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Cancers
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Hepatocyte Growth Factor Pathway in Cancer
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Hepatocyte Growth Factor Pathway in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (28 February 2017) | Viewed by 67906

Special Issue Editor

Prof. Dr. Jill M. Siegfried

E-Mail Website
Guest Editor
Professor and Head, Department of Pharmacology, Frederick and Alice Stark Endowed Chair, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Interests: lung cancer; HGF; estrogen; EGFR; c-Met; targeted therapy; non-small cell lung cancer; cell signaling

Special Issue Information

Dear Colleagues,

Hepatocyte Growth Factor, the ligand for the c-MET receptor, plays a critical role in normal development, wound healing, and tissue regeneration. It is also important in angiogenesis, invasion, and metastasis in cancer. HGF is produced in the tumor microenvironment, usually secreted by mesenchymal cells, while c-MET is expressed by cells of many lineages, including epithelial, endothelial, and hematopoietic. In many solid tumors and hematological malignancies, mutation, amplification or over-expression of c-MET has been reported, as well as up-regulated levels of HGF. Cross-talk between c-MET and other tyrosine kinase receptors is well-documented, with c-MET serving to amplify signaling of the EGFR pathway and to activate HER3. Up-regulation of c-MET signaling is also found in patients who develop resistance to agents targeting EGFR and VEGFR, mainly through amplification or activating mutation.  Preclinical evidence is strong that the HGF/c-MET pathway contributes to many oncogenic processes, and a number of strategies have been developed to inhibit either the ligand or the receptor. Clinical trial results have been disappointing, however, for a number of solid tumors, and combination regimens with agents targeting the HGF/c-MET pathway have not performed, as well as predicted from laboratory and animal studies, or have proven highly toxic.

One of the current challenges is to identify the population of patients who would derive benefit from c-MET pathway interruption. Higher benefit could also justify the risks involved with combination therapies. Recent data suggest that patients with amplification or mutation of c-MET (such as exon 14-skipping mutations), either pre-existing or acquired after failure of another targeted therapy, show the highest dependence on HGF/c-MET signaling. Evidence also suggests that high expression level of c-MET protein confers dependence, but a standardized test of c-MET expression, or another biomarker that would provide guidance for patient selection, is still lacking. This Special Issue will highlight the current state of knowledge about HGF and c-MET in multiple cancers, including results of past clinical trials, agents still in clinical development, and status of biomarkers of sensitivity to these agents.

Prof. Dr. Jill M. Siegfried
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HGF
  • c-Met
  • receptor cross-talk
  • EGFR
  • HER3
  • microenvironment
  • invasion & metastasis
  • angiogenesis
  • lung cancer
  • gastric cancer
  • colorectal cancer

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Published Papers (7 papers)

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Review

18 pages, 256 KiB  
Review
Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer
by Oshin Miranda, Mariya Farooqui and Jill M. Siegfried
Cancers 2018, 10(9), 280; https://doi.org/10.3390/cancers10090280 - 21 Aug 2018
Cited by 53 | Viewed by 5800
Abstract
Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met (Mesenchymal Epithelial Transition Factor also known as Hepatocyte Growth Factor Receptor, HGFR), a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, [...] Read more.
Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met (Mesenchymal Epithelial Transition Factor also known as Hepatocyte Growth Factor Receptor, HGFR), a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, angiogenesis, and motility. The c-Met pathway also stimulates tissue repair in normal cells. A body of past research shows that increased levels of HGF and/or overexpression of c-Met are associated with poor prognosis in several solid tumors, including lung cancer, as well as cancers of the head and neck, gastro-intestinal tract, breast, ovary and cervix. The HGF/c-Met signaling network is complex; both ligand-dependent and ligand-independent signaling occur. This article will provide an update on signaling through the HGF/c-Met axis, the mechanism of action of HGF/c-Met inhibitors, the lung cancer patient populations most likely to benefit, and possible mechanisms of resistance to these inhibitors. Although c-Met as a target in non-small cell lung cancer (NSCLC) showed promise based on preclinical data, clinical responses in NSCLC patients have been disappointing in the absence of MET mutation or MET gene amplification. New therapeutics that selectively target c-Met or HGF, or that target c-Met and a wider spectrum of interacting tyrosine kinases, will be discussed. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
2357 KiB  
Review
Activated HGF-c-Met Axis in Head and Neck Cancer
by Levi Arnold, Jonathan Enders and Sufi Mary Thomas
Cancers 2017, 9(12), 169; https://doi.org/10.3390/cancers9120169 - 12 Dec 2017
Cited by 56 | Viewed by 12511
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
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1438 KiB  
Review
Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma
by Nichola Cruickshanks, Ying Zhang, Fang Yuan, Mary Pahuski, Myron Gibert and Roger Abounader
Cancers 2017, 9(7), 87; https://doi.org/10.3390/cancers9070087 - 11 Jul 2017
Cited by 56 | Viewed by 7656
Abstract
Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has [...] Read more.
Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
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558 KiB  
Review
The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches
by Chi-Tan Hu, Jia-Ru Wu, Chuan-Chu Cheng and Wen-Sheng Wu
Cancers 2017, 9(6), 58; https://doi.org/10.3390/cancers9060058 - 26 May 2017
Cited by 42 | Viewed by 10282
Abstract
The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor [...] Read more.
The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor progression, including HCC. Therefore, c-Met is now regarded as the most promising therapeutic target for the treatment of HCC. However, there are still concerns about resistance and the side effects of using conventional inhibitors of c-Met, such as tyrosine kinase inhibitors. Recently, many alternative strategies of c-Met targeting have been emerging. These include targeting the downstream effectors of c-Met, such as hydrogen peroxide-inducible clone 5 (Hic-5), to block the reactive oxygen species (ROS)-mediated signaling for HCC progression. Also, inhibition of endosomal regulators, such as PKCε and GGA3, may perturb the c-Met endosomal signaling for HCC cell migration. On the other hand, many herbal antagonists of c-Met-dependent signaling, such as saponin, resveratrol, and LZ-8, were identified. Taken together, it can be anticipated that more effective and safer c-Met targeting strategies for preventing HCC progression can be established in the future. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
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1265 KiB  
Review
HGF/Met Signaling in Cancer Invasion: The Impact on Cytoskeleton Remodeling
by Chuan Xiang, Junxia Chen and Panfeng Fu
Cancers 2017, 9(5), 44; https://doi.org/10.3390/cancers9050044 - 5 May 2017
Cited by 42 | Viewed by 9975
Abstract
The invasion of cancer cells into surrounding tissue and the vasculature is essential for tumor metastasis. Increasing evidence indicates that hepatocyte growth factor (HGF) induces cancer cell migration and invasion. A broad spectrum of mechanisms underlies cancer cell migration and invasion. Cytoskeletal reorganization [...] Read more.
The invasion of cancer cells into surrounding tissue and the vasculature is essential for tumor metastasis. Increasing evidence indicates that hepatocyte growth factor (HGF) induces cancer cell migration and invasion. A broad spectrum of mechanisms underlies cancer cell migration and invasion. Cytoskeletal reorganization is of central importance in the development of the phenotype of cancer cells with invasive behavior. Through their roles in cell mechanics, intracellular trafficking, and signaling, cytoskeleton proteins participate in all essential events leading to cell migration. HGF has been involved in cytoskeleton assembly and reorganization, and its role in regulating cytoskeleton dynamics is still expanding. This review summarizes our current understanding of the role of HGF in regulating cytoskeleton remodeling, distribution, and interactions. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
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Figure 1

498 KiB  
Review
Hepatocyte Growth Factor/c-Met Signaling in Head and Neck Cancer and Implications for Treatment
by Natalie J. Rothenberger and Laura P. Stabile
Cancers 2017, 9(4), 39; https://doi.org/10.3390/cancers9040039 - 24 Apr 2017
Cited by 46 | Viewed by 11170
Abstract
Aberrant signaling of the hepatocyte growth factor (HGF)/c-Met pathway has been identified as a promoter of tumorigenesis in several tumor types including head and neck squamous cell carcinoma (HNSCC). Despite a relatively low c-Met mutation frequency, overexpression of HGF and its receptor c-Met [...] Read more.
Aberrant signaling of the hepatocyte growth factor (HGF)/c-Met pathway has been identified as a promoter of tumorigenesis in several tumor types including head and neck squamous cell carcinoma (HNSCC). Despite a relatively low c-Met mutation frequency, overexpression of HGF and its receptor c-Met has been observed in more than 80% of HNSCC tumors, with preclinical and clinical studies linking overexpression with cellular proliferation, invasion, migration, and poor prognosis. c-Met is activated by HGF through a paracrine mechanism to promote cellular morphogenesis enabling cells to acquire mesenchymal phenotypes in part through the epithelial-mesenchymal transition, contributing to metastasis. The HGF/c-Met pathway may also act as a resistance mechanism against epidermal growth factor receptor (EGFR) inhibition in advanced HNSCC. Furthermore, with the identification of a biologically distinct subset of HNSCC tumors acquired from human papillomavirus (HPV) infection that generally portends a good prognosis, high expression of HGF or c-Met in HPV-negative tumors has been associated with worse prognosis. Dysregulated HGF/c-Met signaling results in an aggressive HNSCC phenotype which has led to clinical investigations for targeted inhibition of this pathway. In this review, HGF/c-Met signaling, pathway alterations, associations with clinical outcomes, and preclinical and clinical therapeutic strategies for targeting HGF/c-Met signaling in HNSCC are discussed. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
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2344 KiB  
Review
Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment
by Benjamin Yaw Owusu, Robert Galemmo, James Janetka and Lidija Klampfer
Cancers 2017, 9(4), 35; https://doi.org/10.3390/cancers9040035 - 17 Apr 2017
Cited by 89 | Viewed by 9404
Abstract
The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte [...] Read more.
The tumor microenvironment plays a key role in tumor development and progression. Stromal cells secrete growth factors, cytokines and extracellular matrix proteins which promote growth, survival and metastatic spread of cancer cells. Fibroblasts are the predominant constituent of the tumor stroma and Hepatocyte Growth Factor (HGF), the specific ligand for the tyrosine kinase receptor c-MET, is a major component of their secretome. Indeed, cancer-associated fibroblasts have been shown to promote growth, survival and migration of cancer cells in an HGF-dependent manner. Fibroblasts also confer resistance to anti-cancer therapy through HGF-induced epithelial mesenchymal transition (EMT) and activation of pro-survival signaling pathways such as ERK and AKT in tumor cells. Constitutive HGF/MET signaling in cancer cells is associated with increased tumor aggressiveness and predicts poor outcome in cancer patients. Due to its role in tumor progression and therapeutic resistance, both HGF and MET have emerged as valid therapeutic targets. Several inhibitors of MET and HGF are currently being tested in clinical trials. Preclinical data provide a strong indication that inhibitors of HGF/MET signaling overcome both primary and acquired resistance to EGFR, HER2, and BRAF targeting agents. These findings support the notion that co-targeting of cancer cells and stromal cells is required to prevent therapeutic resistance and to increase the overall survival rate of cancer patients. HGF dependence has emerged as a hallmark of therapeutic resistance, suggesting that inhibitors of biological activity of HGF should be included into therapeutic regimens of cancer patients. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor Pathway in Cancer)
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