Special Issue "New aspects of the Hepatocyte Growth Factor/c-Met System"

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A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (31 December 2014)

Special Issue Editors

Guest Editor
Dr. Giulia Ricci (Website)

Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Interests: growth factors, reproductive biology, embryonic development, testicular germ cell tumours
Guest Editor
Dr. Angela Catizone (Website)

Department of Anatomy, Histology, Forensic Medicine, and Orthopedics "Sapienza" University of Rome, Rome, Italy
Interests: growth factors, reproductive biology, embryonic development, testicular germ cell tumours
Guest Editor
Prof. Dr. Maria Prat (Website)

Department of Health Sciences Universitá del Piemonte Orientale, Novara, Italy
Phone: +390321660662
Interests: Hepatocyte Growth Factor and its receptor in physiology and pathology, adults stem cells, cardiac tissue engineering, nanoparticle carriers
Guest Editor
Dr. Stefania Scarpino (Website)

Department of Clinical and Molecular Medicine "Sapienza" University of Rome Sant'Andrea Hospital, Rome, Italy
Interests: thyroid tumour; cancer genetic
Guest Editor
Dr. Rob Zachow (Website)

Department of Biochemistry and Molecular Biology/Office of Education Rutgers-RobertWood Johnson Medical School Piscataway, NJ, USA
Interests: Endocrinology, reproductive endocrinology, steroidogenesis, ovarian follicular development
Guest Editor
Dr. Zimmer Yitzhak (Website)

Radiation Oncology Research Laboratory, Department of Clinical Research, University of Bern, Freiburgstrasse, Bern, Switzerland
Interests: MET RTK, DNA Damage Response, Mechanisms of Treatment Resistance in Cancer, PTM proteomics

Special Issue Information

Dear Colleagues,

This Special Issue, "New Insights on the Many Faces of the HGF/c-Met System", will mainly focus on the several roles exerted by the Hepatocyte Growth Factor (HGF) in development homeostasis (and related diseases).

The Hepatocyte Growth Factor/c- Met (HGF/c-Met) system has been extensively studied in the past two decades and has been shown to mediate multiple biological activities, such as cellular proliferation, survival, motility, morphogenesis, and angiogenesis. These pleiotropic and complex physiological functions act together during organogenesis and tissue homeostasis but can give rise to a broad spectrum of pathologies when the HGF/c-Met system physiological balance is disrupted. Knowledge of the HGF/c-Met physiological and pathological activities, and the elucidation of the pathways mediating them, have enabled the development of several promising “HGF-based” molecules with therapeutic effects. Examples of such molecules include HGF variants or fragments, HGF chimeras, and c-Met agonists/antagonists. Thus, newly available biotechnologies can help us address the challenges of preventing organ failure and contrasting cancer. We thus consider this subject to be of particular interest; the topic can expand biomedicine toward new horizons.

We invite authors to submit original research and review articles that focus on the biological functions and therapeutic potential of the HGF/c-Met system (or related molecules). Potential topics include, but are not limited to:

  • HGF/c-Met system pathways;
  • The biochemical characteristics of HGF and c-Met;
  • The role of HGF in embryonic development and organogenesis;
  • The role of HGF in tissue regeneration, homeostasis, and repair;
  • HGF/c-Met in carcinogenesis;
  • Recent advances in cancer therapies, based on interference with the HGF/c-Met system’s biological functions.

Dr. Giulia Ricci
Dr. Angela Catizone
Prof. Dr. Maria Prat
Dr. Stefania Scarpino
Dr. Rob Zachow
Dr. Zimmer Yitzhak
Guest Editors

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. Biomedicines is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. For the first couple of issues the Article Processing Charge (APC) will be waived for well-prepared manuscripts. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Published Papers (18 papers)

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Editorial

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Open AccessEditorial Editorial of Special Issue “New Aspects of the Hepatocyte Growth Factor/c-Met System”
Biomedicines 2015, 3(2), 201-202; doi:10.3390/biomedicines3020201
Received: 9 April 2015 / Revised: 1 June 2015 / Accepted: 1 June 2015 / Published: 5 June 2015
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Abstract HGF/c-Met system has covered, in the past two decades, multiple areas of research, from basic cell biology to clinical trials. This research topic witnessed a good deal of scientific interest and progress. [...] Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)

Research

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Open AccessArticle Anti-Differentiation Effect of Oncogenic Met Receptor in Terminally-Differentiated Myotubes
Biomedicines 2015, 3(1), 124-137; doi:10.3390/biomedicines3010124
Received: 23 December 2014 / Accepted: 4 February 2015 / Published: 12 February 2015
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Abstract
Activation of the hepatocyte growth factor/Met receptor is involved in muscle regeneration, through promotion of proliferation and inhibition of differentiation in myogenic stem cells (MSCs). We previously described that the specific expression of an oncogenic version of the Met receptor (Tpr–Met) in [...] Read more.
Activation of the hepatocyte growth factor/Met receptor is involved in muscle regeneration, through promotion of proliferation and inhibition of differentiation in myogenic stem cells (MSCs). We previously described that the specific expression of an oncogenic version of the Met receptor (Tpr–Met) in terminally-differentiated skeletal muscle causes muscle wasting in vivo. Here, we induced Tpr–Met in differentiated myotube cultures derived from the transgenic mouse. These cultures showed a reduced protein level of myosin heavy chain (MyHC), increased phosphorylation of Erk1,2 MAPK, the formation of giant sacs of myonuclei and the collapse of elongated myotubes. Treatment of the cultures with an inhibitor of the MAPK kinase pathway or with an inhibitor of the proteasome increased the expression levels of MyHC. In addition, the inhibition of the MAPK kinase pathway prevented the formation of myosacs and myotube collapse. Finally, we showed that induction of Tpr–Met in primary myotubes was unable to produce endoreplication in their nuclei. In conclusion, our data indicate that multinucleated, fused myotubes may be forced to disassemble their contractile apparatus by the Tpr–Met oncogenic factor, but they resist the stimulus toward the reactivation of the cell cycle. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessArticle Expression of Hepatocyte Growth Factor-Like Protein in Human Wound Tissue and Its Biological Functionality in Human Keratinocytes
Biomedicines 2015, 3(1), 110-123; doi:10.3390/biomedicines3010110
Received: 29 June 2014 / Revised: 29 September 2014 / Accepted: 27 January 2015 / Published: 4 February 2015
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Abstract
Hepatocyte growth factor-like protein (HGFl) and its receptor, Recepteur d'Origine Nantais (RON), have been implicated in the development of wound chronicity. HGFl and RON expression was detected in acute wound tissue, chronic wound tissue and in normal skin using quantitative polymerase chain [...] Read more.
Hepatocyte growth factor-like protein (HGFl) and its receptor, Recepteur d'Origine Nantais (RON), have been implicated in the development of wound chronicity. HGFl and RON expression was detected in acute wound tissue, chronic wound tissue and in normal skin using quantitative polymerase chain reaction (Q-PCR). HGFl and RON expression was also assessed in chronic healing and chronic non-healing wound tissues using Q-PCR and immunohistochemical staining. Expression was similarly detected in the HaCaT immortalized human keratinocyte cell line using reverse transcription polymerase chain reaction (RT-PCR). rhHGFl was used to assess the impact of this molecule on HaCaT cell functionality using in vitro growth assays and electric cell-substrate impendence sensing (ECIS) migration assays. HGFl and RON transcript expression were significantly increased in acute wound tissue compared to chronic wound tissue and were also elevated, though non-significantly, in comparison to normal skin. Minimal expression was seen in both healing and non-healing chronic wounds. Treatment of HaCaT cells with rhHGFl had no effect on growth rates but did enhance cell migration. This effect was abolished by the addition of a phospholipase C gamma (PLCγ) small molecule inhibitor. The increased expression of HGFl and RON in acute, healing wounds and the pro-migratory effect of HGFl in an in vitro human keratinocyte model, may indicate a role for HGFl in active wound healing. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
Open AccessArticle HGF Modulates Actin Cytoskeleton Remodeling and Contraction in Testicular Myoid Cells
Biomedicines 2015, 3(1), 89-109; doi:10.3390/biomedicines3010089
Received: 29 September 2014 / Revised: 10 November 2014 / Accepted: 21 January 2015 / Published: 28 January 2015
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Abstract
The presence of the HGF/Met system in the testicular myoid cells was first discovered by our group. However, the physiological role of this pathway remains poorly understood. We previously reported that HGF increases uPA secretion and TGF-β activation in cultured tubular fragments [...] Read more.
The presence of the HGF/Met system in the testicular myoid cells was first discovered by our group. However, the physiological role of this pathway remains poorly understood. We previously reported that HGF increases uPA secretion and TGF-β activation in cultured tubular fragments and that HGF is maximally expressed at Stages VII–VIII of the seminiferous epithelium cycle, when myoid cell contraction occurs. It is well known that the HGF/Met pathway is involved in cytoskeletal remodeling; moreover, the interaction of uPA with its receptor, uPAR, as well as the activation of TGF-β have been reported to be related to the actin cytoskeleton contractility of smooth muscle cells. Herein, we report that HGF induces actin cytoskeleton remodeling in vitro in isolated myoid cells and myoid cell contraction in cultured seminiferous tubules. To better understand these phenomena, we evaluated: (1) the regulation of the uPA machinery in isolated myoid cells after HGF administration; and (2) the effect of uPA or Met inhibition on HGF-treated tubular fragments. Because uPA activates latent TGF-β, the secretion of this factor was also evaluated. We found that both uPA and TGF-β activation increase after HGF administration. In testicular tubular fragments, HGF-induced TGF-β activation and myoid cell contraction are abrogated by uPA or Met inhibitor administration. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessArticle Epithelial-Mesenchymal Transition in Metastatic Cancer Cell Populations Affects Tumor Dormancy in a Simple Mathematical Model
Biomedicines 2014, 2(4), 384-402; doi:10.3390/biomedicines2040384
Received: 29 August 2014 / Revised: 7 November 2014 / Accepted: 28 November 2014 / Published: 9 December 2014
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Abstract
Signaling from the c-Met receptor tyrosine kinase is associated with progression and metastasis of epithelial tumors. c-Met, the receptor for hepatocyte growth factor, triggers epithelial-mesenchymal transition (EMT) of cultured cells, which is thought to drive migration of tumor cells and confer on [...] Read more.
Signaling from the c-Met receptor tyrosine kinase is associated with progression and metastasis of epithelial tumors. c-Met, the receptor for hepatocyte growth factor, triggers epithelial-mesenchymal transition (EMT) of cultured cells, which is thought to drive migration of tumor cells and confer on them critical stem cell properties. Here, we employ mathematical modeling to better understand how EMT affects population dynamics in metastatic tumors. We find that without intervention, micrometastatic tumors reach a steady-state population. While the rates of proliferation, senescence and death only have subtle effects on the steady state, changes in the frequency of EMT dramatically alter population dynamics towards exponential growth. We also find that therapies targeting cell proliferation or cell death are markedly more successful when combined with one that prevents EMT, though such therapies do little when used alone. Stochastic modeling reveals the probability of tumor recurrence from small numbers of residual differentiated tumor cells. EMT events in metastatic tumors provide a plausible mechanism by which clinically detectable tumors can arise from dormant micrometastatic tumors. Modeling the dynamics of this process demonstrates the benefit of a treatment that eradicates tumor cells and reduces the rate of EMT simultaneously. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Review

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Open AccessReview Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment
Biomedicines 2015, 3(1), 149-181; doi:10.3390/biomedicines3010149
Received: 22 January 2015 / Revised: 25 February 2015 / Accepted: 3 March 2015 / Published: 19 March 2015
Cited by 2 | PDF Full-text (1248 KB) | HTML Full-text | XML Full-text
Abstract
The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated [...] Read more.
The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview HGF/Met-Signaling Contributes to Immune Regulation by Modulating Tolerogenic and Motogenic Properties of Dendritic Cells
Biomedicines 2015, 3(1), 138-148; doi:10.3390/biomedicines3010138
Received: 23 December 2014 / Revised: 6 February 2015 / Accepted: 13 February 2015 / Published: 3 March 2015
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Abstract
Hepatocyte growth factor (HGF)-signaling via Met can induce mitogenic, morphogenic, and motogenic activity in various cell types. Met expression in the immune system is limited to cells with antigen-presenting capacities, including dendritic cells (DCs). Thus, it appears highly conceivable that Met-signaling impacts [...] Read more.
Hepatocyte growth factor (HGF)-signaling via Met can induce mitogenic, morphogenic, and motogenic activity in various cell types. Met expression in the immune system is limited to cells with antigen-presenting capacities, including dendritic cells (DCs). Thus, it appears highly conceivable that Met-signaling impacts on adaptive immune responses. However, the mechanisms by which HGF imparts its effects on immunological responses are not yet fully understood. DCs possess unique functionalities that are critically involved in controlling both tolerance and immunity. HGF conveys immunoregulatory functions, which strongly correlate with that of DCs orchestrating the apt immune response in inflammation. Therefore, this review focuses on the current knowledge of Met-signaling in DCs with specific emphasis on the morphogenic and motogenic activities. HGF has been identified to play a role in peripheral immune tolerance by directing DC differentiation towards a tolerogenic phenotype. In skin immunity, Met-signaling was shown to drive mobilization of DCs by regulating matrix metalloproteinase activities. This is strikingly reminiscent of the role of Met for regulating a cell fate program during embryonic development, wound healing, and in tumor invasion known as epithelial-mesenchymal transition (EMT). Thus, the concept emerges that an EMT program is executed by Met-signaling in DCs, which will be also discussed. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation
Biomedicines 2015, 3(1), 71-88; doi:10.3390/biomedicines3010071
Received: 30 September 2014 / Accepted: 9 December 2014 / Published: 22 January 2015
Cited by 2 | PDF Full-text (4272 KB) | HTML Full-text | XML Full-text
Abstract
Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each [...] Read more.
Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF) is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview c-Met and Other Cell Surface Molecules: Interaction, Activation and Functional Consequences
Biomedicines 2015, 3(1), 46-70; doi:10.3390/biomedicines3010046
Received: 29 September 2014 / Accepted: 8 January 2015 / Published: 15 January 2015
Cited by 1 | PDF Full-text (3677 KB) | HTML Full-text | XML Full-text
Abstract
The c-Met receptor, also known as the HGF receptor, is one of the most studied tyrosine kinase receptors, yet its biological functions and activation mechanisms are still not fully understood. c-Met has been implicated in embryonic development and organogenesis, in tissue remodelling [...] Read more.
The c-Met receptor, also known as the HGF receptor, is one of the most studied tyrosine kinase receptors, yet its biological functions and activation mechanisms are still not fully understood. c-Met has been implicated in embryonic development and organogenesis, in tissue remodelling homeostasis and repair and in cancer metastasis. These functions are indicative of the many cellular processes in which the receptor plays a role, including cell motility, scattering, survival and proliferation. In the context of malignancy, sustained activation of c-Met leads to a signalling cascade involving a multitude of kinases that initiate an invasive and metastatic program. Many proteins can affect the activation of c-Met, including a variety of other cell surface and membrane-spanning molecules or receptors. Some cell surface molecules share structural homology with the c-Met extracellular domain and can activate c-Met via clustering through this domain (e.g., plexins), whereas other receptor tyrosine kinases can enhance c-Met activation and signalling through intracellular signalling cascades (e.g., EGFR). In this review, we provide an overview of c-Met interactions and crosstalk with partner molecules and the functional consequences of these interactions on c-Met activation and downstream signalling, c-Met intracellular localization/recycling and c-Met degradation. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview c-Met and miRs in Cancer
Biomedicines 2015, 3(1), 32-44; doi:10.3390/biomedicines3010032
Received: 29 September 2014 / Accepted: 24 December 2014 / Published: 5 January 2015
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Abstract
c-Met, a member of the receptor tyrosine kinase family, is involved in a wide range of cellular processes, including tumor survival, cell growth, angiogenesis and metastasis, and resulting in overexpression in many human cancers, leading to a constitutive activation of the downstream [...] Read more.
c-Met, a member of the receptor tyrosine kinase family, is involved in a wide range of cellular processes, including tumor survival, cell growth, angiogenesis and metastasis, and resulting in overexpression in many human cancers, leading to a constitutive activation of the downstream pathways. Recently identified MicroRNAs are a family of small noncoding RNA molecules, extensively studied in cancer, that exert their action by inhibiting gene expression at the posttranscriptional level in several biological processes. Aberrant regulation of microRNAs expression has been implicated in the pathogenesis of different human neoplasia. Several publications point out the connections between c-Met and its ligand hepatocyte growth factor (HGF) and microRNAs. This review summarizes the current knowledge about the interplay between c-Met/HGF and microRNAs and provides evidence that microRNAs are a novel and additional system to regulate c-Met expression in tumors. In the future, microRNAs connected to c-Met may provide an additional option to inhibiting this oncogene from orchestrating an invasive growth program. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview Physiological Signaling and Structure of the HGF Receptor MET
Biomedicines 2015, 3(1), 1-31; doi:10.3390/biomedicines3010001
Received: 30 September 2014 / Accepted: 9 December 2014 / Published: 31 December 2014
Cited by 2 | PDF Full-text (7075 KB) | HTML Full-text | XML Full-text
Abstract
The “hepatocyte growth factor” also known as “scatter factor”, is a multifunctional cytokine with the peculiar ability of simultaneously triggering epithelial cell proliferation, movement and survival. The combination of those proprieties results in the induction of an epithelial to mesenchymal transition in [...] Read more.
The “hepatocyte growth factor” also known as “scatter factor”, is a multifunctional cytokine with the peculiar ability of simultaneously triggering epithelial cell proliferation, movement and survival. The combination of those proprieties results in the induction of an epithelial to mesenchymal transition in target cells, fundamental for embryogenesis but also exploited by tumor cells during metastatization. The hepatocyte growth factor receptor, MET, is a proto-oncogene and a prototypical transmembrane tyrosine kinase receptor. Inhere we discuss the MET molecular structure and the hepatocyte growth factor driven physiological signaling which coordinates epithelial proliferation, motility and morphogenesis. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
Open AccessReview Monoclonal Antibodies against the MET/HGF Receptor and Its Ligand: Multitask Tools with Applications from Basic Research to Therapy
Biomedicines 2014, 2(4), 359-383; doi:10.3390/biomedicines2040359
Received: 6 October 2014 / Revised: 21 November 2014 / Accepted: 24 November 2014 / Published: 3 December 2014
Cited by 1 | PDF Full-text (1006 KB) | HTML Full-text | XML Full-text
Abstract
Monoclonal antibodies can be seen as valuable tools for many aspects of basic as well as applied sciences. In the case of MET/HGFR, they allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing [...] Read more.
Monoclonal antibodies can be seen as valuable tools for many aspects of basic as well as applied sciences. In the case of MET/HGFR, they allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing structure–function relationships. Antibodies directed against MET extracellular domain were found to be full or partial receptor agonists or antagonists. The agonists can mimic the effects of the different isoforms of the natural ligand, but with the advantage of being more stable than the latter. Thus, some agonist antibodies promote all the biological responses triggered by MET activation, including motility, proliferation, morphogenesis, and protection from apoptosis, while others can induce only a migratory response. On the other hand, antagonists can inhibit MET-driven biological functions either by competing with the ligand or by removing the receptor from the cell surface. Since MET/HGFR is often over-expressed and/or aberrantly activated in tumors, monoclonal antibodies can be used as probes for MET detection or as “bullets” to target MET-expressing tumor cells, thus pointing to their use in diagnosis and therapy. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview Role of HGF–MET Signaling in Primary and Acquired Resistance to Targeted Therapies in Cancer
Biomedicines 2014, 2(4), 345-358; doi:10.3390/biomedicines2040345
Received: 22 August 2014 / Revised: 11 November 2014 / Accepted: 17 November 2014 / Published: 25 November 2014
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Abstract
The Hepatocyte growth factor (HGF)—mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. [...] Read more.
The Hepatocyte growth factor (HGF)—mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. HGF–MET aberrant activation in tumorigenesis acts through various mechanisms: paracrine/autocrine HGF production, MET overexpression, MET germ-line and sporadic mutations and cross-talk with other growth factor receptors. In addition, MET activation could represent a mechanism of escape from other targeted therapies, through receptor amplification or over-stimulation by the ligand, as demonstrated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and also in models of melanoma resistant to the BRAF inhibitor vemurafenib. As a consequence, a lot of molecules targeting MET signaling are under clinical investigation as single agent or in combination with other targeted drugs. Patient selection, based on MET expression on tumor samples (eventually, by re-biopsy of new metastatic sites), and pharmacokinetic/pharmacodynamic markers are needed. Authors review the latest data on the role of MET and the molecular mechanism underlying primary or acquired resistance to biological agents, focusing on NSCLC, CRC and melanoma. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis
Biomedicines 2014, 2(4), 327-344; doi:10.3390/biomedicines2040327
Received: 30 September 2014 / Revised: 3 November 2014 / Accepted: 6 November 2014 / Published: 14 November 2014
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Abstract
Malignant mesothelioma (MM) is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF) and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in [...] Read more.
Malignant mesothelioma (MM) is a highly aggressive cancer related to asbestos or erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF) and its tyrosine kinase receptor Met regulate cell growth, survival, motility/migration, and invasion. HGF and Met are expressed in MM cells, suggesting that the HGF/Met signaling plays a role in development and progression of this tumor, by autocrine and/or paracrine mechanisms. Upregulation and ligand-independent activation of Met, which is under suppressive control of miR-34 family members, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. Moreover, Simian Virus 40 (SV40) Tag expression also induces a HGF autocrine circuit in an Rb-dependent manner in human mesothelial cells (HM) and possibly other cell types, enhancing cell adhesion, invasion and angiogenesis. The resulting activation of Met causes HM transformation and cell cycle progression, and contributes to virus particle assembling and infection of adjacent cells. The constitutive activation of Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, Met expression, activation state, subcellular localization and also HGF co-receptors expression, such as CD44, have clinical relevance for novel targeted therapies in a cancer for which no effective treatment is currently available. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview Hepatocyte Growth Factor Isoforms in Tissue Repair, Cancer, and Fibrotic Remodeling
Biomedicines 2014, 2(4), 301-326; doi:10.3390/biomedicines2040301
Received: 19 August 2014 / Revised: 21 October 2014 / Accepted: 27 October 2014 / Published: 5 November 2014
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Abstract
Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleotropic factor required for normal organ development during embryogenesis. In the adult, basal expression of HGF maintains tissue homeostasis and is up-regulated in response to tissue injury. HGF expression is [...] Read more.
Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleotropic factor required for normal organ development during embryogenesis. In the adult, basal expression of HGF maintains tissue homeostasis and is up-regulated in response to tissue injury. HGF expression is necessary for the proliferation, migration, and survival of epithelial and endothelial cells involved in tissue repair in a variety of organs, including heart, lung, kidney, liver, brain, and skin. The administration of full length HGF, either as a protein or using exogenous expression methodologies, increases tissue repair in animal models of tissue injury and increases angiogenesis. Full length HGF is comprised of an N-terminal hairpin turn, four kringle domains, and a serine protease-like domain. Several naturally occurring alternatively spliced isoforms of HGF were also identified. The NK1 variant contains the N-terminal hairpin and the first kringle domain, and the NK2 variant extends through the second kringle domain. These alternatively spliced forms of HGF activate the same receptor, MET, but they differ from the full length protein in their cellular activities and their biological functions. Here, we review the species-specific expression of the HGF isoforms, their regulation, the signal transduction pathways they activate, and their biological activities. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview HGF–Met Pathway in Regeneration and Drug Discovery
Biomedicines 2014, 2(4), 275-300; doi:10.3390/biomedicines2040275
Received: 25 August 2014 / Revised: 15 September 2014 / Accepted: 13 October 2014 / Published: 31 October 2014
Cited by 4 | PDF Full-text (1429 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocyte growth factor (HGF) is composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. Activation of the HGF–Met pathway evokes dynamic biological responses that support morphogenesis (e.g., epithelial tubulogenesis), regeneration, and [...] Read more.
Hepatocyte growth factor (HGF) is composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. Activation of the HGF–Met pathway evokes dynamic biological responses that support morphogenesis (e.g., epithelial tubulogenesis), regeneration, and the survival of cells and tissues. Characterizations of conditional Met knockout mice have indicated that the HGF–Met pathway plays important roles in regeneration, protection, and homeostasis in various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. The promotion of cell growth, survival, migration, and morphogenesis that is associated with extracellular matrix proteolysis are the biological activities that underlie the therapeutic actions of HGF. Recombinant HGF protein and the expression vectors for HGF are biological drug candidates for the treatment of patients with diseases and injuries that are associated with impaired tissue function. The intravenous/systemic administration of recombinant HGF protein has been well tolerated in phase I/II clinical trials. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview The Pathogenetic Role of the HGF/c-Met System in Papillary Carcinoma of the Thyroid
Biomedicines 2014, 2(4), 263-274; doi:10.3390/biomedicines2040263
Received: 12 September 2014 / Revised: 6 October 2014 / Accepted: 17 October 2014 / Published: 24 October 2014
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Abstract
The MET oncogene encodes for Met protein, a trans-membrane tyrosine kinase identified as the high affinity receptor for hepatocyte growth factor (HGF). Immunohistochemical studies have demonstrated that Met protein is intensely expressed in tumor cells of >95% cases of thyroid papillary carcinoma. [...] Read more.
The MET oncogene encodes for Met protein, a trans-membrane tyrosine kinase identified as the high affinity receptor for hepatocyte growth factor (HGF). Immunohistochemical studies have demonstrated that Met protein is intensely expressed in tumor cells of >95% cases of thyroid papillary carcinoma. High density of Met protein in tumor cells is the result of increased transcription of a normal MET gene, probably due to a combination of intracellular and extracellular signals. Over-expression of Met protein is more pronounced at the invading front of the tumor and can profoundly affect the tumorigenesis of papillary carcinoma of the thyroid. In fact, Met protein-positive papillary carcinoma cells are highly responsive to hepatocyte growth factor (HGF), which is effective in stimulating tumor cell adhesion, migration and invasiveness. In addition, HGF stimulation of papillary carcinoma of the thyroid (PTC) cells causes up-regulation of COX-2 and down-regulation of CD82/KAI-1; both these molecules have a major role in controlling tumor cell invasiveness. Finally, HGF stimulation of tumor cells may significantly affect the tumor microenvironment. In fact, HGF induces tumor cells to release chemokines active in the recruitment of dendritic cells, and is involved in regulating the production of proangiogenic factors. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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Open AccessReview HGF/Met Axis in Heart Function and Cardioprotection
Biomedicines 2014, 2(4), 247-262; doi:10.3390/biomedicines2040247
Received: 19 August 2014 / Revised: 18 September 2014 / Accepted: 13 October 2014 / Published: 21 October 2014
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Abstract
Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (Met) play important roles in myocardial function both in physiological and pathological situations. In the developing heart, HGF influences cardiomyocyte proliferation and differentiation. In the adult, HGF/Met signaling controls heart homeostasis and prevents [...] Read more.
Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (Met) play important roles in myocardial function both in physiological and pathological situations. In the developing heart, HGF influences cardiomyocyte proliferation and differentiation. In the adult, HGF/Met signaling controls heart homeostasis and prevents oxidative stress in normal cardiomyocytes. Thus, the possible cardiotoxicity of current Met-targeted anti-cancer therapies has to be taken in consideration. In the injured heart, HGF plays important roles in cardioprotection by promoting: (1) prosurvival (anti-apoptotic and anti-autophagic) effects in cardiomyocytes, (2) angiogenesis, (3) inhibition of fibrosis, (4) anti-inflammatory and immunomodulatory signals, and (5) regeneration through activation of cardiac stem cells. Furthermore, we discuss the putative role of elevated HGF as prognostic marker of severity in patients with cardiac diseases. Finally, we examine the potential of HGF-based molecules as new therapeutic tools for the treatment of cardiac diseases. Full article
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
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