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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [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: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Mohan CD, Shanmugam MK, Gowda SGS, Chinnathambi A, Rangappa KS, Sethi G. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155379. [PMID: 38503157 DOI: 10.1016/j.phymed.2024.155379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
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Affiliation(s)
- Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226 001, India
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kanchugarakoppal S Rangappa
- Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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Qin A, Qin Y, Lee J, Musket A, Ying M, Krenciute G, Marincola FM, Yao ZQ, Musich PR, Xie Q. Tyrosine kinase signaling-independent MET-targeting with CAR-T cells. J Transl Med 2023; 21:682. [PMID: 37779207 PMCID: PMC10544186 DOI: 10.1186/s12967-023-04521-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/11/2023] [Indexed: 10/03/2023] Open
Abstract
BACKGROUND Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. METHODS MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. RESULTS MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. CONCLUSION We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo.
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Affiliation(s)
- Anna Qin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Yuan Qin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Joseph Lee
- Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Anna Musket
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Mingyao Ying
- Department of Neurology, Hugo W. Moser Research Institute at Kennedy Krieger, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Giedre Krenciute
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | | | - Zhi Q Yao
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
- Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Phillip R Musich
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Qian Xie
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
- Center of Excellence for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
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Yang MH, Lee M, Deivasigamani A, Le DD, Mohan CD, Hui KM, Sethi G, Ahn KS. Decanoic Acid Exerts Its Anti-Tumor Effects via Targeting c-Met Signaling Cascades in Hepatocellular Carcinoma Model. Cancers (Basel) 2023; 15:4681. [PMID: 37835375 PMCID: PMC10571573 DOI: 10.3390/cancers15194681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/01/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
DA, one of the medium-chain fatty acids found in coconut oil, is suggested to have diverse biochemical functions. However, its possible role as a chemoprevention agent in HCC has not been deciphered. Aberrant activation of c-Met can modulate tumor growth and progression in HCC. Here, we report that DA exhibited pro-found anti-tumor effects on human HCC through the suppression of HGF/c-Met signaling cascades in vitro and in vivo. It was noted that DA inhibited HGF-induced activation of c-Met and its downstream signals. DA induced apoptotic cell death and inhibited the expression of diverse tumorigenic proteins. In addition, DA attenuated tumor growth and lung metastasis in the HCC mouse model. Similar to in vitro studies, DA also suppressed the expression of c-Met and its downstream signals in mice tissues. These results highlight the substantial potential of DA in the prevention and treatment of HCC.
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Affiliation(s)
- Min Hee Yang
- Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Mina Lee
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si 57922, Republic of Korea; (M.L.); (D.D.L.)
| | - Amudha Deivasigamani
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; (A.D.); (K.M.H.)
| | - Duc Dat Le
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si 57922, Republic of Korea; (M.L.); (D.D.L.)
| | - Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India;
| | - Kam Man Hui
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; (A.D.); (K.M.H.)
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
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An J, An S, Choi M, Jung JH, Kim B. Natural Products for Esophageal Cancer Therapy: From Traditional Medicine to Modern Drug Discovery. Int J Mol Sci 2022; 23:13558. [PMID: 36362345 PMCID: PMC9657766 DOI: 10.3390/ijms232113558] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 02/02/2024] Open
Abstract
Esophageal cancer (EC) is one of the most malignant types of cancer worldwide and has a high incidence and mortality rate in Asian countries. When it comes to treating EC, although primary methods such as chemotherapy and surgery exist, the prognosis remains poor. The purpose of this current research is to review the range of effects that natural products have on cancer by analyzing studies conducted on EC. Fifty-seven studies were categorized into four anti-cancer mechanisms, as well as clinical trials. The studies that were scrutinized in this research were all reported within five years. The majority of the substances reviewed induced apoptosis in EC, acting on a variety of mechanisms. Taken together, this study supports the fact that natural products have the potential to act as a candidate for treating EC.
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Affiliation(s)
| | | | | | | | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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Zhang T, Wang Y, Xie M, Ji X, Luo X, Chen X, Zhang B, Liu D, Feng Y, Sun M, Huang W, Xia L. HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET. J Exp Clin Cancer Res 2022; 41:275. [PMID: 36109787 PMCID: PMC9479266 DOI: 10.1186/s13046-022-02475-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 08/24/2022] [Indexed: 12/14/2022] Open
Abstract
Background Metastasis is a major determinant of death in patients with hepatocellular carcinoma (HCC). Dissecting key molecular mediators that promote this malignant feature may help yield novel therapeutic insights. Here, we investigated the role of E-twenty-six transformation-specific variant 1 (ETV1), a member of the E-twenty-six transformation-specific (ETS) family, in HCC metastasis. Methods The clinical significance of ETV1 and its target genes in two independent cohorts of HCC patients who underwent curative resection were assessed by Kaplan–Meier analysis and Multivariate Cox proportional hazards model. Luciferase reporter assay and chromatin immunoprecipitation assay were used to detect the transcriptional regulation of target gene promoters by ETV1. The effect of ETV1 on invasiveness and metastasis of HCC were detected by transwell assays and the orthotopically metastatic model. Results ETV1 expression was frequently elevated in human HCC specimens. Increased ETV1 expression was associated with the malignant biological characteristics and poor prognosis of HCC patients. ETV1 facilitated invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, ETV1 promoted HCC metastasis via upregulating metastasis-related genes, including protein tyrosine kinase 2 (PTK2) and MET. Down-regulated the expression of PTK2 or tyrosine protein kinase Met (c-MET) decreased ETV1-mediated HCC metastasis. Hepatocyte growth factor (HGF) upregulated ETV1 expression through activating c-MET-ERK1/2-ELK1 pathway. Notably, in two independent cohorts, patients with positive coexpression of ETV1/PTK2 or ETV1/c-MET had worse prognosis. Furthermore, the combination of PTK2 inhibitor defactinib and c-MET inhibitor capmatinib significantly suppressed HCC metastasis induced by ETV1. Conclusion This study uncovers functional and prognostic roles for ETV1 in HCC and exposes a positive feedback loop of HGF-ERK1/2-ETV1-c-MET. Targeting this pathway may provide a potential therapeutic intervention for ETV1-overexpressing HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02475-2.
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Zhang Z, Li D, Yun H, Tong J, Liu W, Chai K, Zeng T, Gao Z, Xie Y. Opportunities and challenges of targeting c-Met in the treatment of digestive tumors. Front Oncol 2022; 12:923260. [PMID: 35978812 PMCID: PMC9376446 DOI: 10.3389/fonc.2022.923260] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.
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Affiliation(s)
- Zhengchao Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Dong Li
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Jie Tong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Wei Liu
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Keqiang Chai
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Tongwei Zeng
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Zhenghua Gao
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
| | - Yongqiang Xie
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
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Yang X, Liao HY, Zhang HH. Roles of MET in human cancer. Clin Chim Acta 2021; 525:69-83. [PMID: 34951962 DOI: 10.1016/j.cca.2021.12.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 01/18/2023]
Abstract
The MET proto-oncogene was first identified in osteosarcoma cells exposed to carcinogens. Although expressed in many normal cells, MET is overexpressed in many human cancers. MET is involved in the initiation and development of various human cancers and mediates proliferation, migration and invasion. Accordingly, MET has been successfully used as a biomarker for diagnosis and prognosis, survival, post-operative recurrence, risk assessment and pathologic grading, as well as a therapeutic target. In addition, recent work indicates that inhibition of MET expression and function has potential clinical benefit. This review summarizes the role, mechanism, and clinical significance of MET in the formation and development of human cancer.
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Affiliation(s)
- Xin Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, PR China; Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou 730000, PR China
| | - Hai-Yang Liao
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, PR China; Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou 730000, PR China
| | - Hai-Hong Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, PR China; Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou 730000, PR China.
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Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis. Signal Transduct Target Ther 2021; 6:401. [PMID: 34848680 PMCID: PMC8632923 DOI: 10.1038/s41392-021-00790-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/24/2022] Open
Abstract
Met tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.
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Mir IH, Guha S, Behera J, Thirunavukkarasu C. Targeting molecular signal transduction pathways in hepatocellular carcinoma and its implications for cancer therapy. Cell Biol Int 2021; 45:2161-2177. [PMID: 34270844 DOI: 10.1002/cbin.11670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/22/2021] [Accepted: 07/11/2021] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma is a substantial health concern. It is currently the third dominating cause of mortality associated with cancer worldwide. The development of hepatocellular carcinoma is an intricate process that encompasses the impairment of genetic, epigenetic, and signal transduction mechanisms contributing to an aberrant metabolic system, enabling tumorigenesis. Throughout the past decade, research has led to the revelation of molecular pathways implicated in the progression of this notorious disorder. The altered signal transduction pathways, such as the mitogen-activated protein kinase pathway, phosphoinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, WNT/β-catenin pathway, hepatocyte growth factor/c-MET pathway, and just another kinase/signal transducers and activators of transcription signaling pathway is of much therapeutic significance, as targeting them may avail to revert, retard or avert hepatocarcinogenesis. The present review article sums up the contemporary knowledge of such signaling mechanisms, including their therapeutic targets and betokens that novel and efficacious therapies can be developed only by the keen understanding of their character in hepatocarcinogenesis. In additament, we address the role of consequential therapeutic agents and preclinical nondrug therapies known for combating hepatocarcinogenesis.
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Affiliation(s)
- Ishfaq Hassan Mir
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - Shreyoshi Guha
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - Jajnasenee Behera
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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Yılmaz Y, Batur T, Korhan P, Öztürk M, Atabey N. Targeting c-Met and AXL Crosstalk for the Treatment of Hepatocellular Carcinoma. LIVER CANCER IN THE MIDDLE EAST 2021:333-364. [DOI: 10.1007/978-3-030-78737-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Yu J, Chen GG, Lai PBS. Targeting hepatocyte growth factor/c-mesenchymal-epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies. Med Res Rev 2020; 41:507-524. [PMID: 33026703 DOI: 10.1002/med.21738] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/27/2020] [Accepted: 09/27/2020] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c-Met as a tumor progression and prognostic marker, discussed the anti-c-Met therapy in vitro, summarized the outcome of c-Met inhibitors in clinical trials, and identified potential impetus for future anti-c-Met treatments. We also analyzed the inconsistency of HGF/c-Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c-Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.
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Affiliation(s)
- Jianqing Yu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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14
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D'Angelo A, Sobhani N, Bagby S, Casadei-Gardini A, Roviello G. Cabozantinib as a second-line treatment option in hepatocellular carcinoma. Expert Rev Clin Pharmacol 2020; 13:623-629. [PMID: 32394749 DOI: 10.1080/17512433.2020.1767591] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most frequent tumors affecting the gastrointestinal tract and a universal cause of morbidity and mortality. Cabozantinib is a strong multi-inhibitor of receptor tyrosine kinases approved for renal cell carcinoma that could be useful also for the treatment of HCC. AREAS COVERED This review describes the chemical structure, the pharmacologic properties and current knowledge of the efficacy of cabozantinib in the treatment of HCC based on data available from first phase and later phase clinical trials. The ongoing studies testing cabozantinib, either alone or in combination with other drugs, are also described. EXPERT OPINION Despite the recent achievements in the use of cabozantinib for patients diagnosed with hepatocellular carcinoma, data are still needed to allow clinicians to make better decisions on how to treat specific patient subgroups.
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Affiliation(s)
- Alberto D'Angelo
- Department of Biology and Biochemistry, University of Bath , Bath, UK
| | - Navid Sobhani
- Department of Medicine, Baylor College , Houston, TX, USA
| | - Stefan Bagby
- Department of Biology and Biochemistry, University of Bath , Bath, UK
| | - Andrea Casadei-Gardini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia , Modena, Italy
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15
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Dimri M, Satyanarayana A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12020491. [PMID: 32093152 PMCID: PMC7072513 DOI: 10.3390/cancers12020491] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.
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16
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Wang H, Rao B, Lou J, Li J, Liu Z, Li A, Cui G, Ren Z, Yu Z. The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:55. [PMID: 32117981 PMCID: PMC7018668 DOI: 10.3389/fcell.2020.00055] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/22/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, leading to a large global cancer burden. Hepatocyte growth factor (HGF) and its high-affinity receptor, mesenchymal epithelial transition factor (c-Met), are closely related to the onset, progression, and metastasis of multiple tumors. The HGF/c-Met axis is involved in cell proliferation, movement, differentiation, invasion, angiogenesis, and apoptosis by activating multiple downstream signaling pathways. In this review, we focus on the function of the HGF/c-Met axis in HCC. The HGF/c-Met axis promotes the onset, proliferation, invasion, and metastasis of HCC. Moreover, it can serve as a biomarker for diagnosis and prognosis, as well as a therapeutic target for HCC. In addition, it is closely related to drug resistance during HCC treatment.
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Affiliation(s)
- Haiyu Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Benchen Rao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiamin Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhao Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenguo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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17
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Zhang R, Gao X, Zuo J, Hu B, Yang J, Zhao J, Chen J. STMN1 upregulation mediates hepatocellular carcinoma and hepatic stellate cell crosstalk to aggravate cancer by triggering the MET pathway. Cancer Sci 2019; 111:406-417. [PMID: 31785057 PMCID: PMC7004522 DOI: 10.1111/cas.14262] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/20/2019] [Accepted: 11/26/2019] [Indexed: 12/12/2022] Open
Abstract
STMN1 has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. However, the detailed functions and underlying mechanisms of STMN1 are still largely unknown in hepatocellular carcinoma (HCC) development. Herein, we analyzed STMN1 expression and the related clinical significance in HCC by using well‐established Protein Atlas, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cancer databases. Analysis indicated that STMN1 was highly expressed in HCC and closely associated with vascular invasion, higher histological grade, advanced clinical grade and shorter survival time in HCC patients. Overexpressing and silencing STMN1 in HCC cell lines showed that STMN1 could regulate cell proliferation, migration, drug resistance, cancer stem cell properties in vitro as well as tumor growth in vivo. Further experiments showed that STMN1 mediated intricate crosstalk between HCC and hepatic stellate cells (HSC) by triggering the hepatocyte growth factor (HGF)/MET signal pathway. When HSC were cocultured with HCC cells, HSC secreted more HGF to stimulate the expression of STMN1 in HCC cells. Mutually, STMN1 upregulation in HCC cells facilitated HSC activation to acquire cancer‐associated fibroblast (CAF) features. The MET inhibitor crizotinib significantly blocked this crosstalk and slowed tumor growth in vivo. In conclusion, our findings shed new insight on STMN1 function, and suggest that STMN1 may be used as a potential marker to identify patients who may benefit from MET inhibitor treatment.
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Affiliation(s)
- Rui Zhang
- Department of General Surgery, Fudan University, Shanghai, China
| | - Xiaomei Gao
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jieliang Zuo
- Department of General Surgery, Fudan University, Shanghai, China
| | - Beiyuan Hu
- Department of General Surgery, Fudan University, Shanghai, China
| | - Jimeng Yang
- Department of General Surgery, Fudan University, Shanghai, China
| | - Jing Zhao
- Department of General Surgery, Fudan University, Shanghai, China
| | - Jinhong Chen
- Department of General Surgery, Fudan University, Shanghai, China
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18
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Guerra MT, Florentino RM, Franca A, Filho ACL, dos Santos ML, Fonseca RC, Lemos FO, Fonseca MC, Kruglov E, Mennone A, Njei B, Gibson J, Guan F, Cheng YC, Ananthanarayanam M, Gu J, Jiang J, Zhao H, Lima CX, Vidigal PT, Oliveira AG, Nathanson MH, Leite MF. Expression of the type 3 InsP 3 receptor is a final common event in the development of hepatocellular carcinoma. Gut 2019; 68:1676-1687. [PMID: 31315892 PMCID: PMC7087395 DOI: 10.1136/gutjnl-2018-317811] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 06/25/2019] [Accepted: 06/30/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & OBJECTIVES Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC. DESIGN Expression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice. RESULTS ITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis. CONCLUSIONS These results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.
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MESH Headings
- Adult
- Animals
- Apoptosis/physiology
- Calcium Signaling/physiology
- Carcinogenesis/genetics
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation/physiology
- Cells, Cultured
- DNA Methylation
- Female
- Gene Expression Regulation, Neoplastic/physiology
- Hepatocytes/metabolism
- Humans
- Inositol 1,4,5-Trisphosphate Receptors/deficiency
- Inositol 1,4,5-Trisphosphate Receptors/genetics
- Inositol 1,4,5-Trisphosphate Receptors/metabolism
- Liver/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Regeneration/physiology
- Male
- Mice, Knockout
- Middle Aged
- Survival Analysis
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Affiliation(s)
- Mateus T Guerra
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Rodrigo M Florentino
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Andressa Franca
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Antonio C Lima Filho
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Marcone L dos Santos
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Roberta C Fonseca
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Fernanda O Lemos
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Matheus C Fonseca
- Centro Nacional de Pesquisa em Energia e Materiais, Campinas, Brazil
| | - Emma Kruglov
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Albert Mennone
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Basile Njei
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Joanna Gibson
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Fulan Guan
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Yung-Chi Cheng
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | | | - Jianlei Gu
- Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, China
| | - Jianping Jiang
- Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Bioinformatics and Biostatistics, SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, China
| | - Hongyu Zhao
- Department of Biostatistics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Cristiano X Lima
- Department of Surgery, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Paula T Vidigal
- Department of Pathological Anatomy and Forensic Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Andre G Oliveira
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Michael H Nathanson
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Maria Fatima Leite
- Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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19
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Chun HW, Hong R. Significance of PD-L1 clones and C-MET expression in hepatocellular carcinoma. Oncol Lett 2019; 17:5487-5498. [PMID: 31186768 PMCID: PMC6507339 DOI: 10.3892/ol.2019.10222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 03/29/2019] [Indexed: 12/18/2022] Open
Abstract
Programmed cell death ligand 1 (PD-L1) is an essential immune checkpoint protein implicated in immune evasion by malignant tumors. Overexpression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 is associated with poor prognosis in various types of cancer. Recently, multiple advances have occurred in the area of cancer immunotherapy. Inhibiting the ligation of PD-1 by PD-L1 has been the major focus of anti-tumor immunotherapy. In diagnostic pathology, it has become crucial to detect PD-L1+ tumor cases using a validated immunohistochemistry (IHC) approach. Preliminary data demonstrate that C-MET promotes survival of some (e.g., renal) cancer types through regulation of PD-L1. However, C-MET expression, and its association with PD-L1, has not been well-characterized in the context of hepatocellular carcinoma (HCC), and no anti-HCC immunotherapy is currently available in Korea. Therefore, it is crucial to investigate the expression of C-MET and PD-L1, and their association with clinicopathologic factors, to facilitate the development of targeted treatments for HCC. PD-L1 expression was examined in tumor cells (TC) and immune cells (IC) of 70 patient-derived HCC specimens using IHC. Two anti-PD-L1 monoclonal antibodies (MAbs), SP263 and SP142, were utilized. Additionally, TC C-MET expression was assessed. Correlations between PD-L1 expression (as identified by both MAbs), C-MET expression and clinicopathologic factors were assessed. More PD-L1+ cases were identified via SP263 than via SP142 when assessing both TC and IC; in the former group, SP236 identified 14/70 positive cases, while SP142 identified only 2/70. In the latter group, SP236 identified 49/70 positive cases, while SP142 identified 30/70. Both MAbs demonstrated a higher frequency of PD-L1 expression by IC than TC. The Edmondson-Steiner grade statistically correlated with a higher frequency of SP236-detected TC PD-L1 expression. C-MET was significantly associated with advanced tumor size and was positively correlated with SP263-detected PD-L1 expression in TC. These results suggest that C-MET may serve a role in regulating PD-L1 expression in HCC. Furthermore, while SP263 generally exhibited a higher sensitivity for PD-L1 detection, concordance in PD-L1+ case detection between the two different MAbs was generally good. These background data may be helpful in the development of targeted anti-HCC immunotherapy focused on PD-L1 or C-MET, and in evaluating selection criteria for target populations best suited to such treatments.
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Affiliation(s)
- Hyung-Wook Chun
- Sunchun Sarang Hospital, Suncheon-si, Jeollanam-do 57993, Republic of Korea
| | - Ran Hong
- Department of Pathology, College of Medicine, Chosun University, Donggu, Gwangju 61453, Republic of Korea
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20
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Heo MJ, Yun J, Kim SG. Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma. Arch Pharm Res 2019; 42:48-62. [PMID: 30610616 DOI: 10.1007/s12272-018-01104-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 12/23/2018] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a tumor with poor prognosis and frequently aggressive. The development of HCC is associated with fibrosis and cirrhosis, which mainly results from nonalcoholic fatty liver disease, excessive alcohol consumption, and viral infections. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome, but are not translated into proteins. Recently, ncRNAs emerged as key contributors to tumor development and progression because of their abilities to regulate various targets and modulate cell proliferation, differentiation, apoptosis, and development. In this review, we summarize the frequently activated pathways in HCC and discuss the pathological implications of ncRNAs in the context of human liver disease progression, in particular HCC development and progression. This review aims to summarize the role of ncRNA dysregulation in the diseases and discuss the diagnostic and therapeutic potentials of ncRNAs.
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Affiliation(s)
- Mi Jeong Heo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea
| | - Jessica Yun
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea
| | - Sang Geon Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea.
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21
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Li W, Zheng H, Xu J, Cao S, Xu X, Xiao P. Imaging c-Met expression using 18F-labeled binding peptide in human cancer xenografts. PLoS One 2018; 13:e0199024. [PMID: 29894497 PMCID: PMC5997322 DOI: 10.1371/journal.pone.0199024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 05/30/2018] [Indexed: 11/18/2022] Open
Abstract
Objectives c-Met is a receptor tyrosine kinase shown inappropriate expression and actively involved in progression and metastasis in most types of human cancer. Development of c-Met-targeted imaging and therapeutic agents would be extremely useful. Previous studies reported that c-Met-binding peptide (Met-pep1, YLFSVHWPPLKA) specifically targets c-Met receptor. Here, we evaluated 18F-labeled Met-pep1 for PET imaging of c-Met positive tumor in human head and neck squamous cell carcinoma (HNSCC) xenografted mice. Methods c-Met-binding peptide, Met-pep1, was synthesized and labeled with 4-nitrophenyl [18F]-2-fluoropropionate ([18F]-NPFP) ([18F]FP-Met-pep1). The cell uptake, internalization and efflux of [18F]FP-Met-pep1 were assessed in UM-SCC-22B cells. In vivo pharmacokinetics, blocking and biodistribution of the radiotracers were investigated in tumor-bearing nude mice by microPET imaging. Results The radiolabeling yield for [18F]FP-Met-pep1 was over 55% with 97% purity. [18F]FP-Met-pep1 showed high tumor uptake in UM-SCC-22B tumor-bearing mice with clear visualization. The specificity of the imaging tracer was confirmed by significantly decreased tumor uptake after co-administration of unlabeled Met-pep1 peptides. Prominent uptake and rapid excretion of [18F]FP-Met-pep1 was also observed in the kidney, suggesting this tracer is mainly excreted through the renal-urinary routes. Ex vivo biodistribution showed similar results that were consistent with microPET imaging data. Conclusions These results suggest that 18F-labeled c-Met peptide may potentially be used for imaging c-Met positive HNSCC cancer in vivo and for c-Met-targeted cancer therapy.
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Affiliation(s)
- Weihua Li
- Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
- * E-mail: (WHL); (PX)
| | - Hongqun Zheng
- Department of Surgical Oncology and Hepatobiliary Surgery, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jiankai Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Shaodong Cao
- Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiuan Xu
- Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Peng Xiao
- New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, United States of America
- * E-mail: (WHL); (PX)
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22
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Wang M, Sun Y, Xu J, Lu J, Wang K, Yang DR, Yang G, Li G, Chang C. Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling. Int J Cancer 2018; 143:100-112. [PMID: 29396852 DOI: 10.1002/ijc.31289] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 12/13/2017] [Accepted: 01/05/2018] [Indexed: 12/22/2022]
Abstract
While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression levels via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help to develop a new therapy to better suppress the ccRCC metastasis.
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Affiliation(s)
- Mingchao Wang
- Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.,George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Yin Sun
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Junjie Xu
- Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.,George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Jieyang Lu
- Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.,George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Kefeng Wang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Dong-Rong Yang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Guosheng Yang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642
| | - Gonghui Li
- Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, 14642.,Sex Hormone Research Center, China Medical University/Hospital, Taichung, 404, Taiwan
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23
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Harris WP, Wong KM, Saha S, Dika IE, Abou-Alfa GK. Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers. Semin Oncol 2018; 45:116-123. [PMID: 30348531 DOI: 10.1053/j.seminoncol.2018.03.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 03/07/2018] [Indexed: 12/18/2022]
Abstract
The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.
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Affiliation(s)
- William P Harris
- Department of Medicine, Division of Medical Oncology, University of Washington, Seattle WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle WA
| | - Kit Man Wong
- Department of Medicine, Division of Medical Oncology, University of Washington, Seattle WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle WA
| | - Supriya Saha
- Department of Medicine, Division of Medical Oncology, University of Washington, Seattle WA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle WA
| | - Imane El Dika
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ghassan K Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Medical College at Cornell University, New York, NY.
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24
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Wang Q, Yu X, Li Q, Qin L, Tan S, Zeng X, Qiu X, Tang B, Jin J, Liao W, Qiu M, Tan L, He G, Li X, He S, Yu H. Association between miR-199a rs74723057 and MET rs1621 polymorphisms and the risk of hepatocellular carcinoma. Oncotarget 2018; 7:79365-79371. [PMID: 27813498 PMCID: PMC5346720 DOI: 10.18632/oncotarget.13033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 10/21/2016] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) can regulate gene expression at post-transcriptional levels, thereby influence cancer risk. The aim of the current study is to investigate association between miR-199a rs74723057 and MET rs1621 and HCC risk in 1032 HCC patients and 1060 cancer-free controls. These two SNPs were genotyped by using the Agena MassARRAY genotyping system. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated to assess the strength of the associations. We found that compared with the wild-type AA genotype of MET rs1621, the variant GG genotype was associated with a decreased risk for HCC (OR = 0.24, 95% CI = 0.06–0.96, P = 0.043). No association between miR-199a rs74723057 and HCC risk was observed. In addition, an interaction effect on HCC risk between the selected two SNPs was found. Among those who carried the CG/GG genotypes of miR-199a rs74723057, those who carried the GG genotype of MET rs1621 had a reduced risk of HCC, when compared with those who carried the AG/AA genotypes of MET rs1621 (OR = 0.15, 95% CI = 0.03~0.73, P for interaction = 0.018). Our results suggest that MET rs1621 polymorphism, alone and combined with miR-199a rs74723057, may influence susceptibility to HCC. Further large-scale association studies and functional studies are needed to validate our findings.
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Affiliation(s)
- Qianqian Wang
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
| | - Xiangyuan Yu
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
| | - Qiang Li
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
| | - Linyuan Qin
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
| | - Shengkui Tan
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
| | - Xiaoyun Zeng
- Department of Epidemiology and Health Statistics, Guangxi Medical University, Nanning 530021, China
| | - Xiaoqiang Qiu
- Department of Epidemiology and Health Statistics, Guangxi Medical University, Nanning 530021, China
| | - Bo Tang
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Junfei Jin
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Moqin Qiu
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Lijun Tan
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Gaofeng He
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Xiaomei Li
- Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
| | - Songqing He
- Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China.,Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin 541001, China
| | - Hongping Yu
- Department of Epidemiology and Health Statistics, Guangxi Medical University, Nanning 530021, China.,Department of Epidemiology, School of Public Health, Guilin Medical University, Guilin 541004, China
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25
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Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, Wu Y, Li X, Li X, Li G, Zeng Z, Xiong W. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer 2018; 17:45. [PMID: 29455668 PMCID: PMC5817860 DOI: 10.1186/s12943-018-0796-y] [Citation(s) in RCA: 371] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 02/01/2018] [Indexed: 12/15/2022] Open
Abstract
c-Met is a receptor tyrosine kinase belonging to the MET (MNNG HOS transforming gene) family, and is expressed on the surfaces of various cells. Hepatocyte growth factor (HGF) is the ligand for this receptor. The binding of HGF to c-Met initiates a series of intracellular signals that mediate embryogenesis and wound healing in normal cells. However, in cancer cells, aberrant HGF/c-Met axis activation, which is closely related to c-Met gene mutations, overexpression, and amplification, promotes tumor development and progression by stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/β-catenin, and other signaling pathways. Thus, c-Met and its associated signaling pathways are clinically important therapeutic targets. In this review, we elaborate on the molecular structure of c-Met and HGF and the mechanism through which their interaction activates the PI3K/AKT, Ras/MAPK, and Wnt signaling pathways. We also summarize the connection between c-Met and RON and EGFR, which are also receptor tyrosine kinases. Finally, we introduce the current therapeutic drugs that target c-Met in primary tumors, and their use in clinical research.
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Affiliation(s)
- Yazhuo Zhang
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengfang Xia
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ke Jin
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Shufei Wang
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Hang Wei
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Chunmei Fan
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yingfen Wu
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Xiaoling Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guiyuan Li
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Wei Xiong
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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26
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Kawaguchi T, Hirajima S, Ohashi T, Imamura T, Kiuchi J, Arita T, Konishi H, Shiozaki A, Moriumura R, Ikoma H, Okamoto K, Taniguchi H, Itoh Y, Otsuji E. Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function. Oncotarget 2018; 7:53820-53836. [PMID: 27462777 PMCID: PMC5288224 DOI: 10.18632/oncotarget.10781] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/09/2016] [Indexed: 12/21/2022] Open
Abstract
Aims This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. Results (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. Methods We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. Conclusions Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tsutomu Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shoji Hirajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Moriumura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Taniguchi
- Department of Surgery, Kyoto Second Red Cross Hospital, Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Subbotin VM. Privileged portal metastasis of hepatocellular carcinoma in light of the coevolution of a visceral portal system and liver in the chordate lineage: a search for therapeutic targets. Drug Discov Today 2018; 23:548-564. [PMID: 29330122 DOI: 10.1016/j.drudis.2018.01.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/21/2017] [Accepted: 01/04/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) disseminates systemically, but metastases occur in distant organs only in minority of patients, whereas HCC routinely metastasizes to liver and its vessels. HCC cells disseminate via hepatic veins, but portal veins are affected by metastasis more frequently than are hepatic veins, and correlates with poor prognosis. In this review, I suggest that privileged HCC portal metastasis occurs because of high levels of pancreatic family hormones and growth factors (PHGFs) in the portal blood. The analysis suggests that the appearance of the portal system carrying PHGFs in the evolution of invertebrate chordate (Amphioxus) led to the evolution of the liver in vertebrate; given that the portal pattern of HCC metastasis and selection of more-aggressive clones are PHGF dependent, PHGFs and their ligands constitute therapeutic targets.
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Affiliation(s)
- Vladimir M Subbotin
- Department of Oncology, University of Wisconsin, Madison, WI 53705, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
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28
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Prognostic value of c-Met overexpression in hepatocellular carcinoma: a meta-analysis and review. Oncotarget 2017; 8:90351-90357. [PMID: 29163834 PMCID: PMC5685755 DOI: 10.18632/oncotarget.20087] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 07/26/2017] [Indexed: 12/11/2022] Open
Abstract
The overexpression of c-Met protein has been detected in hepatocellular carcinoma (HCC). However, its prognostic impact remains uncertain. We performed this meta-analysis to evaluate the prognostic value of c-Met overexpression in patients who underwent curative surgical resection for HCC. A systematic computerized search of the electronic databases was carried out. From 5 studies, 1,408 patients who underwent surgical resection for HCC were included in the meta-analysis. Compared with patients with HCC having low c-Met expression, patients with c-Met-high tumor showed significantly worse relapse-free survival (hazard ratio = 1.26 [95% confidence interval, 1.02–1.56], P = 0.03) and overall survival (hazard ratio = 1.16 [95% confidence interval, 1.03–1.31], P = 0.01). In conclusion, our meta-analysis indicates that c-Met overexpression is a significant adverse prognostic factor for recurrence and survival in patients who underwent surgical resection for HCC.
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29
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Zhou F, Shang W, Yu X, Tian J. Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. Med Res Rev 2017. [PMID: 28621802 DOI: 10.1002/med.21455] [Citation(s) in RCA: 242] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Liver cancer is the second leading cause of cancer-related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican-3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.
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Affiliation(s)
- Fubo Zhou
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Wenting Shang
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiaoling Yu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jie Tian
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
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30
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Bradley CA, Dunne PD, Bingham V, McQuaid S, Khawaja H, Craig S, James J, Moore WL, McArt DG, Lawler M, Dasgupta S, Johnston PG, Van Schaeybroeck S. Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer. Oncotarget 2016; 7:78932-78945. [PMID: 27793046 PMCID: PMC5346688 DOI: 10.18632/oncotarget.12933] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 10/19/2016] [Indexed: 12/12/2022] Open
Abstract
c-MET and its ligand HGF are frequently overexpressed in colorectal cancer (CRC) and increased c-MET levels are found in CRC liver metastases. This study investigated the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Pre-clinically, we found marked upregulation of c-MET at both protein and mRNA levels in several invasive CRC cells. Down-regulation of c-MET using RNAi suppressed migration/invasion of parental and invasive CRC cells. Stimulation of CRC cells with rh-HGF or co-culture with HGF-expressing colonic myofibroblasts, resulted in significant increases in their migratory/invasive capacity. Importantly, HGF-induced c-MET activation promoted rapid downregulation of c-MET protein levels, while the MET transcript remained unaltered. Using RNA in situ hybridization (RNA ISH), we further showed that MET mRNA, but not protein levels, were significantly upregulated in tumor budding foci at the invasive front of a cohort of stage III CRC tumors (p < 0.001). Taken together, we show for the first time that transcriptional upregulation of MET is a key molecular event associated with CRC invasion and tumor budding. This data also indicates that RNA ISH, but not immunohistochemistry, provides a robust methodology to assess MET levels as a potential driving force of CRC tumor invasion and metastasis.
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Affiliation(s)
- Conor A. Bradley
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Philip D. Dunne
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Victoria Bingham
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Stephen McQuaid
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
- Tissue Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK
| | - Hajrah Khawaja
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Stephanie Craig
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Jackie James
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
- Tissue Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK
| | - Wendy L. Moore
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Darragh G. McArt
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Mark Lawler
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Sonali Dasgupta
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Patrick G. Johnston
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Sandra Van Schaeybroeck
- Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
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31
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Pievsky D, Pyrsopoulos N. Profile of tivantinib and its potential in the treatment of hepatocellular carcinoma: the evidence to date. J Hepatocell Carcinoma 2016; 3:69-76. [PMID: 27896243 PMCID: PMC5118026 DOI: 10.2147/jhc.s106072] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States and carries a very poor prognosis, with a median survival time of <50% at 1 year for advanced disease. To date, sorafenib is the only therapy approved by the Food and Drug Administration for the treatment of advanced HCC. Tivantinib (ARQ-197), a non-ATP competitive inhibitor of cellular mesenchymal–epithelial transcription factor (c-MET), has shown a survival benefit in patients with advanced HCC who have failed or are intolerant to sorafenib in Phase I and II trials. Those patients who have tumors with high concentrations of MET (MET-high) appear to derive the greatest benefit from tivantinib therapy. Currently, two large randomized double-blind placebo-controlled Phase III trials (METIV-HCC [NCT01755767] and JET-HCC [NCT02029157]) are evaluating tivantinib in patients with MET-high advanced HCC, with the primary end points of overall survival and progression-free survival, respectively. This study reviews the evidence for the use of tivantinib in advanced HCC. Specific topics addressed include the pharmacology, dosing, toxicity, and biomarkers associated with tivantinib use.
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Affiliation(s)
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, University Hospital, Newark, NJ, USA
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32
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Yau TCC, Lencioni R, Sukeepaisarnjaroen W, Chao Y, Yen CJ, Lausoontornsiri W, Chen PJ, Sanpajit T, Camp A, Cox DS, Gagnon RC, Liu Y, Raffensperger KE, Kulkarni DA, Kallender H, Ottesen LH, Poon RTP, Bottaro DP. A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res 2016; 23:2405-2413. [PMID: 27821605 DOI: 10.1158/1078-0432.ccr-16-1789] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 10/04/2016] [Accepted: 10/08/2016] [Indexed: 12/21/2022]
Abstract
Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients.Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.
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Affiliation(s)
- Thomas C C Yau
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Riccardo Lencioni
- Division of Diagnostic Imaging and Intervention, University of Pisa, Pisa, Italy
| | | | - Yee Chao
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chia-Jui Yen
- Internal Medicine, National Cheng University Hospital, Tainan, Taiwan
| | - Wirote Lausoontornsiri
- Clinical Cancer Research Center, National Cancer Institute of Thailand, Bangkok, Thailand
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Theeranun Sanpajit
- Division of Digestive and Liver Diseases, Phramongkutklao Hospital, Bangkok, Thailand
| | | | - Donna S Cox
- GlaxoSmithKline, King of Prussia, Pennsylvania
| | | | - Yuan Liu
- GlaxoSmithKline, Collegeville, Pennsylvania
| | | | | | | | | | - Ronnie T P Poon
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Donald P Bottaro
- Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
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Chen HA, Kuo TC, Tseng CF, Ma JT, Yang ST, Yen CJ, Yang CY, Sung SY, Su JL. Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. Hepatology 2016; 64:1637-1651. [PMID: 27530187 DOI: 10.1002/hep.28773] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 07/21/2016] [Indexed: 12/18/2022]
Abstract
UNLABELLED Angiopoietin-like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial-mesenchymal transition (EMT)-driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)-dependent early growth response protein 1 (Egr-1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. CONCLUSION ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor-AKT/ERK-Egr-1-Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637-1651).
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Affiliation(s)
- Hsin-An Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tsang-Chih Kuo
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Chi-Feng Tseng
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.,Graduate Program of Biotechnology in Medicine College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Jui-Ti Ma
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Shu-Ting Yang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Chia-Jui Yen
- Division of Hematology-Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Shian-Ying Sung
- Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Jen-Liang Su
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan. .,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. .,Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. .,Department of Biotechnology, Asia University, Taichung, Taiwan.
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Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 2016; 65:798-808. [PMID: 27212245 DOI: 10.1016/j.jhep.2016.05.007] [Citation(s) in RCA: 450] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/20/2016] [Accepted: 05/03/2016] [Indexed: 12/13/2022]
Abstract
The epithelial to mesenchymal transition (EMT) is a multistep biological process whereby epithelial cells change in plasticity by transient de-differentiation into a mesenchymal phenotype. EMT and its reversal, mesenchymal to epithelial transition (MET), essentially occur during embryogenetic morphogenesis and have been increasingly described in fibrosis and cancer during the last decade. In carcinoma progression, EMT plays a crucial role in early steps of metastasis when cells lose cell-cell contacts due to ablation of E-cadherin and acquire increased motility to spread into surrounding or distant tissues. Epithelial plasticity has become a hot issue in hepatocellular carcinoma (HCC), as strong inducers of EMT such as transforming growth factor-β are able to orchestrate both fibrogenesis and carcinogenesis, showing rising cytokine levels in cirrhosis and late stage HCC. In this review, we consider the significance of EMT-MET in malignant hepatocytes as well as changes in the plasticity of hepatic stellate cells for cellular heterogeneity of HCC, and further aim at explaining the current limiting insights into EMT by snapshot analyses of HCC tissues. Recent advances in the identification of clinically relevant mechanisms that impinge on important EMT-transcription factors, as well as on miRNAs causing EMT signatures and HCC progression are highlighted. In addition, we draw particular attention to framing EMT in the context of potential clinical relevance for HCC patients. We conclude that some aspects of EMT are still elusive and further studies are required to better link the clinical management of HCC with biomarkers and targeted therapies related to EMT.
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Affiliation(s)
- Gianluigi Giannelli
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
| | - Petra Koudelkova
- Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Austria
| | - Francesco Dituri
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Wolfgang Mikulits
- Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Austria.
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35
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Zhang Y, Du Z, Zhang M. Biomarker development in MET-targeted therapy. Oncotarget 2016; 7:37370-37389. [PMID: 27013592 PMCID: PMC5095083 DOI: 10.18632/oncotarget.8276] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 03/14/2016] [Indexed: 12/16/2022] Open
Abstract
Activation of the MET receptor tyrosine kinase by its ligand, hepatocyte growth factor (HGF), has been implicated in a variety of cellular processes, including cell proliferation, survival, migration, motility and invasion, all of which may be enhanced in human cancers. Aberrantly activated MET/HGF signaling correlates with tumorigenesis and metastasis, and is regarded as a robust target for the development of novel anti-cancer treatments. Various clinical trials were conducted to evaluate the safety and efficacy of selective HGF/MET inhibitors in cancer patients. There is currently no optimal or standardized method for accurate and reliable assessment of MET levels, or other biomarkers that are predictive of the patient response to MET-targeted therapeutics. In this review, we discuss the importance of accurate HGF/MET signal detection as a predictive biomarker to guide patient selection for clinical trials of MET-targeted therapies in human cancers.
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Affiliation(s)
- Yanni Zhang
- Amgen Biopharmaceutical Research and Development (Shanghai) Co., Ltd, Shanghai, China
| | - Zhiqiang Du
- Amgen Biopharmaceutical Research and Development (Shanghai) Co., Ltd, Shanghai, China
| | - Mingqiang Zhang
- Amgen Biopharmaceutical Research and Development (Shanghai) Co., Ltd, Shanghai, China
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36
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Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma. Proc Natl Acad Sci U S A 2016; 113:E3384-93. [PMID: 27247392 DOI: 10.1073/pnas.1606876113] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMT-TFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.
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37
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Fajardo-Puerta AB, Mato Prado M, Frampton AE, Jiao LR. Gene of the month: HGF. J Clin Pathol 2016; 69:575-9. [DOI: 10.1136/jclinpath-2015-203575] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2016] [Indexed: 12/11/2022]
Abstract
Hepatocyte growth factor (HGF) is a multifunctional cytokine with important roles in cell proliferation, survival, motility and morphogenesis. Secreted by cells of mesenchymal origin, HGF is the specific ligand for the tyrosine-kinase receptor c-MET (cellular mesenchymal-epithelial transition), also called MET, which is expressed in different types of epithelial, endothelial and haematopoietic progenitor cells. The HGF/MET axis is involved in several biological processes, such as embryogenesis, organogenesis, adult tissue regeneration (including wound healing and liver regeneration) and carcinogenesis, for both solid and haematological malignancies.1 2 HGF and its particular interaction with the MET receptor have been extensively investigated in the last decades and remain the focus of numerous clinical trials.3–8 This short review focuses on HGF structure and function, as well as its roles in liver regeneration and different types of tumours.
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Okuma HS, Kondo S. Trends in the development of MET inhibitors for hepatocellular carcinoma. Future Oncol 2016; 12:1275-86. [PMID: 26984595 DOI: 10.2217/fon.16.3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Hepatocellular carcinoma is the third most common cause of cancer-related deaths worldwide. The multikinase inhibitor sorafenib has improved survival and is now considered the standard of care; however, the benefits are still disappointing, and thus, new effective treatments are required. In human hepatocellular carcinoma, MET, which is encoded by the HGFR gene, is activated by amplification, overexpression or mutation, and it has recently emerged as a possible therapeutic target in various tumors including hepatocellular carcinoma. In fact, some drugs targeting the HGF/MET axis are currently under investigation in clinical trials. Here, we review the role of MET and trends in the development of MET inhibitors for hepatocellular carcinoma.
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Affiliation(s)
- Hitomi S Okuma
- Department of Experimental Therapeutics, National Cancer Center, Tokyo, Japan
| | - Shunsuke Kondo
- Department of Experimental Therapeutics, National Cancer Center, Tokyo, Japan
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39
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Gao W, Kim H, Ho M. Human Monoclonal Antibody Targeting the Heparan Sulfate Chains of Glypican-3 Inhibits HGF-Mediated Migration and Motility of Hepatocellular Carcinoma Cells. PLoS One 2015; 10:e0137664. [PMID: 26332121 PMCID: PMC4557904 DOI: 10.1371/journal.pone.0137664] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 08/20/2015] [Indexed: 12/11/2022] Open
Abstract
Heparan sulfate proteoglycans (HSPGs) participate in many processes related to tumor development, including tumorigenesis and metastasis. HSPGs contain one or more heparan sulfate (HS) chains that are covalently linked to a core protein. Glypican-3 (GPC3) is a cell surface-associated HSPG that is highly expressed in hepatocellular carcinoma (HCC). GPC3 is involved in Wnt3a-dependent HCC cell proliferation. Our previous study reported that HS20, a human monoclonal antibody targeting the HS chains on GPC3, inhibited Wnt3a/β-catenin activation. In the current study, we showed that the HS chains of GPC3 could mediate HCC cells’ migration and motility. Knocking down GPC3 or targeting the HS chains by HS20 inhibited HCC cell migration and motility. However, HS20 had no effect on GPC3 knockdown cells or GPC3 negative cells. In addition, an antibody that recognizes the core protein of GPC3 did not change the rate of cell motility. HCC cell migration and motility did not respond to either canonical or non-canonical Wnt induction, but did increase under hepatocyte growth factor (HGF) treatment. HS20-treated HCC cells exhibited less ability for HGF-mediated migration and motility. Furthermore, HS20 inhibited in vitro HCC spheroid formation and liver tumor growth in mice. GPC3 interacted with HGF; however, a mutant GPC3 lacking the HS chain showed less interaction with HGF. Blocking the HS chains on GPC3 with HS20 reduced c-Met activation in HGF-treated HCC cells and 3D-cultured spheroids. Taken together, our study suggests that GPC3 is involved in HCC cell migration and motility through HS chain-mediated cooperation with the HGF/Met pathway, showing how HS targeting has potential therapeutic implications for liver cancer.
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Affiliation(s)
- Wei Gao
- Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America
| | - Heungnam Kim
- Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America
| | - Mitchell Ho
- Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America
- * E-mail:
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40
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Thompson AI, Conroy KP, Henderson NC. Hepatic stellate cells: central modulators of hepatic carcinogenesis. BMC Gastroenterol 2015; 15:63. [PMID: 26013123 PMCID: PMC4445994 DOI: 10.1186/s12876-015-0291-5] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 05/15/2015] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90 % of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC.
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Affiliation(s)
- Alexandra I Thompson
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.
| | - Kylie P Conroy
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.
| | - Neil C Henderson
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK.
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41
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Steinway SN, Dang H, You H, Rountree CB, Ding W. The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma. PLoS One 2015; 10:e0128159. [PMID: 26000702 PMCID: PMC4441360 DOI: 10.1371/journal.pone.0128159] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 04/22/2015] [Indexed: 12/22/2022] Open
Abstract
Background c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC) patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance. Methods We utilized the human MHCC97-H c-Met positive (c-Met+) HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells) were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses. Results We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that combination therapy with PHA665752 and Gefitinib (an EGFR inhibitor) significantly reduced cell viability and increased apoptosis compared with either PHA665752 or Gefitinib treatment alone. Conclusion c-Met inhibition monotherapy is not sufficient to eliminate c-Met+ HCC tumor growth. Inhibition of both c-Met and EGFR oncogenic pathways provides superior suppression of HCC tumor growth. Thus, combination of c-Met and EGFR inhibition may represent a superior therapeutic regimen for c-Met+ HCC.
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Affiliation(s)
- Steven N. Steinway
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Hien Dang
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Hanning You
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - C. Bart Rountree
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
| | - Wei Ding
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
- * E-mail:
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Granito A, Guidetti E, Gramantieri L. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma. J Hepatocell Carcinoma 2015; 2:29-38. [PMID: 27508192 PMCID: PMC4918282 DOI: 10.2147/jhc.s77038] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
c-MET is the membrane receptor for hepatocyte growth factor (HGF), also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC). In particular, c-MET amplification is a rare event, accounting for 4%–5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC.
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Affiliation(s)
- Alessandro Granito
- Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna, Bologna, Italy
| | - Elena Guidetti
- Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna, Bologna, Italy
| | - Laura Gramantieri
- Dipartimento dell'Apparato Digerente, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S Orsola-Malpighi e Università di Bologna, Bologna, Italy
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Grech G, Zhan X, Yoo BC, Bubnov R, Hagan S, Danesi R, Vittadini G, Desiderio DM. EPMA position paper in cancer: current overview and future perspectives. EPMA J 2015; 6:9. [PMID: 25908947 PMCID: PMC4407842 DOI: 10.1186/s13167-015-0030-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 02/26/2015] [Indexed: 12/31/2022]
Abstract
At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive, and personalized medicine (PPPM). Individual patients will participate in more aspects of their healthcare. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well-defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper, the current knowledge to understand cancer predisposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies in screening and diagnosis, and provision of better drug development solutions are discussed in the context of a better implementation of personalized medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies (EPMA J. 4(1):6, 2013). Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures is disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify healthcare costs, and the parameters screened should provide information that allow an actionable and deliverable solution, for better healthcare provision.
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Affiliation(s)
- Godfrey Grech
- />Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - Xianquan Zhan
- />Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, China
| | - Byong Chul Yoo
- />Colorectal Cancer Branch, Division of Translational and Clinical Research I, Research Institute, National Cancer Center, Gyeonggi, 410-769 Republic of Korea
| | - Rostyslav Bubnov
- />Clinical Hospital ‘Pheophania’ of State Management of Affairs Department, Kyiv, Ukraine
- />Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Suzanne Hagan
- />Dept of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
| | - Romano Danesi
- />Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giorgio Vittadini
- />Bracco Imaging, Centro Ricerche Bracco, San Donato Milanese, Italy
| | - Dominic M Desiderio
- />Department of Neurology, University of Tennessee Center for Health Science, Memphis, USA
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High levels of c-Met is associated with poor prognosis in glioblastoma. J Neurooncol 2015; 122:517-27. [PMID: 25800004 DOI: 10.1007/s11060-015-1723-3] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 01/18/2015] [Indexed: 10/23/2022]
Abstract
The tyrosine kinase receptor c-Met has been suggested to be involved in crucial parts of glioma biology like tumor stemness, growth and invasion. The aim of this study was to investigate the prognostic value of c-Met in a population-based glioma patient cohort. Tissue samples from 238 patients with WHO grade I, II, III and IV tumors were analyzed using immunohistochemical staining and advanced image analysis. Strong c-Met expression was found in tumor cells, blood vessels, and peri-necrotic areas. At the subcellular level, c-Met was identified in the cytoplasm and in the cell membrane. Measurements of high c-Met intensity correlated with high WHO grade (p = 0.006) but no association with survival was observed in patients with WHO grade II (p = 0.09) or III (p = 0.17) tumors. High expression of c-Met was associated with shorter overall survival in patients with glioblastoma multiforme (p = 0.03). However the prognostic effect of c-Met in glioblastomas was time-dependent and only observed in patients who survived more than 8.5 months, and not within the first 8.5 months after diagnosis. This was significant in multivariate analysis (HR 1.99, 95 % CI 1.29-3.08, p = 0.002) adjusted for treatment and the clinical variables age (HR 1.01, 95 % CI 0.99-1.03, p = 0.30), performance status (HR 1.34, 95 % CI 1.17-1.53, p < 0.001), and tumor crossing midline (HR 1.28, 95 % CI 0.79-2.07, p = 0.29). In conclusion, this study showed that high levels of c-Met holds unfavorable prognostic value in glioblastomas.
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Dang H, Steinway SN, Ding W, Rountree CB. Induction of tumor initiation is dependent on CD44s in c-Met⁺ hepatocellular carcinoma. BMC Cancer 2015; 15:161. [PMID: 25886575 PMCID: PMC4380258 DOI: 10.1186/s12885-015-1166-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 03/05/2015] [Indexed: 12/16/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumor-initiating stem-like cells (TISC) in several cancers including HCC. In this work, we examine the complex relationship between c-Met and CD44s (standard form), and investigate the specific role of CD44s as a tumor initiator and stemness marker in HCC. Methods Gene and protein expression assays were utilized to investigate the relationship between CD44s and c-Met in HCC cell lines. Tumor-sphere assays and in vivo tumor assays were performed to investigate the role of CD44+ cells as TISCs. Student’s t-test or one-way ANOVA with Tukeys post-hoc test was performed to test for differences amongst groups with a p < .05 as significant. Results In an immunohistochemical and immunoblot analysis of human HCC samples, we observed that more than 39% of human HCC samples express c-Met and CD44. To study the relationship between c-Met and CD44, we used MHCC97-H cells, which are CD44+/c-Met+. The knockdown of c-Met in MHCC97-H cells decreased CD44s, reduced TISC characteristics and decreased tumorsphere formation. Furthermore, we demonstrate that the inhibition of PI3K/AKT signaling decreased CD44s expression and subsequently decreased tumorsphere formation. The down-regulation of CD44s leads to a significant loss of a TISC and mesenchymal phenotype. Finally, the down-regulation of CD44s in MHCC97-H cells decreased tumor initiation in vivo compared with the scrambled control. Conclusions In summary, our data suggest that CD44s is modulated by the c-Met-PI3K-AKT signaling cascade to support a mesenchymal and TISC phenotype in HCC cells. Moreover, c-Met could be a potential therapeutic drug for targeting HCC cells with TISC and mesenchymal phenotypes. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1166-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hien Dang
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Penn State Children's Hospital, Hershey, PA, USA. .,Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, MD, 20892, USA.
| | - Steven N Steinway
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Penn State Children's Hospital, Hershey, PA, USA.
| | - Wei Ding
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Penn State Children's Hospital, Hershey, PA, USA.
| | - Carl B Rountree
- Department of Pediatrics and Pharmacology, The Pennsylvania State University, College of Medicine, Penn State Children's Hospital, Hershey, PA, USA. .,Bon Secours St. Mary's Hospital, 5875 Bremo Road, MOB South Suite 303, Richmond, VA, 23226, USA.
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Rimassa L, Personeni N, Santoro A. Tivantinib for hepatocellular carcinoma. Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2015.1009038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Lee D, Sung ES, Ahn JH, An S, Huh J, You WK. Development of antibody-based c-Met inhibitors for targeted cancer therapy. Immunotargets Ther 2015; 4:35-44. [PMID: 27471710 PMCID: PMC4918247 DOI: 10.2147/itt.s37409] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Signaling pathways mediated by receptor tyrosine kinases (RTKs) and their ligands play important roles in the development and progression of human cancers, which makes RTK-mediated signaling pathways promising therapeutic targets in the treatment of cancer. Compared with small-molecule compounds, antibody-based therapeutics can more specifically recognize and bind to ligands and RTKs. Several antibody inhibitors of RTK-mediated signaling pathways, such as human epidermal growth factor receptor 2, vascular endothelial growth factor, epidermal growth factor receptor or vascular endothelial growth factor receptor 2, have been developed and are widely used to treat cancer patients. However, since the therapeutic options are still limited in terms of therapeutic efficacy and types of cancers that can be treated, efforts are being made to identify and evaluate novel RTK-mediated signaling pathways as targets for more efficacious cancer treatment. The hepatocyte growth factor/c-Met signaling pathway has come into the spotlight as a promising target for development of potent cancer therapeutic agents. Multiple antibody-based therapeutics targeting hepatocyte growth factor or c-Met are currently in preclinical or clinical development. This review focuses on the development of inhibitors of the hepatocyte growth factor/c-Met signaling pathway for cancer treatment, including critical issues in clinical development and future perspectives for antibody-based therapeutics.
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Affiliation(s)
- Dongheon Lee
- Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea
| | - Eun-Sil Sung
- Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea
| | - Jin-Hyung Ahn
- Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea
| | - Sungwon An
- Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea
| | - Jiwon Huh
- Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea
| | - Weon-Kyoo You
- Hanwha Chemical R&D Center, Biologics Business Unit, Daejeon, Republic of Korea
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Wu JR, Hu CT, You RI, Ma PL, Pan SM, Lee MC, Wu WS. Preclinical trials for prevention of tumor progression of hepatocellular carcinoma by LZ-8 targeting c-Met dependent and independent pathways. PLoS One 2015; 10:e0114495. [PMID: 25607934 PMCID: PMC4301873 DOI: 10.1371/journal.pone.0114495] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 11/07/2014] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most lethal cancers. Mounting studies highlighted the essential role of the HGF/c-MET axis in driving HCC tumor progression. Therefore, c-Met is a potential therapeutic target for HCC. However, several concerns remain unresolved in c-Met targeting. First, the status of active c-Met in HCC must be screened to determine patients suitable for therapy. Second, resistance and side effects have been observed frequently when using conventional c-Met inhibitors. Thus, a preclinical system for screening the status of c-Met signaling and identifying efficient and safe anti-HCC agents is urgently required. In this study, immunohistochemical staining of phosphorylated c-Met (Tyr1234) on tissue sections indicated that HCCs with positive c-Met signaling accounted for approximately 46% in 26 cases. Second, many patient-derived HCC cell lines were established and characterized according to motility and c-Met signaling status. Moreover, LZ8, a medicinal peptide purified from the herb Lingzhi, featuring immunomodulatory and anticancer properties, was capable of suppressing cell migration and slightly reducing the survival rate of both c-Met positive and negative HCCs, HCC372, and HCC329, respectively. LZ8 also suppressed the intrahepatic metastasis of HCC329 in SCID mice. On the molecular level, LZ8 suppressed the expression of c-Met and phosphorylation of c-Met, ERK and AKT in HCC372, and suppressed the phosphorylation of JNK, ERK, and AKT in HCC329. According to receptor array screening, the major receptor tyrosine kinase activated in HCC329 was found to be the epidermal growth factor receptor (EGFR). Moreover, tyrosine-phosphorylated EGFR (the active EGFR) was greatly suppressed in HCC329 by LZ8 treatment. In addition, LZ8 blocked HGF-induced cell migration and c-Met-dependent signaling in HepG2. In summary, we designed a preclinical trial using LZ8 to prevent the tumor progression of patient-derived HCCs with c-Met-positive or -negative signaling.
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Affiliation(s)
- Jia-Ru Wu
- Institute of Medical Sciences, Tzu Chi University, Hualein, Taiwan
| | - Chi-Tan Hu
- Research Centre for Hepatology, Buddhist Tzu Chi General Hospital and Department of Internal Medicine Tzu Chi University, Hualien, Taiwan
| | - Ren-In You
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualein, Taiwan
| | - Pei-Ling Ma
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualein, Taiwan
| | - Siou-Mei Pan
- Research Centre for Hepatology, Buddhist Tzu Chi General Hospital and Department of Internal Medicine Tzu Chi University, Hualien, Taiwan
| | - Ming-Che Lee
- Department of Surgery, Buddhist Tzu Chi General Hospital, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Wen-Sheng Wu
- Institute of Medical Sciences, Tzu Chi University, Hualein, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualein, Taiwan
- * E-mail:
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Puzanov I, Sosman J, Santoro A, Saif MW, Goff L, Dy GK, Zucali P, Means-Powell JA, Ma WW, Simonelli M, Martell R, Chai F, Lamar M, Savage RE, Schwartz B, Adjei AA. Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. Invest New Drugs 2014; 33:159-68. [PMID: 25294187 PMCID: PMC4295023 DOI: 10.1007/s10637-014-0167-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 09/29/2014] [Indexed: 01/24/2023]
Abstract
PURPOSE This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.
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Affiliation(s)
- Igor Puzanov
- Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, USA,
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Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma. PLoS One 2014; 9:e105278. [PMID: 25148256 PMCID: PMC4141763 DOI: 10.1371/journal.pone.0105278] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 07/22/2014] [Indexed: 12/31/2022] Open
Abstract
c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC.
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