Special Issue "MET in Cancer"

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

Deadline for manuscript submissions: closed (31 May 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Livio Trusolino

Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, 10060 Candiolo, Torino, Italy
Website | E-Mail
Fax: +39 011 993 3225
Interests: MET oncogene; tyrosine kinase signalling; anti-cancer targeted therapies; genetic determinants of response and resistance; preclinical animal models; molecular pathology of colorectal cancer

Special Issue Information

Dear Colleagues,

This special issue invites investigators to contribute original research reports as well as review articles that describe studies on the MET oncogene.

The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET signaling triggers pro-mitogenic and anti-apoptotic pathways that sustain tumor growth and progression in several cancer settings. Accordingly, relentless activation of MET due to protein overexpression or gain-of-function genetic abnormalities is a hallmark of several malignancies and correlates with aggressive disease. Recent drug development efforts have led to the characterization of several MET-blocking reagents, including monoclonal antibodies and small molecule inhibitors, some of which have entered clinical trials. The challenge now is to leverage what is known about MET genetics, signals and functions for molecularly-based stratification of patients potentially responsive to MET inhibition.

Tentative topics include, but are not limited to:

  • Insights into the signaling mechanisms of MET activity: receptor recycling, degradation, and signal compartmentalization.
  • Predictive biomarkers of response and resistance to MET inhibitors
  • Tumor settings that might benefit from rational treatment with MET inhibitors
  • MET activation and resistance to targeted therapies
  • MET in the tumor microenvironment

Prof. Dr. Livio Trusolino
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • cell migration and invasion
  • prognostic and predictive biomarkers
  • MET inhibitors
  • MET-dependent signal transduction pathways
  • oncogene addiction
  • tumor-stroma interactions

Published Papers (9 papers)

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Research

Jump to: Review

Open AccessArticle Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder
Cancers 2014, 6(4), 2313-2329; doi:10.3390/cancers6042313
Received: 8 August 2014 / Revised: 5 November 2014 / Accepted: 13 November 2014 / Published: 25 November 2014
Cited by 4 | PDF Full-text (2020 KB) | HTML Full-text | XML Full-text
Abstract
There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell
[...] Read more.
There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted. Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessArticle The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models
Cancers 2014, 6(3), 1736-1752; doi:10.3390/cancers6031736
Received: 28 May 2014 / Revised: 22 July 2014 / Accepted: 31 July 2014 / Published: 19 August 2014
Cited by 7 | PDF Full-text (1294 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy
[...] Read more.
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase with hepatocyte growth factor (HGF) as its only high-affinity ligand. Aberrant activation of c-Met is associated with many human malignancies, including hepatocellular carcinoma (HCC). We investigated the in vivo antitumor and antimetastatic efficacy of the c-Met inhibitor MSC2156119J (EMD 1214063) in patient-derived tumor explants. BALB/c nude mice were inoculated with MHCC97H cells or with tumor fragments of 10 patient-derived primary liver cancer explants selected according to c-Met/HGF expression levels. MSC2156119J (10, 30, and 100 mg/kg) and sorafenib (50 mg/kg) were administered orally as single-agent treatment or in combination, with vehicle as control. Tumor response, metastases formation, and alpha fetoprotein (AFP) levels were measured. MSC2156119J inhibited tumor growth and induced complete regression in mice bearing subcutaneous and orthotopic MHCC97H tumors. AFP levels were undetectable after 5 weeks of MSC2156119J treatment, and the number of metastatic lung foci was reduced. Primary liver explant models with strong c-Met/HGF activation showed increased responsiveness to MSC2156119J, with MSC2156119J showing similar or superior activity to sorafenib. Tumors characterized by low c-Met expression were less sensitive to MSC2156119J. MSC2156119J was better tolerated than sorafenib, and combination therapy did not improve efficacy. These findings indicate that selective c-Met/HGF inhibition with MSC2156119J is associated with marked regression of c-Met high-expressing tumors, supporting its clinical development as an antitumor treatment for HCC patients with active c-Met signaling. Full article
(This article belongs to the Special Issue MET in Cancer)

Review

Jump to: Research

Open AccessReview Met in Urological Cancers
Cancers 2014, 6(4), 2387-2403; doi:10.3390/cancers6042387
Received: 19 June 2014 / Revised: 3 December 2014 / Accepted: 4 December 2014 / Published: 16 December 2014
Cited by 5 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
Abstract
Met is a tyrosine kinase receptor that is considered to be a proto-oncogene. The hepatocyte growth factor (HGF)-Met signaling system plays an important role in tumor growth, invasion, and metastasis in many types of malignancies. Furthermore, Met expression has been reported to be
[...] Read more.
Met is a tyrosine kinase receptor that is considered to be a proto-oncogene. The hepatocyte growth factor (HGF)-Met signaling system plays an important role in tumor growth, invasion, and metastasis in many types of malignancies. Furthermore, Met expression has been reported to be a useful predictive biomarker for disease progression and patient survival in these malignancies. Many studies have focused on the clinical significance and prognostic role of Met in urological cancers, including prostate cancer (PCa), renal cell carcinoma (RCC), and urothelial cancer. Several preclinical studies and clinical trials are in progress. In this review, the current understanding of the pathological role of Met in cancer cell lines, its clinical significance in cancer tissues, and its predictive value in patients with urological cancers are summarized. In particular, Met-related malignant behavior in castration-resistant PCa and the different pathological roles Met plays in papillary RCC and other histological types of RCC are the subjects of focus. In addition, the pathological significance of phosphorylated Met in these cancers is shown. In recent years, Met has been recognized as a potential therapeutic target in various types of cancer; therapeutic strategies used by Met-targeted agents in urological cancers are summarized in this review. Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessReview MET and Small-Cell Lung Cancer
Cancers 2014, 6(4), 2100-2115; doi:10.3390/cancers6042100
Received: 6 August 2014 / Revised: 21 September 2014 / Accepted: 22 September 2014 / Published: 13 October 2014
Cited by 10 | PDF Full-text (373 KB) | HTML Full-text | XML Full-text
Abstract
Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this
[...] Read more.
Small-cell lung cancer (SCLC) is one of the most aggressive lung tumors. The majority of patients with SCLC are diagnosed at an advanced stage. This tumor type is highly sensitive to chemo-radiation treatment, with very high response rates, but invariably relapses. At this time, treatment options are still limited and the prognosis of these patients is poor. A better knowledge of the molecular biology of SCLC allowed us to identify potential druggable targets. Among these, the MET/HGF axis seems to be one of the most aberrant signaling pathways involved in SCLC invasiveness and progression. In this review, we describe briefly all recent literature on the different molecular profiling in SCLC; in particular, we discuss the specific alterations involving c-MET gene and their implications as a potential target in SCLC. Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessReview Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues
Cancers 2014, 6(4), 1890-1904; doi:10.3390/cancers6041890
Received: 2 July 2014 / Revised: 2 September 2014 / Accepted: 3 September 2014 / Published: 29 September 2014
Cited by 14 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature
[...] Read more.
Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. Given the mildly acidic extracellular environment of solid tumors, matriptase activation may, thus, be accelerated in the tumor microenvironment. HGFA and matriptase activities are regulated by HGFA inhibitor (HAI)-1 (HAI-1) and/or HAI-2 in the pericellular microenvironment. HAIs may have an important role in cancer cell biology by regulating HGF/SF-activating proteases. Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessReview The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?
Cancers 2014, 6(3), 1631-1669; doi:10.3390/cancers6031631
Received: 30 May 2014 / Revised: 4 August 2014 / Accepted: 4 August 2014 / Published: 12 August 2014
Cited by 4 | PDF Full-text (2256 KB) | HTML Full-text | XML Full-text
Abstract
Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid
[...] Read more.
Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs). Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessReview Targeting MET Amplification as a New Oncogenic Driver
Cancers 2014, 6(3), 1540-1552; doi:10.3390/cancers6031540
Received: 21 May 2014 / Revised: 13 July 2014 / Accepted: 15 July 2014 / Published: 22 July 2014
Cited by 10 | PDF Full-text (580 KB) | HTML Full-text | XML Full-text
Abstract
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy
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Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy. Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessReview The Molecular Crosstalk between the MET Receptor Tyrosine Kinase and the DNA Damage Response—Biological and Clinical Aspects
Cancers 2014, 6(1), 1-27; doi:10.3390/cancers6010001
Received: 1 October 2013 / Revised: 6 December 2013 / Accepted: 6 December 2013 / Published: 19 December 2013
Cited by 5 | PDF Full-text (656 KB) | HTML Full-text | XML Full-text
Abstract
Radiation therapy remains an imperative treatment modality for numerous malignancies. Enduring significant technical achievements both on the levels of treatment planning and radiation delivery have led to improvements in local control of tumor growth and reduction in healthy tissue toxicity. Nevertheless, resistance mechanisms,
[...] Read more.
Radiation therapy remains an imperative treatment modality for numerous malignancies. Enduring significant technical achievements both on the levels of treatment planning and radiation delivery have led to improvements in local control of tumor growth and reduction in healthy tissue toxicity. Nevertheless, resistance mechanisms, which presumably also involve activation of DNA damage response signaling pathways that eventually may account for loco-regional relapse and consequent tumor progression, still remain a critical problem. Accumulating data suggest that signaling via growth factor receptor tyrosine kinases, which are aberrantly expressed in many tumors, may interfere with the cytotoxic impact of ionizing radiation via the direct activation of the DNA damage response, leading eventually to so-called tumor radioresistance. The aim of this review is to overview the current known data that support a molecular crosstalk between the hepatocyte growth factor receptor tyrosine kinase MET and the DNA damage response. Apart of extending well established concepts over MET biology beyond its function as a growth factor receptor, these observations directly relate to the role of its aberrant activity in resistance to DNA damaging agents, such as ionizing radiation, which are routinely used in cancer therapy and advocate tumor sensitization towards DNA damaging agents in combination with MET targeting. Full article
(This article belongs to the Special Issue MET in Cancer)
Open AccessReview Role of Met Axis in Head and Neck Cancer
Cancers 2013, 5(4), 1601-1618; doi:10.3390/cancers5041601
Received: 15 October 2013 / Revised: 12 November 2013 / Accepted: 14 November 2013 / Published: 26 November 2013
Cited by 3 | PDF Full-text (354 KB) | HTML Full-text | XML Full-text
Abstract
Head and neck cancer is the sixth most common type of cancer worldwide. Despite advances in aggressive multidisciplinary treatments, the 5-year survival rate for this dreadful disease is only 50%, mostly due to high rate of recurrence and early involvement of regional lymph
[...] Read more.
Head and neck cancer is the sixth most common type of cancer worldwide. Despite advances in aggressive multidisciplinary treatments, the 5-year survival rate for this dreadful disease is only 50%, mostly due to high rate of recurrence and early involvement of regional lymph nodes and subsequent metastasis. Understanding the molecular mechanisms responsible for invasion and metastasis is one of the most pressing goals in the field of head and neck cancer. Met, also known as hepatocyte growth factor receptor (HGFR), is a member of the receptor protein tyrosine kinase (RPTK) family. There is compelling evidence that Met axis is dysregulated and plays important roles in tumorigenesis, progression, metastasis, angiogenesis, and drug resistance in head and neck cancer. We describe in this review current understanding of Met axis in head and neck cancer biology and development of therapeutic inhibitors targeting Met axis. Full article
(This article belongs to the Special Issue MET in Cancer)

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