goiter, and 896 population-based normal controls were recruited. The genotyping of MET SNPs was carried out using the Sequenom MassARRAY system. The distribution of MET SNPs (rs1621 and rs6566) was different among groups. Gender stratification analysis revealed a significant association between the rs1621 genotype and PTC in female patients (P = 0.037), but not in male patients (P > 0.05). For female patients, the rs1621 AG genotype was significantly higher in patients with PTC than in normal controls (P = 0.01) and revealed an increasing risk of PTC (OR: 1.465, 95% CI: 1.118-1.92). However, association analysis of the rs1621 genotype with metastasis and prognosis revealed no significant correlation in both male and female patients. The findings of our study showed that polymorphism of SNP locus rs1621 in MET gene may be associated with gender disparity in PTC. Higher AG genotypes in rs1621 were correlated with PTC in female patients, but not in male patients.
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Affiliation(s)
- Lifeng Ning
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
- National Research Institute for Family Planning, Beijing 100081, China
| | - Yaqin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
| | - Xiaoli Liu
- Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Lizhe Ai
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
| | - Xin Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
| | - Wenwang Rao
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
| | - Jieping Shi
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
| | - Hui Sun
- Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, China-Japan Union Hospital, Jilin University, Changchun 130033, China
| | - Qiong Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China
- *Qiong Yu:
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Dong C, Ye DX, Zhang WB, Pan HY, Zhang ZY, Zhang L. Overexpression of c-fos promotes cell invasion and migration via CD44 pathway in oral squamous cell carcinoma. J Oral Pathol Med 2014; 44:353-60. [PMID: 25482572 DOI: 10.1111/jop.12296] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Cong Dong
- Department of Oral and Cranio-Maxillofacial Science; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Stomatology; Shanghai China
- Shanghai Stomatological Disease Center; Shanghai China
| | - Dong-Xia Ye
- Shanghai Key Laboratory of Stomatology; Shanghai China
| | - Wen-Bin Zhang
- Department of Oral and Cranio-Maxillofacial Science; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Stomatology; Shanghai China
| | - Hong-Ya Pan
- Shanghai Key Laboratory of Stomatology; Shanghai China
| | | | - Lei Zhang
- Department of Oral and Cranio-Maxillofacial Science; Ninth People's Hospital; Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Stomatology; Shanghai China
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30
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Montagne R, Furlan A, Kherrouche Z, Tulasne D. [Thirty years of Met receptor research: from the discovery of an oncogene to the development of targeted therapies]. Med Sci (Paris) 2014; 30:864-73. [PMID: 25311021 DOI: 10.1051/medsci/20143010013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies.
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Affiliation(s)
- Rémi Montagne
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
| | - Alessandro Furlan
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
| | - Zoulika Kherrouche
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
| | - David Tulasne
- CNRS UMR 8161, Institut de biologie de Lille, Institut Pasteur de Lille, université de Lille 1 et 2, SIRIC ONCOLille, IFR142, 1, rue du Professeur Calmette, 59021 Lille, France
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Zheng Q, Wu H, Cao J, Ye J. Hepatocyte growth factor activator inhibitor type‑1 in cancer: advances and perspectives (Review). Mol Med Rep 2014; 10:2779-85. [PMID: 25310042 DOI: 10.3892/mmr.2014.2628] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Accepted: 06/05/2014] [Indexed: 11/06/2022] Open
Abstract
Cancer is one of the most common diseases, with high morbidity and mortality rates. Large‑scale efforts have been made to understand the pathogenesis of the disease, particularly in the advanced stages, in order to develop effective therapeutic approaches. Hepatocyte growth factor activator inhibitor type-1 (HAI-1), also known as serine protease inhibitor Kunitz type 1, inhibits the activity of several trypsin-like serine proteases. In particular, HAI-1 suppresses hepatocyte growth factor (HGF) activator and matriptase, resulting in subsequent inhibition of HGF/scatter factor and macrophage‑stimulating protein (MSP). HGF and MSP are involved in cancer development and progression, via the receptors Met receptor tyrosine kinase (RTK) and Ron RTK, respectively. Therefore, HAI-1-mediated downregulation of HGF and MSP signaling may suppress tumorigenesis and progression in certain types of cancers. Abnormal HAI-1 expression levels have been observed in various types of human cancer. The exact function of HAI-1 in cancer pathogenesis, however, has not been fully elucidated. In this review, the focus is on the potential impact of aberrant HAI-1 expression levels on tumorigenesis and progression, the underlying mechanisms, and areas that require further investigation to clarify the precise role of HAI-1 in cancer.
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Affiliation(s)
- Qiaoli Zheng
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Haijian Wu
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jiang Cao
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Jingjia Ye
- Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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Opposite role of CD44-standard and CD44-variant-3 in tubular injury and development of renal fibrosis during chronic obstructive nephropathy. Kidney Int 2014; 86:558-69. [PMID: 24717295 DOI: 10.1038/ki.2014.87] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 12/30/2013] [Accepted: 02/06/2014] [Indexed: 02/07/2023]
Abstract
Chronic kidney diseases (CKDs) are characterized by tubular atrophy and interstitial fibrosis. We previously showed that in obstructive nephropathy de novo CD44 renal expression contributes to renal fibrosis but attenuates tubular damage/apoptosis. As CD44-standard (CD44s) has been linked to TGF-β1-mediated actions and CD44-variant-3 (CD44v3) favors HGF-c-Met binding, we compared the functional properties of these CD44 isoforms in the progression of obstructive nephropathy, using specific CD44-variant knockout/knockin mice. The presence of CD44v3 diminished tubular damage during obstructive nephropathy, decreased apoptosis, and increased proliferation of tubular epithelial cells, and prevented renal fibrosis development. In contrast, expression of CD44s led to increased tubular damage and tubular epithelial cell apoptosis, and more renal fibrosis. A relative increase in renal β-catenin expression, HGF production, and HGF/c-Met signaling, together with a relative inhibition of TGF-β1 downstream signaling and TGF-β type I receptor expression, was found in CD44v3 mice compared with CD44s littermates. In line with this, Wnt3a/HGF treatment of tubular cells resulted in higher β-catenin/p-AKT levels in CD44v3(+) tubular epithelial cells, whereas TGF-β1 induced a mild collagen I upregulation in CD44v3(+) mouse embryonic fibroblasts as compared with CD44s(+) cells. Thus, CD44s and CD44v3 exert opposite roles in the progression of obstructive nephropathy, with CD44v3-v10 being the protective isoform that delays evolution of the renal pathology.
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Teng L, Lu J. cMET as a potential therapeutic target in gastric cancer (Review). Int J Mol Med 2013; 32:1247-54. [PMID: 24141315 DOI: 10.3892/ijmm.2013.1531] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 10/16/2013] [Indexed: 11/05/2022] Open
Abstract
Gastric cancer is one of the most common malignancies worldwide. Despite improvements in surgery and chemotherapy, the outcomes in patients with advanced gastric cancer remain poor. cMET is a member of the receptor tyrosine kinase family, and plays a key role in tumor survival, growth, angiogenesis and metastasis. cMET overexpression and/or gene amplification occurs in a significant proportion of gastric cancers. cMET is associated with a high tumor stage and poor prognosis. Several cMET inhibitors have been investigated in clinical trials, and the initial results are encouraging. It has become increasingly apparent that cMET is a promising therapeutic target in gastric cancer. In this review, we summarize the development of cMET inhibitors in the preclinical and clinical environment. In addition, we discuss the challenges of cMET-targeted therapy in gastric cancer and explore possible solutions.
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Affiliation(s)
- Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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Medová M, Pochon B, Streit B, Blank-Liss W, Francica P, Stroka D, Keogh A, Aebersold DM, Blaukat A, Bladt F, Zimmer Y. The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants. Mol Cancer Ther 2013; 12:2415-24. [PMID: 24061647 DOI: 10.1158/1535-7163.mct-13-0151] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results show a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five of the eight cell lines (IC50 2-43 nmol/L). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell-cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biologic functions, such as cellular morphology, MET-dependent cell motility, and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET-mutated variants. Animals were randomized for the treatment with EMD1214063 (50 mg/kg/d) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, whereas tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small-molecule inhibitor with selective activity towards mutated MET variants.
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Affiliation(s)
- Michaela Medová
- Corresponding Author: Michaela Medová, Radiation Oncology, Department of Clinical Research, University of Bern/Inselspital, MEM-E815, Murtenstrassse 35, 3010 Bern, Switzerland.
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Graveel CR, Tolbert D, Vande Woude GF. MET: a critical player in tumorigenesis and therapeutic target. Cold Spring Harb Perspect Biol 2013; 5:a009209. [PMID: 23818496 PMCID: PMC3685898 DOI: 10.1101/cshperspect.a009209] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Since its discovery more than 25 years ago, numerous studies have established that the MET receptor is unique among tyrosine kinases. Signaling through MET is necessary for normal development and for the progression of a wide range of human cancers. MET activation has been shown to drive numerous signaling pathways; however, it is not clear how MET signaling mediates diverse cellular responses such as motility, invasion, growth, and angiogenesis. Great strides have been made in understanding the pleotropic aspects of MET signaling using three-dimensional molecular structures, cell culture systems, human tumors, and animal models. These combined approaches have driven the development of MET-targeted therapeutics that have shown promising results in the clinic. Here we examine the unique features of MET and hepatocyte growth factor/scatter factor (HGF/SF) structure and signaling, mutational activation, genetic mouse models of MET and HGF/SF, and MET-targeted therapeutics.
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Affiliation(s)
- Carrie R Graveel
- Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
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36
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Met-induced membrane blebbing leads to amoeboid cell motility and invasion. Oncogene 2013; 33:1788-98. [DOI: 10.1038/onc.2013.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 02/26/2013] [Indexed: 02/07/2023]
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Ding X, Pan H, Li J, Zhong Q, Chen X, Dry SM, Wang CY. Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis. Sci Signal 2013; 6:ra28.1-13, S0-15. [PMID: 23633675 DOI: 10.1126/scisignal.2003884] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The transcription factor AP1 (activating protein 1), a heterodimer of the JUN and FOS proteins, promotes the invasive growth and metastasis of various tumors such as squamous cell carcinoma (SCC), breast cancer, and melanoma. AP1 activity is transcriptionally induced through a positive feedback loop. We identified the histone demethylase KDM4A (lysine-specific demethylase 4A) as a key epigenetic priming factor in this positive feedback loop. KDM4A contributed to the induction of genes encoding the AP1 transcription factors and the invasive growth and metastasis of SCC. KDM4A knockdown decreased the growth factor-induced messenger RNA expression and protein abundance of AP1 family members, including JUN and FOSL1. Mechanistically, histone demethylation by KDM4A facilitated the binding of the AP1 complex to the promoters of JUN and FOSL1, thereby promoting the positive feedback loop that maintains activation of AP1. In a mouse model of SCC, KDM4A knockdown inhibited lymph node metastasis. Moreover, the abundance of KDM4A correlated with the abundance of JUN and FOSL1 in human SCC tissues, and KDM4A expression was increased in human lymph node metastases. Our studies provide insights into the epigenetic control of AP1 and tumor invasion and suggest that KDM4A could be an important therapeutic target for inhibiting invasive SCC growth and metastasis.
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Affiliation(s)
- Xiangming Ding
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Northrup AB, Katcher MH, Altman MD, Chenard M, Daniels MH, Deshmukh SV, Falcone D, Guerin DJ, Hatch H, Li C, Lu W, Lutterbach B, Allison TJ, Patel SB, Reilly JF, Reutershan M, Rickert KW, Rosenstein C, Soisson SM, Szewczak AA, Walker D, Wilson K, Young JR, Pan BS, Dinsmore CJ. Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met. J Med Chem 2013; 56:2294-310. [PMID: 23379595 DOI: 10.1021/jm301619u] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.
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Affiliation(s)
- Alan B Northrup
- Department of Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, BMB-3, Boston, Massachusetts 02115, USA.
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Scagliotti GV, Novello S, von Pawel J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev 2013; 39:793-801. [PMID: 23453860 DOI: 10.1016/j.ctrv.2013.02.001] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 01/31/2013] [Accepted: 02/02/2013] [Indexed: 02/06/2023]
Abstract
The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in many tumor types, can occur by multiple mechanisms, and promotes cellular proliferation and metastasis via growth factor receptors and other oncogenic receptor pathways. Thus, MET/HGF inhibition has emerged as targeted anticancer therapies. Preclinically, neoplastic and metastatic phenotypes of several tumor cells, including non-small cell lung cancer, hepatocellular carcinoma, and gastric cancer, were abrogated by MET inhibition. Ongoing clinical development with tivantinib, cabozantinib, onartuzumab, crizotinib, rilotumumab, and ficlatuzumab has shown encouraging results. These trials have established a key role for MET in a variety of tumor types. Evidence is emerging for identification of aberrant MET activity biomarkers and selection of patient subpopulations that may benefit from targeted MET and HGF inhibitor treatment.
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Chen R, Li J, Feng CH, Chen SK, Liu YP, Duan CY, Li H, Xia XM, He T, Wei M, Dai RY. c-Met function requires n-linked glycosylation modification of pro-Met. J Cell Biochem 2013; 114:816-22. [DOI: 10.1002/jcb.24420] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 10/01/2012] [Indexed: 12/22/2022]
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Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related morbidity and mortality worldwide. Despite improvements in local therapies, including surgical resection, liver transplantation, and transarterial embolization, the prognosis remains poor for the majority of patients who develop recurrence or present with advanced disease. Systemic therapy with the tyrosine kinase inhibitor sorafenib represents a milestone in advanced HCC but provides a limited survival benefit. Ongoing efforts to study hepatocarcinogenesis have identified an important role for c-MET signaling in the promotion of tumor growth, angiogenesis, and metastasis. In this review, we summarize the preclinical data from human tissue, cell lines, and animal models that implicate c-MET in the pathogenesis of HCC. We also evaluate potential biomarkers that may estimate prognosis or predict response to c-MET inhibitors for more rational clinical trial design. Finally, we discuss the latest clinical trials of c-MET inhibitors in advanced HCC.
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Affiliation(s)
- Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA
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Giunti S, Antonelli A, Amorosi A, Santarpia L. Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma. Int J Endocrinol 2013; 2013:803171. [PMID: 23509459 PMCID: PMC3594951 DOI: 10.1155/2013/803171] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 01/08/2013] [Accepted: 01/10/2013] [Indexed: 12/12/2022] Open
Abstract
Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET) and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR) cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.
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Affiliation(s)
- Serena Giunti
- Department of Pathology, Centro Oncologico Fiorentino, Sesto Fiorentino, 50019 Firenze, Italy
| | - Alessandro Antonelli
- Department of Internal Medicine, University of Pisa School of Medicine, 56100 Pisa, Italy
| | - Andrea Amorosi
- Department of Pathology, Centro Oncologico Fiorentino, Sesto Fiorentino, 50019 Firenze, Italy
| | - Libero Santarpia
- Translational Research Unit, Department of Oncology, Istituto Toscano Tumori, 59100 Prato, Italy
- *Libero Santarpia:
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Dai R, Li J, Fu J, Chen Y, Wang R, Zhao X, Luo T, Zhu J, Ren Y, Cao J, Qian Y, Li N, Wang H. The tyrosine kinase c-Met contributes to the pro-tumorigenic function of the p38 kinase in human bile duct cholangiocarcinoma cells. J Biol Chem 2012; 287:39812-23. [PMID: 23024367 DOI: 10.1074/jbc.m112.406520] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Pro-tumorigenic function of the p38 kinase plays a critical role in human cholangiocarcinogenesis. However, the underlying mechanism remains incompletely understood. Here, we report that c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), contributes to the pro-tumorigenic ability of p38 in human cholangiocarcinoma cells. Both p38 and c-Met promote the proliferation and invasion of human cholangiocarcinoma cells. Importantly, inhibition or knockdown of p38 decreased the basal activation of c-Met. Tyrosine phosphatase inhibitor studies revealed that p38 promotes the activity of c-Met, at least in part, by inhibiting dephosphorylation of the receptor. Moreover, density enhanced phosphatase-1 (DEP-1) is involved in p38-mediated inhibiting dephosphorylation of c-Met. Furthermore, p38 inhibits the degradation of c-Met. Taken together, these data provide a potential mechanism to explain how p38 promotes human cholangiocarcinoma cell proliferation and invasion. We propose that the link between p38 and c-Met is implicated in the progression of human cholangiocarcinoma.
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Affiliation(s)
- Rongyang Dai
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438
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NLRR1 Enhances EGF-Mediated MYCN Induction in Neuroblastoma and Accelerates Tumor Growth In Vivo. Cancer Res 2012; 72:4587-96. [DOI: 10.1158/0008-5472.can-12-0943] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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45
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Eckhardt BL, Francis PA, Parker BS, Anderson RL. Strategies for the discovery and development of therapies for metastatic breast cancer. Nat Rev Drug Discov 2012; 11:479-97. [PMID: 22653217 DOI: 10.1038/nrd2372] [Citation(s) in RCA: 266] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nearly all deaths caused by solid cancers occur as a result of metastasis--the formation of secondary tumours in distant organs such as the lungs, liver, brain and bone. A major obstruction to the development of drugs with anti-metastatic efficacy is our fragmented understanding of how tumours 'evolve' and metastasize, at both the biological and genetic levels. Furthermore, although there is significant overlap in the metastatic process among different types of cancer, there are also marked differences in the propensity to metastasize, the extent of metastasis, the sites to which the tumour metastasizes, the kinetics of the process and the mechanisms involved. Here, we consider the case of breast cancer, which has some marked distinguishing features compared with other types of cancer. Considerable progress has been made in the development of preclinical models and in the identification of relevant signalling pathways and genetic regulators of metastatic breast cancer, and we discuss how these might facilitate the development of novel targeted anti-metastatic drugs.
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Affiliation(s)
- Bedrich L Eckhardt
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Abstract
Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.
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Affiliation(s)
- Ermanno Gherardi
- Medical Research Council (MRC) Centre, Hills Road, Cambridge CB2 2QH, UK.
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47
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Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma. Proc Natl Acad Sci U S A 2011; 109:570-5. [PMID: 22203985 DOI: 10.1073/pnas.1119059109] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics.
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48
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Abstract
Despite recent advances, there remains an unmet need for more effective treatments for newly diagnosed and recurrent glioblastoma (GBM). While currently available alkylator-based and antiangiogenic agents provide some efficacy, novel antiangiogenic and antiglioma treatments that provide enhanced efficacy with improvements in overall survival, the potential to overcome drug resistance and decreased treatment-related toxicity are still needed. Although VEGF-directed angiogenesis is critical during GBM pathogenesis, alternative proangiogenic and glioma-promoting pathways also play a key role in tumor progression. This article reviews the limitations of current GBM treatment, the importance of angiogenic signaling pathways in GBM pathogenesis and the preliminary results of novel antiangiogenic-targeted treatments being evaluated in GBM. Therapies that inhibit multiple glioma signaling pathways, including angiogenesis, have the possibility for further improving outcome in GBM and may represent the best option for increasing overall survival.
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Affiliation(s)
- Marc Chamberlain
- University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, 825 Eastlake Ave E, POB 19023, MS G4-940, Seattle, WA 98109-1023, USA.
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Sattler M, Reddy MM, Hasina R, Gangadhar T, Salgia R. The role of the c-Met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol 2011; 3:171-84. [PMID: 21904579 DOI: 10.1177/1758834011408636] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Hepatocyte growth factor receptor (HGFR), the product of the MET gene, plays an important role in normal cellular function and oncogenesis. In cancer, HGFR has been implicated in cellular proliferation, cell survival, invasion, cell motility, metastasis and angiogenesis. Activation of HGFR can occur through binding to its ligand, hepatocyte growth factor (HGF), overexpression/amplification, mutation, and/or decreased degradation. Amplification of HGFR can occur de novo or in resistance to therapy. Mutations of HGFR have been described in the tyrosine kinase domain, juxtamembrane domain, or semaphorin domain in a number of tumors. These mutations appear to have gain of function, and also reflect differential sensitivity to therapeutic inhibition. There have been various drugs developed to target HGFR, including antibodies to HGFR/HGF, small-molecule inhibitors against the tyrosine kinase domain of HGFR and downstream targets. Different HGFR inhibitors are currently in clinical trials in lung cancer and a number of solid tumors. Several phase I trials have already been completed, and two specific trials have been reported combining HGFR with epidermal growth factor receptor (EGFR) inhibition in non-small cell lung cancer. In particular, trials involving MetMAb and ARQ197 (tivantinib) have gained interest. Ultimately, as individualized therapies become a reality for cancers, HGFR will be an important molecular target.
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Affiliation(s)
- Martin Sattler
- Department of Medical Oncology, Dana-Farber Cancer Institute, and Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA
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50
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Li Y, Zhang S, Tang Z, Chen J, Kong W. Silencing of c-Met by RNA interference inhibits the survival, proliferation, and invasion of nasopharyngeal carcinoma cells. Tumour Biol 2011; 32:1217-24. [PMID: 21922276 DOI: 10.1007/s13277-011-0225-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2011] [Accepted: 08/10/2011] [Indexed: 12/18/2022] Open
Abstract
c-Met is a tyrosine kinase receptor that mediates pleiotropic cellular responses following its activation by hepatocyte growth factor. The overexpression of c-Met in nasopharyngeal carcinoma (NPC) has been described recently, but the functional role of c-Met in NPC remains incompletely understood. This study aimed to investigate the potential mechanism by which c-Met contributes to the tumorigenesis of NPC. In the present study, by using RNA interference we silenced the expression of c-Met in CNE-2 cells, a poorly differentiated NPC cell line. Our in vitro studies showed that shRNA-mediated depletion of c-Met resulted in the suppression of proliferation, migration, and invasion, as well as an increase in the apoptosis of CNE-2 cells. Moreover, in xenograft nude mice we demonstrated that the depletion of c-Met resulted in reduced tumor growth and increased apoptosis in xenografts. Taken together, these results suggest that c-Met plays an oncogenic role in the development of NPC and reveal it as a potential novel therapeutic target for NPC.
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Affiliation(s)
- Yuncheng Li
- Department of Otolaryngology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, China, 430022
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