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Lombardi AM, Sangiolo D, Vigna E. MET Oncogene Targeting for Cancer Immunotherapy. Int J Mol Sci 2024; 25:6109. [PMID: 38892318 PMCID: PMC11173045 DOI: 10.3390/ijms25116109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).
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Affiliation(s)
| | | | - Elisa Vigna
- Department of Oncology, University of Torino, 10043 Torino, Italy; (A.M.L.); (D.S.)
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Ramesh S, Cifci A, Javeri S, Minne RL, Longhurst CA, Nickel KP, Kimple RJ, Baschnagel AM. MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2024; 118:1379-1390. [PMID: 37979706 DOI: 10.1016/j.ijrobp.2023.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 10/30/2023] [Accepted: 11/05/2023] [Indexed: 11/20/2023]
Abstract
PURPOSE The objective of this study was to investigate the effects of inhibiting the MET receptor with capmatinib, a potent and clinically relevant ATP-competitive tyrosine kinase inhibitor, in combination with radiation in MET exon 14-mutated and MET-amplified non-small cell lung (NSCLC) cancer models. METHODS AND MATERIALS In vitro effects of capmatinib and radiation on cell proliferation, colony formation, MET signaling, apoptosis, and DNA damage repair were evaluated. In vivo tumor responses were assessed in cell line xenograft and patient-derived xenograft models. Immunohistochemistry was used to confirm the in vitro results. RESULTS In vitro clonogenic survival assays demonstrated radiosensitization with capmatinib in both MET exon 14-mutated and MET-amplified NSCLC cell lines. No radiation-enhancing effect was observed in MET wild-type NSCLC and a human bronchial epithelial cell line. Minimal apoptosis was detected with the combination of capmatinib and radiation. Capmatinib plus radiation compared with radiation alone resulted in inhibition of DNA double-strand break repair, as measured by prolonged expression of γH2AX. In vivo, the combination of capmatinib and radiation significantly delayed tumor growth compared with vehicle control, capmatinib alone, or radiation alone. Immunohistochemistry indicated inhibition of phospho-MET and phospho-S6 and a decrease in Ki67 with inhibition of MET. CONCLUSIONS Inhibition of MET with capmatinib enhances the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.
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Affiliation(s)
- Shrey Ramesh
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Ahmet Cifci
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Saahil Javeri
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Rachel L Minne
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Colin A Longhurst
- Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Kwangok P Nickel
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
| | - Randall J Kimple
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
| | - Andrew M Baschnagel
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
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Ramesh S, Cifci A, Javeri S, Minne R, Longhurst CA, Nickel KP, Kimple RJ, Baschnagel AM. MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.26.564232. [PMID: 37961176 PMCID: PMC10634863 DOI: 10.1101/2023.10.26.564232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Purpose The objective of this study was to investigate the effects of inhibiting the MET receptor with capmatinib, a potent and clinically relevant ATP-competitive tyrosine kinase inhibitor, in combination with radiation in MET exon 14-mutated and MET-amplified non-small cell lung (NSCLC) cancer models. Methods and Materials In vitro effects of capmatinib and radiation on cell proliferation, colony formation, MET signaling, apoptosis, and DNA damage repair were evaluated. In vivo tumor responses were assessed in cell line xenograft and patient-derived xenograft models. Immunohistochemistry (IHC) was used to confirm in vitro results. Results In vitro clonogenic survival assays demonstrated radiosensitization with capmatinib in both MET exon 14-mutated and MET-amplified NSCLC cell lines. No radiation-enhancing effect was observed in MET wild-type NSCLC and human bronchial epithelial cell line. Minimal apoptosis was detected with the combination of capmatinib and radiation. Capmatinib plus radiation compared to radiation alone resulted in inhibition of DNA double-strand break repair as measured by prolonged expression of γH2AX. In vivo, the combination of capmatinib and radiation significantly delayed tumor growth compared to vehicle control, capmatinib alone, or radiation alone. IHC indicated inhibition of phospho-MET and phospho-S6 and a decrease in Ki67 with inhibition of MET. Conclusions Inhibition of MET with capmatinib enhanced the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.
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Affiliation(s)
- Shrey Ramesh
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Ahmet Cifci
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Saahil Javeri
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Rachel Minne
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Colin A. Longhurst
- Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Kwangok P. Nickel
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Randall J. Kimple
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Andrew M. Baschnagel
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
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Al-Jamaei AAH, de Visscher JGAM, Forouzanfar T, Brakenhoff RH, Leemans CR, Stikvoort A, Zandieh-Doulabi B, Helder MN. Radiation modulates expression and related activities of c-Met protein in oral tongue squamous cell carcinoma cell lines. J Cancer Res Clin Oncol 2023; 149:4173-4184. [PMID: 36053327 PMCID: PMC10349745 DOI: 10.1007/s00432-022-04307-4] [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: 07/15/2022] [Accepted: 08/15/2022] [Indexed: 10/14/2022]
Abstract
OBJECTIVES c-Met, a receptor tyrosine kinase, is involved in the growth, invasion and metastasis of a variety of cancers. In a set of cell lines from several solid tumors, a five-fold increase in c-Met expression after irradiation has been reported. This study aimed to assess if c-Met is likewise abundantly expressed in oral tongue squamous cell carcinoma (OTSCC) upon exposure to irradiation, followed by a Met-induced biological response. MATERIALS AND METHODS Six OTSCC cell lines were exposed to gamma radiation doses of 2, 4, and 6 Gray. The changes in c-Met protein levels were assessed by western blot and flow cytometry. c-Met gene expression, cell migration, proliferation and cell cycle assays were performed as phenotypic readouts. RESULTS Irradiation resulted in upregulation of c.Met in all cell lines with different time kinetics. On average the cells displayed minimal c-Met expression on their surface ranging from 5 to 30% of total protein. Abrupt downregulation of c-Met surface expression occurred one hour after radiation but recovered 48 h post-radiation. Intracellularly, the highest level of expression was found on day 5 after radiation exposure. Irradiation induced aggressive invasive potential of the cells as determined in cell migration assays, particularly in cell lines with the highest c-Met expression. CONCLUSIONS These results provide novel insights into both intracellular and extracellular dynamics of c-Met expression profiles upon irradiation of OTSCC cells in vitro. It might also suggest that radiation enhances cell migration, indicative of invasiveness, through c-Met up-regulation, at least for certain types of OTSCC cells.
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Affiliation(s)
- Aisha A H Al-Jamaei
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam UMC-Location, VUMC/Academic Centre for Dentistry Amsterdam (ACTA), PO Box 7057, 1007, Amsterdam, The Netherlands
- Amsterdam UMC-Location VUmc, Otolaryngology-Head and Neck Surgery, Cancer Center, Amsterdam, The Netherlands
| | - Jan G A M de Visscher
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam UMC-Location, VUMC/Academic Centre for Dentistry Amsterdam (ACTA), PO Box 7057, 1007, Amsterdam, The Netherlands
| | - Tymour Forouzanfar
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam UMC-Location, VUMC/Academic Centre for Dentistry Amsterdam (ACTA), PO Box 7057, 1007, Amsterdam, The Netherlands
| | - Ruud H Brakenhoff
- Amsterdam UMC-Location VUmc, Otolaryngology-Head and Neck Surgery, Cancer Center, Amsterdam, The Netherlands
| | - C René Leemans
- Department of Haematology, Amsterdam UMC-Location VUmc, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Arwen Stikvoort
- Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Behrouz Zandieh-Doulabi
- Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Marco N Helder
- Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam UMC-Location, VUMC/Academic Centre for Dentistry Amsterdam (ACTA), PO Box 7057, 1007, Amsterdam, The Netherlands.
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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Kinoshita M, Watanabe S, Mizojiri G, Sada A, Kai H, Masuike Y, Nagasawa Y, Maruyama K, Lee K, Ohata M, Ishikawa O, Oka H. Impact of pathological complete response following neoadjuvant chemotherapy (gemcitabine, nab-paclitaxel, S-1) and radiation for borderline resectable pancreatic cancer: a case report and review of literature. Surg Case Rep 2022; 8:169. [PMID: 36103018 PMCID: PMC9474757 DOI: 10.1186/s40792-022-01529-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/10/2022] [Indexed: 12/02/2022] Open
Abstract
Background Pancreatic cancer (PC) is a highly lethal malignancy, even if surgical resection is possible (median survival: < 30 months). The prognosis of borderline resectable pancreatic cancer (BR-PC) is even worse. There is no clear consensus on the optimal treatment strategy, including pre/postoperative therapy, for BR-PC. We report a patient with BR-PC who achieved clinical partial response with neoadjuvant chemoradiation therapy (NACRT) and underwent curative resection, resulting in pathological complete response (pCR). Case presentation A 71-year-old man with jaundice and liver dysfunction was referred to our department because of a 48-mm hypo-vascular mass in the pancreatic head with obstruction of the pancreatic and bile ducts and infiltration of superior mesenteric vein and portal vein. The lesion was identified as atypical cells which suggested adenocarcinoma by biopsy, and he was administered NACRT: gemcitabine and nab-paclitaxel, following S-1 and intensity modulated radiation therapy. After reduction in the tumor size (clinical partial response), pancreaticoduodenectomy was performed, and pCR achieved. Postoperative adjuvant chemotherapy with S-1 was initially administered and the patient is currently alive with no recurrence as of 2 years after surgery. Conclusions NACRT is a potentially useful treatment for BR-PC that may lead to pCR and help improve prognosis.
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Maksoud S. The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies. Mol Neurobiol 2022; 59:5326-5365. [PMID: 35696013 DOI: 10.1007/s12035-022-02915-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 06/05/2022] [Indexed: 12/12/2022]
Abstract
Gliomas are the most frequent type of tumor in the central nervous system, which exhibit properties that make their treatment difficult, such as cellular infiltration, heterogeneity, and the presence of stem-like cells responsible for tumor recurrence. The response of this type of tumor to chemoradiotherapy is poor, possibly due to a higher repair activity of the genetic material, among other causes. The DNA double-strand breaks are an important type of lesion to the genetic material, which have the potential to trigger processes of cell death or cause gene aberrations that could promote tumorigenesis. This review describes how the different cellular elements regulate the formation of DNA double-strand breaks and their repair in gliomas, discussing the therapeutic potential of the induction of this type of lesion and the suppression of its repair as a control mechanism of brain tumorigenesis.
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Affiliation(s)
- Semer Maksoud
- Experimental Therapeutics and Molecular Imaging Unit, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
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Tan C, Wang X, Wang X, Weng W, Ni SJ, Zhang M, Jiang H, Wang L, Huang D, Sheng W, Xu MD. Molecular signatures of tumor progression in pancreatic adenocarcinoma identified by energy metabolism characteristics. BMC Cancer 2022; 22:404. [PMID: 35418066 PMCID: PMC9006543 DOI: 10.1186/s12885-022-09487-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 04/04/2022] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND In this study, we performed a molecular evaluation of primary pancreatic adenocarcinoma (PAAD) based on the comprehensive analysis of energy metabolism-related gene (EMRG) expression profiles. METHODS Molecular subtypes were identified by nonnegative matrix clustering of 565 EMRGs. An overall survival (OS) predictive gene signature was developed and internally and externally validated based on three online PAAD datasets. Hub genes were identified in molecular subtypes by weighted gene correlation network analysis (WGCNA) coexpression algorithm analysis and considered as prognostic genes. LASSO cox regression was conducted to establish a robust prognostic gene model, a four-gene signature, which performed better in survival prediction than four previously reported models. In addition, a novel nomogram constructed by combining clinical features and the 4-gene signature showed high-confidence clinical utility. According to gene set enrichment analysis (GSEA), gene sets related to the high-risk group participate in the neuroactive ligand receptor interaction pathway. CONCLUSIONS In summary, EMRG-based molecular subtypes and prognostic gene models may provide a novel research direction for patient stratification and trials of targeted therapies.
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Affiliation(s)
- Cong Tan
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Xu Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Weiwei Weng
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Shu-Juan Ni
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Meng Zhang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Hesheng Jiang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Lei Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Dan Huang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Institute of Pathology, Fudan University, Shanghai, 200032, China.
| | - Mi-Die Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Institute of Pathology, Fudan University, Shanghai, 200032, China.
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To KKW, Cho WCS. Mesenchymal Epithelial Transition Factor (MET): A Key Player in Chemotherapy Resistance and an Emerging Target for Potentiating Cancer Immunotherapy. Curr Cancer Drug Targets 2022; 22:269-285. [PMID: 35255791 DOI: 10.2174/1568009622666220307105107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/10/2021] [Accepted: 01/10/2022] [Indexed: 11/22/2022]
Abstract
The MET protein is a cell surface receptor tyrosine kinase predominately expressed in epithelial cells. Upon binding of its only known ligand, hepatocyte growth factor (HGF), MET homodimerizes, phosphorylates, and stimulates intracellular signalling to drive cell proliferation. Amplification or hyperactivation of MET is frequently observed in various cancer types and it is associated with poor response to conventional and targeted chemotherapy. More recently, emerging evidence also suggests that MET/HGF signalling may play an immunosuppressive role and it could confer resistance to cancer immunotherapy. In this review, we summarized the preclinical and clinical evidence of MET's role in drug resistance to conventional chemotherapy, targeted therapy, and immunotherapy. Previous clinical trials investigating MET-targeted therapy in unselected or MET-overexpressing cancers yielded mostly unfavourable results. More recent clinical studies focusing on MET exon 14 alterations and MET amplification have produced encouraging treatment responses to MET inhibitor therapy. The translational relevance of MET inhibitor therapy to overcome drug resistance in cancer patients is discussed.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
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Mori S, Akita H, Kobayashi S, Iwagami Y, Yamada D, Tomimaru Y, Noda T, Gotoh K, Takeda Y, Tanemura M, Doki Y, Eguchi H. Inhibition of c-MET reverses radiation-induced malignant potential in pancreatic cancer. Cancer Lett 2021; 512:51-59. [PMID: 33965452 DOI: 10.1016/j.canlet.2021.04.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/22/2021] [Accepted: 04/11/2021] [Indexed: 01/27/2023]
Abstract
As a treatment option for PDAC, radiation therapy induces good local control. However, radiation also reportedly enhances the malignant potential (e.g., invasion and migration ability) in various cancers, thus increasing the risk of distant metastasis. It remains unclear how radiation induces malignant potential, and how such enhanced malignant potential can be suppressed. In the current study, we evaluated the sequential change of c-Met expression in pancreatic cancer cells following irradiation. We found that irradiation transiently induced c-Met expression in vitro. In an in vivo subcutaneous tumor mouse model, irradiation also enhanced downstream phosphorylated Met (p-Met). Furthermore, this enhancement of p-Met protein expression was suppressed by oral administration of the c-Met inhibitor INC280. Irradiated pancreatic cancer cells with enhanced c-Met expression exhibited higher malignant potential, including invasion and migration ability, compared with cells showing low c-Met expression. Pancreatic cancer cells that overexpressed c-met also showed enhanced malignant potential, which was reversed by c-Met inhibition. Additionally, c-Met inhibitor suppressed the metastatic potential in a liver metastasis mouse model using c-met-overexpressing cells. Overall, our present results revealed that irradiation could induce c-met expression in pancreatic cancer cells, leading to enhanced malignant potential (e.g., invasion and migration ability) and thus promoting distant metastasis. Moreover, a c-Met inhibitor could reverse this enhanced malignant potential.
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Affiliation(s)
- Soichiro Mori
- Department of Surgery, Osaka Rosai Hospital, Osaka, 591-8025, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, 541-8567, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Yutaka Takeda
- Department of Surgery, Kansai Rosai Hospital, Hyogo, 660-8511, Japan
| | - Masahiro Tanemura
- Department of Surgery, Rinku General Medical Center, Osaka, 598-8577, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
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Pothula SP, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Targeting HGF/c-MET Axis in Pancreatic Cancer. Int J Mol Sci 2020; 21:E9170. [PMID: 33271944 PMCID: PMC7730415 DOI: 10.3390/ijms21239170] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal-tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.
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Affiliation(s)
- Srinivasa P. Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - David Goldstein
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Romano C. Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Jeremy S. Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Minoti V. Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.P.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia;
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12
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El Darsa H, El Sayed R, Abdel-Rahman O. MET Inhibitors for the Treatment of Gastric Cancer: What's Their Potential? J Exp Pharmacol 2020; 12:349-361. [PMID: 33116950 PMCID: PMC7547764 DOI: 10.2147/jep.s242958] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.
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Affiliation(s)
- Haidar El Darsa
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rola El Sayed
- Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar Abdel-Rahman
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
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13
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Silva Paiva R, Gomes I, Casimiro S, Fernandes I, Costa L. c-Met expression in renal cell carcinoma with bone metastases. J Bone Oncol 2020; 25:100315. [PMID: 33024658 PMCID: PMC7527574 DOI: 10.1016/j.jbo.2020.100315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 12/12/2022] Open
Abstract
Bone is a common metastatic site in renal cell carcinoma (RCC). HGF/c-Met pathway is particularly relevant in tumors with bone metastases. c-Met/HGF pathway is involved in RCC progression, conferring poor prognosis. Several c-Met targeting therapies are currently in clinical development. c-Met expression is an important therapeutic target in RCC with bone metastases. Hepatocyte growth factor (HGF)/c-Met pathway is implicated in embryogenesis and organ development and differentiation. Germline or somatic mutations, chromosomal rearrangements, gene amplification, and transcriptional upregulation in MET or alterations in autocrine or paracrine c-Met signalling have been associated with cancer cell proliferation and survival, including in renal cell carcinoma (RCC), and associated with disease progression. HGF/c-Met pathway has been shown to be particularly relevant in tumors with bone metastases (BMs). However, the efficacy of targeting c-Met in bone metastatic disease, including in RCC, has not been proven. Therefore, further investigation is required focusing the particular role of HGF/c-Met pathway in bone microenvironment (BME) and how to effectively target this pathway in the context of bone metastatic disease.
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Key Words
- ALK, anaplastic lymphoma kinase gene
- AR, androgen receptor
- ATP, adenosine triphosphate
- AXL, AXL Receptor Tyrosine Kinase
- BME, bone microenvironment
- BMPs, bone morphogenetic proteins
- BMs, bone metastases
- BPs, Bisphosphonates
- BTAs, Bone-targeting agents
- Bone metastases
- CCL20, chemokine (C-C motif) ligand 20
- CI, confidence interval
- CRPC, Castration Resistant Prostate Cancer
- CSC, cancer stem cells
- CTC, circulating tumor cells
- CaSR, calcium/calcium-sensing receptor
- EMA, European Medicines Agency
- EMT, epithelial-to-mesenchymal transition
- FDA, US Food and Drug Administration
- FLT-3, FMS-like tyrosine kinase 3
- GEJ, Gastroesophageal Junction
- HCC, Hepatocellular Carcinoma
- HGF, hepatocyte growth factor
- HGF/c-Met
- HIF, hypoxia-inducible factors
- HR, hazard ratio
- IGF, insulin-like growth factor
- IGF2BP3, insulin mRNA Binding Protein-3
- IL, interleukin
- IRC, independent review committees
- KIT, tyrosine-protein kinase KIT
- Kidney cancer
- M-CSF, macrophage colony-stimulating factor
- MET, MET proto-oncogene, receptor tyrosine kinase
- NSCLC, non-small cell lung carcinoma
- ORR, overall response rate
- OS, overall survival
- PDGF, platelet-derived growth factor
- PFS, progression free survival
- PTHrP, parathyroid hormone-related peptide
- RANKL, receptor activator of nuclear factor-κB ligand
- RCC, renal cell carcinoma
- RET, rearranged during transfection proto-oncogene
- ROS, proto-oncogene tyrosine-protein kinase ROS
- RTK, receptor tyrosine kinase
- SCLC, Squamous Cell Lung Cancer
- SREs, skeletal-related events
- SSE, symptomatic skeletal events
- TGF-β, transforming growth factor-β
- TIE-2, Tyrosine-Protein Kinase Receptor TIE-2
- TKI, tyrosine kinase inhibitor
- TRKB, Tropomyosin receptor kinase B
- Targeted therapy
- VEGFR, vascular endothelial growth factor receptor
- VHL, Hippel-Lindau tumor suppressor gene
- ZA, zoledronic acid
- ccRCC, clear-cell RCC
- mAb, monoclonal antibodies
- pRCC, papillary renal cell carcinoma
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Affiliation(s)
- Rita Silva Paiva
- Oncology Division, Hospital de Santa Maria, CHULN, 1649-035 Lisboa, Portugal
| | - Inês Gomes
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Sandra Casimiro
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Isabel Fernandes
- Oncology Division, Hospital de Santa Maria, CHULN, 1649-035 Lisboa, Portugal
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Luís Costa
- Oncology Division, Hospital de Santa Maria, CHULN, 1649-035 Lisboa, Portugal
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
- Corresponding author at: Oncology Division, Hospital de Santa Maria, 1649-035 Lisbon, Portugal.
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14
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Sjöström M, Veenstra C, Holmberg E, Karlsson P, Killander F, Malmström P, Niméus E, Fernö M, Stål O. Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery: a long-term follow-up of the SweBCG91-RT randomised trial. Mol Oncol 2020; 14:2713-2726. [PMID: 32946618 PMCID: PMC7607179 DOI: 10.1002/1878-0261.12803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/19/2020] [Accepted: 09/11/2020] [Indexed: 01/15/2023] Open
Abstract
Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91‐RT trial, which randomly assigned patients to breast‐conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGFcyt and pMetcyt and high levels of pAktnuc derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037–0.30), 0.066 (0.016–0.28) and 0.094 (0.028–0.31), respectively] compared to patients with high expression of HGFcyt and pMetcyt, and low pAktnuc [HR: 0.36 (0.19–0.67), 0.35 (0.20–0.64) and 0.47 (0.32–0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P‐values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast‐conserving surgery concerning the risk of developing IBTR.
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Affiliation(s)
- Martin Sjöström
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
| | - Cynthia Veenstra
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Department of Oncology, Linköping University, Linköping, Sweden
| | - Erik Holmberg
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Per Karlsson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Fredrika Killander
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.,Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Per Malmström
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.,Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Emma Niméus
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.,Division of Surgery, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.,Department of Surgery, Skåne University Hospital, Lund, Sweden
| | - Mårten Fernö
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
| | - Olle Stål
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Department of Oncology, Linköping University, Linköping, Sweden
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15
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A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction. Radiother Oncol 2019; 138:9-16. [DOI: 10.1016/j.radonc.2019.05.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/07/2019] [Accepted: 05/10/2019] [Indexed: 01/05/2023]
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16
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Orlando E, Aebersold DM, Medová M, Zimmer Y. Oncogene addiction as a foundation of targeted cancer therapy: The paradigm of the MET receptor tyrosine kinase. Cancer Lett 2019; 443:189-202. [DOI: 10.1016/j.canlet.2018.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 12/13/2022]
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17
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Wolfe AR, Williams TM. Altering the response to radiation: radiosensitizers and targeted therapies in pancreatic ductal adenocarcinoma: preclinical and emerging clinical evidence. ACTA ACUST UNITED AC 2018; 1. [PMID: 32656528 DOI: 10.21037/apc.2018.08.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Radiation therapy continues to have an evolving role in pancreatic ductal adenocarcinoma. While metastatic failure likely contributes to the majority of patient mortality, achieving local control through surgery and/or radiation appears to be important as certain studies suggest that mortality is contributed by local failure. Many studies support that pancreatic cancer is a relatively radiation resistant tumor type. In addition, the ability to further improve radiation through dose escalation strategies in the non-metastatic setting is hampered by closeness of normal organs, including small bowel and stomach, to the tumor. Thus subverting molecular pathways that promote radiation resistance will be critical to further success of radiation in this disease. There is a wealth of preclinical data supporting the targeting of various molecular pathways in combination with radiation therapy, including DNA repair, cell cycle checkpoint proteins, receptor tyrosine kinases, oncoproteins, stem cells, and immunomodulation. A number of clinical trials have been completed or are on-going with novel molecular inhibitors. In this review, we summarize existing preclinical and clinical molecular strategies for improving the efficacy of radiation in pancreatic cancer, and highlight recent and ongoing clinical trials combining radiation and various targeted therapies.
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Affiliation(s)
- Adam R Wolfe
- Department of Radiation Oncology, The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210, USA
| | - Terence M Williams
- Department of Radiation Oncology, The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210, USA
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18
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Bhattacharya P, Shetake NG, Pandey BN, Kumar A. Receptor tyrosine kinase signaling in cancer radiotherapy and its targeting for tumor radiosensitization. Int J Radiat Biol 2018; 94:628-644. [DOI: 10.1080/09553002.2018.1478160] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Poushali Bhattacharya
- Radiation Signaling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Neena G. Shetake
- Radiation Signaling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Badri N. Pandey
- Radiation Signaling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Amit Kumar
- Radiation Signaling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India
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19
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Zeng J, Zhang H, Tan Y, Sun C, Liang Y, Yu J, Zou H. Aggregation of lipid rafts activates c-met and c-Src in non-small cell lung cancer cells. BMC Cancer 2018; 18:611. [PMID: 29848294 PMCID: PMC5977465 DOI: 10.1186/s12885-018-4501-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 05/11/2018] [Indexed: 11/30/2022] Open
Abstract
Background Activation of c-Met, a receptor tyrosine kinase, induces radiation therapy resistance in non-small cell lung cancer (NSCLC). The activated residual of c-Met is located in lipid rafts (Duhon et al. Mol Carcinog 49:739-49, 2010). Therefore, we hypothesized that disturbing the integrity of lipid rafts would restrain the activation of the c-Met protein and reverse radiation resistance in NSCLC. In this study, a series of experiments was performed to test this hypothesis. Methods NSCLC A549 and H1993 cells were incubated with methyl-β-cyclodextrin (MβCD), a lipid raft inhibitor, at different concentrations for 1 h before the cells were X-ray irradiated. The following methods were used: clonogenic (colony-forming) survival assays, flow cytometry (for cell cycle and apoptosis analyses), immunofluorescence microscopy (to show the distribution of proteins in lipid rafts), Western blotting, and biochemical lipid raft isolation (purifying lipid rafts to show the distribution of proteins in lipid rafts). Results Our results showed that X-ray irradiation induced the aggregation of lipid rafts in A549 cells, activated c-Met and c-Src, and induced c-Met and c-Src clustering to lipid rafts. More importantly, MβCD suppressed the proliferation of A549 and H1993 cells, and the combination of MβCD and radiation resulted in additive increases in A549 and H1993 cell apoptosis. Destroying the integrity of lipid rafts inhibited the aggregation of c-Met and c-Src to lipid rafts and reduced the expression of phosphorylated c-Met and phosphorylated c-Src in lipid rafts. Conclusions X-ray irradiation induced the aggregation of lipid rafts and the clustering of c-Met and c-Src to lipid rafts through both lipid raft-dependent and lipid raft-independent mechanisms. The lipid raft-dependent activation of c-Met and its downstream pathways played an important role in the development of radiation resistance in NSCLC cells mediated by c-Met. Further studies are still required to explore the molecular mechanisms of the activation of c-Met and c-Src in lipid rafts induced by radiation. Electronic supplementary material The online version of this article (10.1186/s12885-018-4501-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Juan Zeng
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China
| | - Heying Zhang
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China
| | - Yonggang Tan
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China
| | - Cheng Sun
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China
| | - Yusi Liang
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China
| | - Jinyang Yu
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China
| | - Huawei Zou
- The First Oncology Department, Shengjing Hospital affiliated with China Medical University, Shenyang, 110004, China.
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20
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Abstract
Radiotherapy remains one of the corner stones in the treatment of various malignancies and often leads to an improvement in overall survival. Nonetheless, pre-clinical evidence indicates that radiation can entail pro-metastatic effects via multiple pathways. Via direct actions on cancer cells and indirect actions on the tumor microenvironment, radiation has the potential to enhance epithelial-to-mesenchymal transition, invasion, migration, angiogenesis and metastasis. However, the data remains ambiguous and clinical observations that unequivocally prove these findings are lacking. In this review we discuss the pre-clinical and clinical data on the local and systemic effect of irradiation on the metastatic process with an emphasis on the molecular pathways involved.
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21
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Veenstra C, Pérez-Tenorio G, Stelling A, Karlsson E, Mirwani SM, Nordensköljd B, Fornander T, Stål O. Met and its ligand HGF are associated with clinical outcome in breast cancer. Oncotarget 2018; 7:37145-37159. [PMID: 27175600 PMCID: PMC5095065 DOI: 10.18632/oncotarget.9268] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 04/26/2016] [Indexed: 12/22/2022] Open
Abstract
Few biomarkers exist to predict radiotherapy response in breast cancer. In vitro studies suggest a role for Met and its ligand HGF. To study this suggested role, MET and HGF gene copy numbers were determined by droplet digital PCR in tumours from 205 pre-menopausal and 184 post-menopausal patients, both cohorts randomised to receive either chemo- or radiotherapy. MET amplification was found in 8% of the patients in both cohorts and HGF amplification in 7% and 6% of the patients in the pre- and post-menopausal cohort, respectively. Met, phosphorylated Met (pMet), and HGF protein expression was determined by immunohistochemistry in the pre-menopausal cohort. Met, pMet, and HGF was expressed in 33%, 53%, and 49% of the tumours, respectively. MET amplification was associated with increased risk of distant recurrence for patients receiving chemotherapy. For the pre-menopausal patients, expression of cytoplasmic pMet and HGF significantly predicted benefit from radiotherapy in terms of loco-regional recurrence. Similar trends were seen for MET and HGF copy gain. In the post-menopausal cohort, no significant association of benefit from radiotherapy with neither genes nor proteins was found. The present results do not support that inhibition of Met prior to radiotherapy would be favourable for pre-menopausal breast cancer, as previously suggested.
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Affiliation(s)
- Cynthia Veenstra
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
| | - Gizeh Pérez-Tenorio
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
| | - Anna Stelling
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
| | - Elin Karlsson
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
| | - Sanam Mirwani Mirwani
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
| | - Bo Nordensköljd
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
| | - Tommy Fornander
- Department of Oncology-Pathology, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden
| | - Olle Stål
- Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping, Sweden
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22
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Radiation-induced inflammatory cascade and its reverberating crosstalks as potential cause of post-radiotherapy second malignancies. Cancer Metastasis Rev 2017; 36:375-393. [DOI: 10.1007/s10555-017-9669-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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23
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Clémenson C, Chargari C, Liu W, Mondini M, Ferté C, Burbridge MF, Cattan V, Jacquet-Bescond A, Deutsch E. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy. Mol Cancer Ther 2017; 16:2107-2119. [PMID: 28619752 DOI: 10.1158/1535-7163.mct-17-0112] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/21/2017] [Accepted: 06/05/2017] [Indexed: 11/16/2022]
Abstract
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR.
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Affiliation(s)
- Céline Clémenson
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France
| | - Cyrus Chargari
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.,Gustave Roussy, Université Paris-Saclay, Département de Radiothérapie, Villejuif, France.,Institut de Recherche Biomédicale des Armées, Brétigny-Sur-Orge, France
| | - Winchygn Liu
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France
| | - Michele Mondini
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France
| | - Charles Ferté
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.,INSERM, U981, Villejuif, France
| | - Mike F Burbridge
- Oncology Unit, Institut de Recherches Internationales Servier, Suresnes, France
| | - Valérie Cattan
- Oncology Unit, Institut de Recherches Internationales Servier, Suresnes, France
| | | | - Eric Deutsch
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France. .,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.,Gustave Roussy, Université Paris-Saclay, Département de Radiothérapie, Villejuif, France.,Univ Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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24
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Tomihara H, Yamada D, Eguchi H, Iwagami Y, Noda T, Asaoka T, Wada H, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Mori M, Doki Y. MicroRNA-181b-5p, ETS1, and the c-Met pathway exacerbate the prognosis of pancreatic ductal adenocarcinoma after radiation therapy. Cancer Sci 2017; 108:398-407. [PMID: 28064436 PMCID: PMC5378264 DOI: 10.1111/cas.13159] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 12/27/2016] [Accepted: 12/29/2016] [Indexed: 12/20/2022] Open
Abstract
Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c‐Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c‐Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c‐Met expression, and these cells may exacerbate patients’ prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c‐Met expression; moreover, high c‐Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c‐Met upregulation in PDAC cells. We established GEM‐resistant and radioresistant PDAC cells to analyze the transcriptome involved in c‐Met expression. The microarray data for the established radiation‐resistant PDAC cells indicated miR‐181b‐5p downregulation, which targets ETS1, one of the transcription factors for c‐Met, and it was shown that radiation exposure induced c‐Met expression through ETS1 increase by the suppression of miR‐181b‐5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.
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Affiliation(s)
- Hideo Tomihara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yutaka Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.,Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.,Department of Surgery, Osaka Police Hospital, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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25
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Basha R, Mohiuddin Z, Rahim A, Ahmad S. Ovarian Cancer and Resistance to Therapies: Clinical and Laboratory Perspectives. DRUG RESISTANCE IN BACTERIA, FUNGI, MALARIA, AND CANCER 2017:511-537. [DOI: 10.1007/978-3-319-48683-3_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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26
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Vilalta M, Rafat M, Graves EE. Effects of radiation on metastasis and tumor cell migration. Cell Mol Life Sci 2016; 73:2999-3007. [PMID: 27022944 PMCID: PMC4956569 DOI: 10.1007/s00018-016-2210-5] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/25/2016] [Accepted: 03/22/2016] [Indexed: 12/25/2022]
Abstract
It is well known that tumor cells migrate from the primary lesion to distant sites to form metastases and that these lesions limit patient outcome in a majority of cases. However, the extent to which radiation influences this process and to which migration in turn alters radiation response remains controversial. There are preclinical and clinical reports showing that focal radiotherapy can both increase the development of distant metastasis, as well as that it can induce the regression of established metastases through the abscopal effect. More recently, preclinical studies have suggested that radiation can attract migrating tumor cells and may, thereby, facilitate tumor recurrence. In this review, we summarize these phenomena and their potential mechanisms of action, and evaluate their significance for modern radiation therapy strategies.
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Affiliation(s)
- Marta Vilalta
- Department of Radiation Oncology, Stanford University, 269 Campus Dr., CCSR South Rm. 1255A, Stanford, CA, 94305-5152, USA
| | - Marjan Rafat
- Department of Radiation Oncology, Stanford University, 269 Campus Dr., CCSR South Rm. 1255A, Stanford, CA, 94305-5152, USA
| | - Edward E Graves
- Department of Radiation Oncology, Stanford University, 269 Campus Dr., CCSR South Rm. 1255A, Stanford, CA, 94305-5152, USA.
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27
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Wang L, Zhou R, Zhao Y, Dong S, Zhang J, Luo Y, Huang N, Shi M, Bin J, Liao Y, Liao W. MACC-1 Promotes Endothelium-Dependent Angiogenesis in Gastric Cancer by Activating TWIST1/VEGF-A Signal Pathway. PLoS One 2016; 11:e0157137. [PMID: 27280289 PMCID: PMC4900635 DOI: 10.1371/journal.pone.0157137] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/25/2016] [Indexed: 12/15/2022] Open
Abstract
Endothelium-dependent angiogenesis is thought to be a crucial step in cancer progression. We previously reported that metastasis-associated in colon cancer-1 (MACC1) contributed to the vasculogenic mimicry in gastric cancer (GC), but it remains unknown whether MACC1 promotes endothelium-dependent angiogenesis of GC and whether TWIST1 is involved in this process. In the present study, we detected MACC1 expression and microvessel density (MVD) by immunohistochemistry in 159 patients with stage I-III GC, and investigated the role of TWIST1 and vascular endothelial growth factor A (VEGF-A) in MACC1-induced endothelium-dependent angiogenesis using nude mice with GC xenografts, and human umbilical vein endothelial cells (HUVECs) that were co-cultured with conditioned media from overexpression and interference MACC1 GC cells. We found that MACC1 expression was positively correlated with an increased MVD and tumor recurrence in GC patients. In GC xenograft models, MACC1 elevated MVD and upregulated the expression of VEGF-A as well as accelerated tumor growth. In addition, MACC1 obviously increased the expression of TWIST1 and induced tube-like formation of HUVECs, whereas attenuation of TWIST1 suppressed the protein expression of VEGF-A and repealed the effect of MACC1 on tube formation. Our findings shed light on the function of MACC1 in endothelium-dependent angiogenesis of GC and suggest potential prognostic and therapeutic value.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Epithelial-Mesenchymal Transition
- Human Umbilical Vein Endothelial Cells
- Humans
- Lymphatic Metastasis
- Male
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Neoplasm Recurrence, Local/blood supply
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/pathology
- Neoplasm Staging
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Prognosis
- Signal Transduction
- Stomach Neoplasms/blood supply
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Survival Rate
- Trans-Activators
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Twist-Related Protein 1/genetics
- Twist-Related Protein 1/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Lin Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Zhou
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Zhao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shaoting Dong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingwen Zhang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuhao Luo
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Na Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianping Bin
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yulin Liao
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- * E-mail:
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28
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Van Der Steen N, Giovannetti E, Pauwels P, Peters GJ, Hong DS, Cappuzzo F, Hirsch FR, Rolfo C. cMET Exon 14 Skipping: From the Structure to the Clinic. J Thorac Oncol 2016; 11:1423-32. [PMID: 27223456 DOI: 10.1016/j.jtho.2016.05.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/02/2016] [Accepted: 05/03/2016] [Indexed: 12/28/2022]
Abstract
The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMET) promotes cellular transformation, tumor motility, and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer. In particular, several cMET inhibitors have been developed as innovative therapeutic candidates and are currently under investigation in clinical trials. However, one of the challenges in establishing effective targeted treatments against cMET remains the accurate identification of biomarkers for the selection of responsive subsets of patients. Recently, splice site mutations have been discovered in cMET that lead to the skipping of exon 14, impairing the breakdown of the receptor. Patients with NSCLC who are carrying this splice variant typically overexpress the cMET receptor and show a response to small molecule inhibitors of cMET. Here, we review the main differences at the structural level between the wild-type and the splice variants of cMET and their influence on cMET signaling. We clarify the reason why this variant responds to small molecule inhibitors and their prognostic/predictive role.
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Affiliation(s)
- Nele Van Der Steen
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Pathology, Antwerp University Hospital, Edegem, Antwerp, Belgium; Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Cancer Pharmacology Lab, Italian Association for Cancer Research Start-Up Unit, University of Pisa, Hospital of Cisanello, Pisa, Italy
| | - Patrick Pauwels
- Department of Pathology, Antwerp University Hospital, Edegem, Antwerp, Belgium; Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - David S Hong
- Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | | | - Fred R Hirsch
- Division of Medical Oncology, University of Colorado, Aurora, Colorado
| | - Christian Rolfo
- Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium; Phase I Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Antwerp, Belgium.
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29
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Hepatocyte Growth Factor from a Clinical Perspective: A Pancreatic Cancer Challenge. Cancers (Basel) 2015; 7:1785-805. [PMID: 26404380 PMCID: PMC4586794 DOI: 10.3390/cancers7030861] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 08/07/2015] [Accepted: 08/17/2015] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and incidence rates are rising. Both detection and treatment options for pancreatic cancer are limited, providing a less than 5% five-year survival advantage. The need for new biomarkers for early detection and treatment of pancreatic cancer demands the efficient translation of bench knowledge to provide clinical benefit. One source of therapeutic resistance is the pancreatic tumor microenvironment, which is characterized by desmoplasia and hypoxia making it less conducive to current therapies. A major factor regulating desmoplasia and subsequently promoting chemoresistance in pancreatic cancer is hepatocyte growth factor (HGF), the sole ligand for c-MET (mesenchymal-epithelial transition), an epithelial tyrosine kinase receptor. Binding of HGF to c-MET leads to receptor dimerization and autophosphorylation resulting in the activation of multiple cellular processes that support cancer progression. Inhibiting activation of c-MET in cancer cells, in combination with other approaches for reducing desmoplasia in the tumor microenvironment, might significantly improve the success of chemotherapy. Therefore, HGF makes a potent novel target for developing therapeutic strategies in combination with existing drugs for treating pancreatic adenocarcinoma. This review provides a comprehensive analysis of HGF and its promising potential as a chemotherapeutic target for pancreatic cancer.
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Abstract
Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.
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31
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Raghav KPS, Gonzalez-Angulo AM, Blumenschein GR. Role of HGF/MET axis in resistance of lung cancer to contemporary management. Transl Lung Cancer Res 2015; 1:179-93. [PMID: 25806180 DOI: 10.3978/j.issn.2218-6751.2012.09.04] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Accepted: 09/17/2012] [Indexed: 12/14/2022]
Abstract
Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes. The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this MET/HGF axis interacts with other oncogenic signaling pathways such as the epidermal growth factor receptor (EGFR) pathway and the vascular endothelial growth factor receptor (VEGFR) pathway. This functional cross-talk forms the basis for the role of MET/HGF axis in resistance against anti-EGFR and anti-VEGF targeted therapies. MET and/or HGF overexpression from gene amplification and activation are mechanisms of resistance to cetuximab and EGFR-TKIs. VEGF inhibition promotes hypoxia induced transcriptional activation of MET proto-oncogene that promotes angiogenesis and confers resistance to anti-angiogenic therapy. An extensive understanding of these resistance mechanisms is essential to design combinations with enhanced cytotoxic effects. Lung cancer treatment is challenging. Current therapies have limited efficacy due to primary and acquired resistance. The MET/HGF axis plays a key role in development of this resistance. Combining MET/HGF inhibitors with chemotherapy, radiotherapy and targeted therapy holds promise for improving outcomes.
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32
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Van Der Steen N, Pauwels P, Gil-Bazo I, Castañon E, Raez L, Cappuzzo F, Rolfo C. cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance. Cancers (Basel) 2015; 7:556-73. [PMID: 25815459 PMCID: PMC4491670 DOI: 10.3390/cancers7020556] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 02/19/2015] [Accepted: 03/05/2015] [Indexed: 01/05/2023] Open
Abstract
In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR) inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism.
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Affiliation(s)
- Nele Van Der Steen
- Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium; E-Mails: (N.V.D.S.); (P.P.)
| | - Patrick Pauwels
- Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium; E-Mails: (N.V.D.S.); (P.P.)
- Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650, Belgium
| | - Ignacio Gil-Bazo
- Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008, Spain; E-Mails: (I.G.-B.); (E.C.)
| | - Eduardo Castañon
- Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008, Spain; E-Mails: (I.G.-B.); (E.C.)
- Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650, Belgium
| | - Luis Raez
- Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024, USA; E-Mail:
| | - Federico Cappuzzo
- Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024, USA; E-Mail:
| | - Christian Rolfo
- Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610, Belgium; E-Mails: (N.V.D.S.); (P.P.)
- Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650, Belgium
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +32-3-821-3646; Fax: +32-3-825-1592
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Han Y, Luo Y, Zhao J, Li M, Jiang Y. Overexpression of c-Met increases the tumor invasion of human prostate LNCaP cancer cells in vitro and in vivo.. Oncol Lett 2014; 8:1618-1624. [PMID: 25202379 PMCID: PMC4156182 DOI: 10.3892/ol.2014.2390] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Accepted: 05/15/2014] [Indexed: 12/15/2022] Open
Abstract
c-Met is a transmembrane tyrosine kinase receptor that may be activated by hepatocyte growth factor, an inducer of epithelial-mesenchymal transition (EMT), to regulate the associated downstream gene expression. This process is critical to cell migration in normal and pathological conditions. In the present study, the function of c-Met in the process of EMT was investigated in prostate cancer. Initially, a c-Met stable expression cell line was constructed using EMT- and c-Met-negative LNCaP prostate cancer cells. Following the identification of c-Met in the transfected cells, the changes in EMT, phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase pathway biomarkers were determined by western blot analysis. MTT, soft agar and Transwell assays, and xenograft studies were used to investigate the effects of c-Met on the proliferation, migration and tumorigenicity of LNCaP cells. The results of the present study revealed downregulation of E-cadherin and upregulation of vimentin in LNCaP-Met cells. The results demonstrated that c-Met enhanced proliferation, migration and tumorigenicity capacity when compared with LNCaP and LNCaP-pcDNA3.1 cells. Furthermore, these EMT-like changes were mediated via the PI3K and mitogen-activated protein kinase signaling pathways. The present study clearly demonstrates a crucial function for c-Met in EMT development in prostate cancer. c-Met-targeted treatment may be an effective adjuvant therapy for improving survival rates in patients with prostate cancer.
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Affiliation(s)
- Yili Han
- Department of Urology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, P.R. China
| | - Yong Luo
- Department of Urology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, P.R. China
| | - Jiahui Zhao
- Department of Urology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, P.R. China
| | - Mingchuan Li
- Department of Urology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, P.R. China
| | - Yongguang Jiang
- Department of Urology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, P.R. China
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Basilico C, Hultberg A, Blanchetot C, de Jonge N, Festjens E, Hanssens V, Osepa SI, De Boeck G, Mira A, Cazzanti M, Morello V, Dreier T, Saunders M, de Haard H, Michieli P. Four individually druggable MET hotspots mediate HGF-driven tumor progression. J Clin Invest 2014; 124:3172-86. [PMID: 24865428 DOI: 10.1172/jci72316] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 04/03/2014] [Indexed: 12/22/2022] Open
Abstract
Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2-3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2-3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2-3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer.
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35
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Kumazawa S, Kajiyama H, Umezu T, Mizuno M, Suzuki S, Yamamoto E, Mitsui H, Sekiya R, Shibata K, Kikkawa F. Possible association between stem-like hallmark and radioresistance in human cervical carcinoma cells. J Obstet Gynaecol Res 2014; 40:1389-98. [DOI: 10.1111/jog.12357] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 11/12/2013] [Indexed: 01/20/2023]
Affiliation(s)
- Shoko Kumazawa
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Tomokazu Umezu
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Mika Mizuno
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Shiro Suzuki
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Eiko Yamamoto
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Hiroko Mitsui
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Ryuichiro Sekiya
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Kiyosumi Shibata
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology; Nagoya University Graduate School of Medicine; Nagoya Japan
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The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response-Biological and Clinical Aspects. Cancers (Basel) 2013; 6:1-27. [PMID: 24378750 PMCID: PMC3980615 DOI: 10.3390/cancers6010001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 12/06/2013] [Accepted: 12/06/2013] [Indexed: 02/07/2023] Open
Abstract
Radiation therapy remains an imperative treatment modality for numerous malignancies. Enduring significant technical achievements both on the levels of treatment planning and radiation delivery have led to improvements in local control of tumor growth and reduction in healthy tissue toxicity. Nevertheless, resistance mechanisms, which presumably also involve activation of DNA damage response signaling pathways that eventually may account for loco-regional relapse and consequent tumor progression, still remain a critical problem. Accumulating data suggest that signaling via growth factor receptor tyrosine kinases, which are aberrantly expressed in many tumors, may interfere with the cytotoxic impact of ionizing radiation via the direct activation of the DNA damage response, leading eventually to so-called tumor radioresistance. The aim of this review is to overview the current known data that support a molecular crosstalk between the hepatocyte growth factor receptor tyrosine kinase MET and the DNA damage response. Apart of extending well established concepts over MET biology beyond its function as a growth factor receptor, these observations directly relate to the role of its aberrant activity in resistance to DNA damaging agents, such as ionizing radiation, which are routinely used in cancer therapy and advocate tumor sensitization towards DNA damaging agents in combination with MET targeting.
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Knockdown of RON receptor kinase delays but does not prevent tumor progression while enhancing HGF/MET signaling in pancreatic cancer cell lines. Oncogenesis 2013; 2:e76. [PMID: 24100611 PMCID: PMC3816215 DOI: 10.1038/oncsis.2013.36] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 06/07/2013] [Accepted: 08/13/2013] [Indexed: 12/14/2022] Open
Abstract
In this study, the role of RON (receptor originated from nantes) in tumor progression was further investigated in context with MET expression and activity. RON and MET expressions were not detected in an immortalized normal human pancreas cell line (HPNE), but were co-expressed in five of seven pancreatic ductal adenocarcinoma (PDAC) cell lines (PANC-1, BxPC-3, Capan-2, CFPAC-1 and AsPC-1). RON expression was knocked down by an shRNA approach in two PDAC cell lines (BxPC-3 and CFPAC-1) that co-express MET. Knockdown of RON significantly inhibited cell growth, clonogenicity and macrophage stimulating protein (MSP), RON ligand induced invasion by in vitro assays and significantly inhibited tumor growth (P<0.001) and metastasis (P<0.009) in an orthotopic pancreatic cancer mouse model at week 7. However, by week 9, the mice implanted with RON knockdown cells had developed similar size primary tumors and metastases compared with that seen in the control group at week 7. Western blotting and immunohistochemistry analyses showed that MET remains highly expressed in cells and tumor tissues where RON was knocked down. Moreover, knockdown of RON did not prevent hepatocyte growth factor (HGF) stimulated invasion in in vitro Matrigel assays. Treating cells with MSP induced the transphosphorylation of MET, suggesting that signaling may be modulated by relative levels of RON and MET receptors and their corresponding ligands. To this point, HGF treatment of RON knockdown cells caused an increase in intensity and duration of MET signaling, suggesting that MET signaling may compensate for loss of RON signaling. Treatment of cells with an MET inhibitor, PHA-665752, had minimal effects on inhibiting cell growth but significantly inhibited cell invasion induce by ligands for either MET or RON. These results suggest that HGF/MET signaling may have a more important role in tumor cell invasion and metastasis rather than in tumor cell proliferation. This study indicates that specific inhibition of RON delays but does not prevent progression of PDAC. Moreover, specific signaling may be modulated by the interaction of RON and MET receptors. This dynamic interaction of RON and MET in pancreatic cancer cells suggests that dual targeting of both RON and MET will be preferable to inhibition of either target alone.
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Landi L, Minuti G, D’Incecco A, Salvini J, Cappuzzo F. MET overexpression and gene amplification in NSCLC: a clinical perspective. LUNG CANCER (AUCKLAND, N.Z.) 2013; 4:15-25. [PMID: 28210131 PMCID: PMC5217438 DOI: 10.2147/lctt.s35168] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The transmembrane tyrosine kinase mesenchymal-epidermal transition (MET) receptor and its ligand, hepatocyte growth factor, also known as scatter factor, have recently been identified as novel promising targets in several human malignancies, including non-small cell lung cancer (NSCLC). Amplification, mutation, or overexpression of the MET gene can result in aberrant activation of the MET axis, leading to migration, invasion, proliferation, metastasis, and neoangiogenesis of cancer cells, suggesting that interfering with the MET/hepatocyte growth factor pathway could represent a potential antitumor strategy. While the role of MET mutations in NSCLC is not as yet fully understood, retrospective studies have shown that an increased MET gene copy number is a negative prognostic factor. In NSCLC, amplification of the MET gene is a relatively rare event, occurring in approximately 4% of patients not previously exposed to systemic therapies and in up to 20% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. In preclinical models, the presence of MET amplification is a predictor of high sensitivity to anti-MET compounds, and several agents have entered in clinical trials for patients having advanced disease, with promising results. The aim of the present review is to summarize available data on the role of MET in NSCLC and to describe therapeutic strategies under investigation.
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Affiliation(s)
- Lorenza Landi
- Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy
| | - Gabriele Minuti
- Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy
| | - Armida D’Incecco
- Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy
| | - Jessica Salvini
- Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy
| | - Federico Cappuzzo
- Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy
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Abstract
Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.
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Bhardwaj V, Cascone T, Cortez MA, Amini A, Evans J, Komaki RU, Heymach JV, Welsh JW. Modulation of c-Met signaling and cellular sensitivity to radiation: potential implications for therapy. Cancer 2013; 119:1768-75. [PMID: 23423860 DOI: 10.1002/cncr.27965] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 12/12/2012] [Accepted: 12/18/2012] [Indexed: 12/13/2022]
Abstract
The c-Met/hepatocyte growth factor receptor and its family members are known to promote cancer cell migration and invasion. Signaling within and beyond this pathway contributes to the systemic spread of metastases through induction of the epithelial-mesenchymal transition, a process also implicated in mediating resistance to current anticancer therapies, including radiation. Induction of c-Met has also been observed after irradiation, suggesting that c-Met participates in radiation-induced disease progression through the epithelial-mesenchymal transition. Therefore, c-Met inhibition is an attractive target for potentially mitigating radiation resistance. This article summarizes key findings regarding crosstalk between radiotherapy and c-Met and discusses studies performed to date in which c-Met inhibition was used as a strategy to increase cellular radiosensitivity.
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Affiliation(s)
- Vikas Bhardwaj
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression. J Thorac Oncol 2012; 7:1211-7. [PMID: 22617250 DOI: 10.1097/jto.0b013e318257cc89] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION The radiation doses used to treat unresectable lung cancer are often limited by the proximity of normal tissues. Overexpression of c-Met, a receptor tyrosine kinase, occurs in about half of non-small-cell lung cancers (NSCLCs) and has been associated with resistance to radiation therapy and poor patient survival. We hypothesized that inhibiting c-Met would increase the sensitivity of NSCLC cells to radiation, enhancing the therapeutic ratio, which may potentially translate into improved local control. METHODS We tested the radiosensitivity of two high-c-Met-expressing NSCLC lines, EBC-1 and H1993, and two low-c-Met-expressing lines, A549 and H460, with and without the small-molecule c-Met inhibitor MK-8033. Proliferation and protein expression were measured with clonogenic survival assays and Western blotting, respectively. γ-H2AX levels were evaluated by immunofluorescence staining. RESULTS MK-8033 radiosensitized the high-c-Met-expressing EBC-1 and H1993 cells but not the low-c-Met-expressing cell lines A549 and H460. However, irradiation of A549 and H460 cells increased the expression of c-Met protein at 30 minutes after the irradiation. Subsequent targeting of this up-regulated c-Met by using MK-8033 followed by a second radiation dose reduced the clonogenic survival of both A549 and H460 cells. MK-8033 reduced the levels of radiation-induced phosphorylated (activated) c-Met in A549 cells. CONCLUSIONS These results suggest that inhibition of c-Met could be an effective strategy to radiosensitize NSCLC tumors with high basal c-Met expression or tumors that acquired resistance to radiation because of up-regulation of c-Met.
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Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2012; 2:270-87. [PMID: 22585997 DOI: 10.1158/2159-8290.cd-11-0240] [Citation(s) in RCA: 327] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met. SIGNIFICANCE This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis.
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Affiliation(s)
- Barbara Sennino
- Comprehensive Cancer Center, Department of Anatomy, University of California-San Francisco (UCSF), San Francisco, CA 94143-0452, USA
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Patel ZS, Grugan KD, Rustgi AK, Cucinotta FA, Huff JL. Ionizing radiation enhances esophageal epithelial cell migration and invasion through a paracrine mechanism involving stromal-derived hepatocyte growth factor. Radiat Res 2011; 177:200-8. [PMID: 22077339 DOI: 10.1667/rr2790.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Esophageal cancer is the sixth leading cause of cancer death worldwide and the seventh leading cause of cancer death in the U.S. male population. Ionizing radiation exposure is a risk factor for development of esophageal squamous cell carcinoma, a histological subtype of esophageal cancer that is highly aggressive and is associated with poor patient prognosis. This study investigated the effects of ionizing radiation on the microenvironment and intercellular communication as it relates to esophageal carcinogenesis. We demonstrate that normal esophageal epithelial cells exhibited increased migration and invasion when cultured in the presence of irradiated stromal fibroblasts or with conditioned medium derived from irradiated stromal fibroblasts. Cytokine antibody arrays and ELISAs were used to identify hepatocyte growth factor (HGF) as an abundant protein that is secreted by esophageal fibroblasts at twofold increased levels in culture medium after γ irradiation. Reverse transcription qPCR analysis confirmed an approximately 50% increase in mRNA levels for HGF at 1 h in irradiated fibroblasts compared to unirradiated controls. Recombinant HGF stimulated increased wound healing, migration and invasion of esophageal epithelial cells, while blocking antibodies against HGF significantly decreased migration and invasion of epithelial cells in coculture with irradiated fibroblasts. Since HGF is known to direct cell migration, invasion and metastasis in a variety of tissues, including the esophagus, its modulation by ionizing radiation may have important implications for nontargeted pathways that influence radiation carcinogenesis in the esophagus.
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Affiliation(s)
- Zarana S Patel
- Division of Space Life Sciences, Universities Space Research Association, Houston, Texas 77058, USA
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De Bacco F, Luraghi P, Medico E, Reato G, Girolami F, Perera T, Gabriele P, Comoglio PM, Boccaccio C. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J Natl Cancer Inst 2011; 103:645-61. [PMID: 21464397 DOI: 10.1093/jnci/djr093] [Citation(s) in RCA: 268] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Ionizing radiation (IR) is effectively used in cancer therapy. However, in subsets of patients, a few radioresistant cancer cells survive and cause disease relapse with metastatic progression. The MET oncogene encodes the hepatocyte growth factor (HGF) receptor and is known to drive "invasive growth", a regenerative and prosurvival program unduly activated in metastasis. METHODS Human tumor cell lines (MDA-MB-231, MDA-MB-435S, U251) were subjected to therapeutic doses of IR. MET mRNA, and protein expression and signal transduction were compared in treated and untreated cells, and the involvement of the DNA-damage sensor ataxia telangiectasia mutated (ATM) and the transcription factor nuclear factor kappa B (NF-κB) in activating MET transcription were analyzed by immunoblotting, chromatin immunoprecipitation, and use of NF-κB silencing RNA (siRNA). Cell invasiveness was measured in wound healing and transwell assays, and cell survival was measured in viability and clonogenic assays. MET was inhibited by siRNA or small-molecule kinase inhibitors (PHA665752 or JNJ-38877605). Combinations of MET-targeted therapy and radiotherapy were assessed in MDA-MB-231 and U251 xenografts (n = 5-6 mice per group). All P values were from two-sided tests. RESULTS After irradiation, MET expression in cell lines was increased up to fivefold via activation of ATM and NF-κB. MET overexpression increased ligand-independent MET phosphorylation and signal transduction, and rendered cells more sensitive to HGF. Irradiated cells became more invasive via a MET-dependent mechanism that was further enhanced in the presence of HGF. MET silencing by siRNA or inhibition of its kinase activity by treatment with PHA665752 or JNJ-38877605 counteracted radiation-induced invasiveness, promoted apoptosis, and prevented cells from resuming proliferation after irradiation in vitro. Treatment with MET inhibitors enhanced the efficacy of IR to stop the growth of or to induce the regression of xenografts (eg, at day 13, U251 xenografts, mean volume increase relative to mean tumor volume at day 0: vehicle = 438%, 5 Gy IR = 151%, 5 Gy IR + JNJ-38877605 = 76%; difference, IR vs JNJ-38877604 + IR = 75%, 95% CI = 59% to 91%, P = .01). CONCLUSION IR induces overexpression and activity of the MET oncogene through the ATM-NF-κB signaling pathway; MET, in turn, promotes cell invasion and protects cells from apoptosis, thus supporting radioresistance. Drugs targeting MET increase tumor cell radiosensitivity and prevent radiation-induced invasiveness.
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Affiliation(s)
- Francesca De Bacco
- IRCC-Institute for Cancer Research at Candiolo, University of Turin Medical School, Candiolo, Italy
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Buchanan IM, Scott T, Tandle AT, Burgan WE, Burgess TL, Tofilon PJ, Camphausen K. Radiosensitization of glioma cells by modulation of Met signalling with the hepatocyte growth factor neutralizing antibody, AMG102. J Cell Mol Med 2010; 15:1999-2006. [PMID: 20629992 PMCID: PMC2976812 DOI: 10.1111/j.1582-4934.2010.01122.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The hepatocyte growth factor (HGF)/Met signalling pathway is up-regulated in many cancers, with downstream mediators playing a role in DNA double strand break repair. Previous studies have shown increased radiosensitization of tumours through modulation of Met signalling by genetic methods. We investigated the effects of the anti-HGF monoclonal antibody, AMG102, on the response to ionizing radiation in a model of glioblastoma multiforme in vitro and in vivo. Radiosensitivity was evaluated in vitro in the U-87 MG human glioma cell line. Met activation was measured by Western blot, and the effect on survival following radiation was evaluated by clonogenic assay. Mechanism of cell death was evaluated by apoptosis and mitotic catastrophe assays. DNA damage was quantitated by γH2AX foci and neutral comet assay. Growth kinetics of subcutaneous tumours was used to assess the effects of AMG102 on in vivo tumour radiosensitivity. AMG102 inhibited Met activation after irradiation. An enhancement of radiation cell killing was shown with no toxicity using drug alone. Retention of γH2AX foci at 6 and 24 hrs following the drug/radiation combination indicated an inhibition of DNA repair following radiation, and comet assay confirmed DNA damage persisting over the same duration. At 48 and 72 hrs following radiation, a significant increase of cells undergoing mitotic catastrophe was seen in the drug/radiation treated cells. Growth of subcutaneous tumours was slowed in combination treated mice, with an effect that was greater than additive for each modality individually. Modulation of Met signalling with AMG102 may prove a novel radiation sensitizing strategy. Our data indicate that DNA repair processes downstream of Met are impaired leading to increased cell death through mitotic catastrophe.
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Affiliation(s)
- Ian M Buchanan
- Radiation Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
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Hamada N, Imaoka T, Masunaga SI, Ogata T, Okayasu R, Takahashi A, Kato TA, Kobayashi Y, Ohnishi T, Ono K, Shimada Y, Teshima T. Recent advances in the biology of heavy-ion cancer therapy. JOURNAL OF RADIATION RESEARCH 2010; 51:365-383. [PMID: 20679739 DOI: 10.1269/jrr.09137] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Superb biological effectiveness and dose conformity represent a rationale for heavy-ion therapy, which has thus far achieved good cancer controllability while sparing critical normal organs. Immediately after irradiation, heavy ions produce dense ionization along their trajectories, cause irreparable clustered DNA damage, and alter cellular ultrastructure. These ions, as a consequence, inactivate cells more effectively with less cell-cycle and oxygen dependence than conventional photons. The modes of heavy ion-induced cell death/inactivation include apoptosis, necrosis, autophagy, premature senescence, accelerated differentiation, delayed reproductive death of progeny cells, and bystander cell death. This paper briefly reviews the current knowledge of the biological aspects of heavy-ion therapy, with emphasis on the authors' recent findings. The topics include (i) repair mechanisms of heavy ion-induced DNA damage, (ii) superior effects of heavy ions on radioresistant tumor cells (intratumor quiescent cell population, TP53-mutated and BCL2-overexpressing tumors), (iii) novel capacity of heavy ions in suppressing cancer metastasis and neoangiogenesis, and (iv) potential of heavy ions to induce secondary (especially breast) cancer.
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Affiliation(s)
- Nobuyuki Hamada
- Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, Komae, Tokyo, Japan.
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Mascarenhas JB, Young KP, Littlejohn EL, Yoo BK, Salgia R, Lang D. PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through activation of the MET tyrosine kinase receptor gene. J Biol Chem 2009; 284:27524-32. [PMID: 19651775 DOI: 10.1074/jbc.m109.047209] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.
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Marchetti F, Coleman MA, Jones IM, Wyrobek AJ. Candidate protein biodosimeters of human exposure to ionizing radiation. Int J Radiat Biol 2009; 82:605-39. [PMID: 17050475 DOI: 10.1080/09553000600930103] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE To conduct a literature review of candidate protein biomarkers for individual radiation biodosimetry of exposure to ionizing radiation. MATERIALS AND METHODS Reviewed approximately 300 publications (1973 - April 2006) that reported protein effects in mammalian systems after either in vivo or in vitro radiation exposure. RESULTS We found 261 radiation-responsive proteins including 173 human proteins. Most of the studies used high doses of ionizing radiation (>4 Gy) and had no information on dose- or time-responses. The majority of the proteins showed increased amounts or changes in phosphorylation states within 24 h after exposure (range: 1.5- to 10-fold). Of the 47 proteins that are responsive at doses of 1 Gy and below, 6 showed phosphorylation changes at doses below 10 cGy. Proteins were assigned to 9 groups based on consistency of response across species, dose- and time-response information and known role in the radiation damage response. CONCLUSIONS ATM (Ataxia telengiectasia mutated), H2AX (histone 2AX), CDKN1A (Cyclin-dependent kinase inhibitor 1A), and TP53 (tumor protein 53) are top candidate radiation protein biomarkers. Furthermore, we recommend a panel of protein biomarkers, each with different dose and time optima, to improve individual radiation biodosimetry for discriminating between low-, moderate-, and high-dose exposures. Our findings have applications for early triage and follow-up medical assessments.
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Affiliation(s)
- Francesco Marchetti
- Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA
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Egami T, Ohuchida K, Mizumoto K, Onimaru M, Toma H, Nishio S, Nagai E, Matsumoto K, Nakamura T, Tanaka M. Radiation Enhances Adenoviral Gene Therapy in Pancreatic Cancer via Activation of Cytomegalovirus Promoter and Increased Adenovirus Uptake. Clin Cancer Res 2008; 14:1859-67. [DOI: 10.1158/1078-0432.ccr-07-0933] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Abstract
Purpose: Adenovirus-mediated gene therapy combined with radiation is expected to be a new approach to treat pancreatic cancer. However, there are no reports of definitive effects of radiation on adenovirus-mediated gene therapies. In the present study, we investigated the effect of radiation on the transduction efficiency of an adenovirus-based gene therapy.
Experimental Design: We used adenovirus expressing NK4 (Ad-NK4), an antagonist for hepatocyte growth factor, as a representative gene therapy. Pancreatic cancer cells preinfected with Ad-NK4 were irradiated, and NK4 levels in culture media of these cells were measured. We investigated cytomegalovirus (CMV) promoter activity and uptake of adenovirus in these cells. To examine the effect of radiation in vivo, Ad-NK4 was given to irradiated subcutaneous tumors in nude mice, and NK4 levels in tumors were measured.
Results: NK4 levels in culture media of irradiated cells were 4.5-fold (P < 0.01) higher than those of nonirradiated cells. Radiation enhanced activation of the CMV promoter and adenovirus uptake (P < 0.01), leading to increased levels of NK4. We found that activation of p38 mitogen-activated protein kinase and up-regulation of dynamin 2 may be involved in the radiation-induced activation of the CMV promoter and adenovirus uptake, respectively. NK4 levels in irradiated tumors were 5.8-fold (P = 0.017) higher than those in nonirradiated tumors.
Conclusions: The present findings suggest that radiation significantly improves the efficiency of adenovirus-mediated gene transfer in pancreatic cancer and probably contributes to decreasing the dose of adenovirus required for gene transfer and controlling side effects of adenovirus infection in nonirradiated normal tissue.
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Affiliation(s)
- Takuya Egami
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Kenoki Ohuchida
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Kazuhiro Mizumoto
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Manabu Onimaru
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Hiroki Toma
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Shoko Nishio
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Eishi Nagai
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
| | - Kunio Matsumoto
- 2Department of Oncology, Division of Biochemistry, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Toshikazu Nakamura
- 2Department of Oncology, Division of Biochemistry, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masao Tanaka
- 1Department of Surgery and Oncology and Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan and
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Müller MW, Giese NA, Swiercz JM, Ceyhan GO, Esposito I, Hinz U, Büchler P, Giese T, Büchler MW, Offermanns S, Friess H. Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int J Cancer 2007; 121:2421-33. [PMID: 17631638 DOI: 10.1002/ijc.22949] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Neural alterations and aberrantly expressed nerve-specific factors promoting tumor progression are known to contribute to pancreatic cancer's extremely poor prognosis. Despite hints that axon guidance factor semaphorin 3A (SEMA3A) may function as a tumor inhibitor, its clinical importance and therapeutic potential have not yet been explored. The present study investigated the role of SEMA3A and its receptors-plexins A1-A4 (PLXNA1-A4) and neuropilin-1 (NRP1)-in pancreatic cancer. QRT-PCR and immunohistochemical analyses revealed overexpression of SEMA3A, NRP1 and PLXNA1 in metaplastic ducts, malignant cells and nerves of cancerous specimens, and showed that elevated levels of corresponding mRNA (6.8-fold, 2.0-fold and 1.5-fold, respectively) clearly correlated with negative clinicopathological manifestations such as shorter survival (SEMA3A and PLXNA1) and a lesser degree of tumor differentiation (NRP1) in Stages I-III patients. High SEMA3A expression in pancreata of Stage IV M1 patients and in peritoneal metastases, and consequent functional studies indicated that poor clinical outcome might be related to the ability of SEMA3A to promote dissemination and invasiveness of pancreatic cancer cells through activation of multiple pathways involving Rac1, GSK3b or p42/p44 MAPK, but not E- to N-cadherin switch, MMP-9 or VEGF induction. Thus, this study is the first to quantify expression of the SEMA3A system in human malignancy and to show that overexpression of SEMA3A by nerves and transformed cells leads to a SEMA3A-rich environment which may favor malignant activities of tumor cells. Furthermore, negative clinicopathological correlations suggest that SEMA3A might represent a novel intervention target but not a treatment option for pancreatic cancer patients.
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Affiliation(s)
- Michael W Müller
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
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