The below list represents only planned manuscripts. Some of these
manuscripts have not been received by the Editorial Office yet. Papers
submitted to MDPI journals are subject to peer-review.
Type of Paper: Review
Title: HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation
Authors: Anna Spina 1 and Luigi Michele Pavone 1,*
Affiliation: 1 Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy
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 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, HGF seems to be 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 contribute to cancer development through a variety of mechanisms. In this review, we describe the specific type of cells of the tumor microenviroment 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 HGF/c- MET axis as therapeutic targets for future clinical trials in cancer diseases.
Keywords: HGF; c-MET; cancer; microenvironment; metastasis, cytokines
Title: Epithelial-Mesenchymal Transition in Metastatic Cancer Cell Populations affects Tumor Dormancy in a Simple Mathematical Model
Author: Marc Hansen
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 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 micro-metastatic 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 micro-metastatic tumors. Modeling the dynamics of this process demonstrates the benefit of a treatment that eradicates tumor cells and reduces the rate of EMT simultaneously.
Title: The HGF/c-Met System in Papillary Carcinoma of the Thyroid: An Update
Authors: Luigi Ruco and Stefania Scarpino.
Abstract: The Met oncogene encodes a trans-membrane tyrosine kinase identified as the 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. Increased levels of Met is probably due to a combination of different molecular mechanisms. Alterations of the MET gene have not been recognized, but evidence has been provided that activated RAS and RET can cause accumulation of MET RNA, but the majority of papillary carcinomas do not have alterations of the RET gene. Hypomethylation is a kind of molecular mechanism leading to promoting high expression of oncogenes that encodes some proteins with tyrosine kinase activity. Investigation of the MET promoter methylation status through the analysis of the CpGs island regions, in cases of papillary carcinoma and in normal thyroid, showed that increased expression is not due to an altered methylation status of the MET promoter. In thyroid papillary carcinoma, the levels of RNA transcripts for hypoxia inducible factor-1 (HIF-1), a potent stimulator of Met gene transcription, were found to be higher than those present in the surrounding normal thyroid tissues suggesting that HIF-1—possibly driven by hypoxia—may be one of the factors leading to the increased transcription of Met gene. The increased expression of the MET gene can profoundly affect the tumor cell biology of papillary carcinoma of the thyroid. In fact, Met protein-positive papillary carcinoma cells may produce hepatocyte growth factor (HGF) and may activate HGF through the urokinase-type plasminogen activator (uPA). Thus, papillary carcinoma cells possess the molecular machinery necessary for a productive HGF–Met interaction. In vitro studies have demonstrated that HGF enhances the motility and invasiveness of tumor cells, induces the synthesis and release of chemokines active in the recruitment of dendritic cells, is involved in the regulating proangiogenic capacity of tumor cells and affect factors involved in the lymphangiogenesis.
Title: MET and other cell surface receptors; interaction, activation and functional consequences
Authors: Giuditta Viticchiè and Patricia A.J. Muller
Affiliation: MRC toxicology unit, Leicester, UK
Abstract: The c-MET receptor, also know as the HGF receptor, is one of the most studied tyrosine kinase receptors whose biological functions and activation mechanisms are still not fully understood. c-MET has been implicated in embryonic development and organogenesis, in tissue remodeling, homeostasis and repair and in cancer metastasis. These functions are indicative of the many cellular processes this receptor plays a role in including cell motility, scattering, survival and proliferation. In the context of oncology, sustained activation of c-MET leads to a signaling 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 molecules. Membrane receptors sharing structural homology with c-MET extracellular domain can activate c-MET via clustering through this domain (e.g plexins), whereas other receptor tyrosine kinases (e.g. EGFR) can enhance MET activation and phosphorylation through intracellular signaling cascades. In the present review we provide an overview of c-MET interactions and crosstalk with other cellular receptors and the functional consequences of these interaction on c-MET activation and downstream signaling, c-MET intracellular localization/ recycling and c-MET degradation.
Title: HGF/c-Met Signalling Is a Critical Player in Malignant Mesothelioma Carcinogenesis
Author: Giovanni Gaudino, Haining Yang and Michele Carbone
Affiliation: University of Hawai-i Cancer Center, University of Hawai’i, Honolulu, Hawaii, USA
Abstract: Malignant mesothelioma (MM) is a highly aggressive cancer related to asbestos and erionite exposure and resistant to current therapies. Hepatocyte Growth Factor (HGF) and its cognate tyrosine kinase receptor c-Mesenchymal Epithelial Transition (c-Met) regulate cell functions such as growth, survival, motility/migration, and invasion. HGF and c-Met are expressed by normal human mesothelial cells (HMC) and mesothelioma (MM), suggesting that the HGF/c-Met signaling system plays a role in development and progression of this tumor, either by autocrine or paracrine mechanisms. HGF is secreted by MM cells to different extents, according to tumor morphology, and enhances cell adhesion
and invasion, and also angiogenesis. Moreover, SV40 Tag expression induces a HGF autocrine circuit in Rb-dependent manner in HM and possibly other cell types. The resulting activation of c-Met causes HM transformation, cell cycle progression, virus particle assembling, and infection of adjacent cells. Upregulation and activation of c-Met, under suppressive control by miR-34-a, correlate with enhanced invasion, migration and metastatic potential in several cancers, including MM. The constitutive
activation of c-Met, frequently occurring in MM, has been successfully targeted in preclinical models of MM. In conclusion, c-Met expression, activation state, subcellular localization, and expression of HGF co-receptors such as CD44 have clinical relevance for novel molecularly targeted therapies in a cancer for which no effective treatment is currently available.
Type of Paper: Review
Title: Regulation of Hepatocyte Growth Factor Isoforms in Tissue Repair and Fibrotic Remodeling
Authors: Ognoon Mungunsukh, Elizabeth A. McCart, Regina M. Day *
Affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences,
Abstract: Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleotropic factor required for normal organ development during embryogenesis. Several alternatively spliced isoforms of HGF were identified in human cells. Full length HGF is comprised of an N-terminal hairpin turn, four kringle domains—each containing multiple disulfide bonds, and a serine protease-like domain; it induces intracellular signaling via the MET receptor. The NK1 variant contains the N-terminal hairpin and the first kringle domain, and the NK2 variant extends through the second kringle (K2) domains. In adults, basal expression of HGF maintains tissue homeostasis. However, HGF expression is dramatically increased in response to injury and 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 was shown to increase tissue repair in animal models of tissue injury. Recent preclinical studies provided evidence that exogenous expression of full length HGF increases angiogenesis. Related Phase I/II clinical trials using exogenous HGF expression for painful diabetic peripheral neuropathy and critical limb ischemia demonstrated improved patient outcomes. However, during fibrotic remodeling, NK2 expression dominates that of full length HGF. NK2 activates the MET receptor to induce cellular migration and survival, but NK2 does not cause cellular proliferation and it antagonizes HGF-induced proliferation. Here we review the phylogenic expression of HGF isoforms, their regulation, and biological functions.
Title: Monoclonal antibodies against the Met/HGF receptor: Multitask tools with applications from basic research to therapy
Author: Maria Prat
Abstract: Monoclonal antibodies can be seen as valuable tools for many aspects of basic and applied science. In the case of the Met/HGFR they have allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing structure–function relationships. Antibodies directed against its 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 antibodies promote all the biological responses, including motility, proliferation, morphogenesis, protection from apoptosis, while others
can induce only a migratory response or even inhibit the HGF-induced biological activities. Since the Met/HGFR is a tumor associated marker that is overexpressed in many tumorhistotypes, monoclonal antibodies can be used as probes to detect its presence and even target the tumor cells, thus opening to
their use in diagnosis and therapy.
Title: HGF Modulates Actin Cytoskeleton Remodeling and Testicular Myoid Cells uPA Expression Level and Secretion
Authors: Angela Catizone 1, Maria Caruso 1, Michela Galdieri 2, Katia Corano Scheri 1,
Virginia Di Paolo 1, Giulia Ricci 2 and Rita Canipari 1
Affiliations: 1 Dept. of Anatomy, Histology, Forensic Medicine and Orthopedics, Section of Histology and Embryology, Sapienza University of Rome, Rome, Italy
2 Department of Experimental Medicine, Histology and Embryology Laboratory, School of Medicine, Second University of Naples, Naples, Italy
Abstract: Testicular myoid cell lineage was the first isolated testicular cell type in which HGF/c-Met system has been discovered (Catizone et al., 1999), but in spite this temporal primacy, the physiological role exerted by this machinery in myoid cell physiology has been poorly understood. Even if HGF has been always found expressed both in pre-natal and post-natal myoid cells (Catizone et al., 1999; Ricci et al., 2002; Catizone et al., 2001), c-Met receptor was detectable only in postnatal cells indicating that this lineage become sensible to HGF only in the postnatal life. c-Met receptor is expressed by myoid cells isolated from prepubertal, pubertal and adult rat testis. Interestingly in adult rats HGF is maximally expressed at stages VII–VIII of the seminiferous epithelium cycle, when germ cells traverse the BTB and when spermiation occurs, whereas its levels fall in the subsequent stages IX–XII and XIII–I (Catizone et al., 2012). Peritubular contractility is important for the progression of spermatozoa toward the rete testis and its fine regulation is supposed to be under endocrine-paracrine control. A parallel between smooth muscle cells actin cytoskeleton remodelling and the interaction of uPA and its receptor uPAR has been reported in the literature (Kjoller, 2002; Lugano et al., 2012).
On the basis of these data, in the present paper, we investigated the capability of HGF to induce myoid cell actin cytoskeleton remodeling and potentially modulate their contraction in order to improve the knowledge about the role exerted by this growth factor in the control of myoid cell biological function. For this reason we decided to evaluate expression level and secretion in myoid cells of uPA, its receptor uPAR and its inhibitor PAI-1 after HGF administration. Moreover, we evaluated the effect of uPA inhibition on HGF treated myoid cells.
Type of Paper: Review
Title: HGF/c-MET and miRNAs in Cancer
Authors: Simona Giglio and Andrea Vecchione
Affiliation: Department of Clinical and Molecular Medicine Sapienza University of Rome, Italy
Abstract: MicroRNAs (MiRNAs) are the most widely studied noncoding RNA molecules in cancer. They act as negative regulators of gene expression at the post-transcriptional level in diverse cellular processes. Aberrant regulation of miRNAs expression has been implicated in the pathogenesis of cancer. Also the oncogene c-Met and its ligand hepatocyte growth factor HGF has been connected to miRNAs. c-Met is a member of the receptor tyrosine kinase family, and plays a key role in tumor survival, growth, angiogenesis and metastasis. c-Met is de-regulated in many human tumors, where its most frequent alteration is overexpression that causes the constitutive activation of down-stream pathways. This review summarizes the current knowledge about the interplay between c-Met/HGF and miRNAs and provides the evidence that miRNAs are a novel and additional system to regulate c-Met expression in tumors. In the future, miRNAs connected to c-Met may be provide an additional option to inhibit this oncogene to orchestrate the invasive growth program.
Keywords: microRNA; c-MET; HGF; cancer
Type of Paper: Review
Title: Role of HGF-MET Signaling in (Primary and Acquired) Resistance to Targeted Therapies in Cancer
Authors: Carminia Maria Della Corte, Morena Fasano, Federica Papaccio, Fortunato Ciardiello and Floriana Morgillo
Abstract: Hepatocyte growth factor (HGF) - mesenchymal-epithelial transition (MET) pathway is dysregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays physiological roles 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 mutations (both germ-line and sporadic ones), and cross-talk with other growth factors receptors. Moreover, MET activation could represent a mechanism of escape from other targeted therapies. MET activation, through receptor amplification or over-stimulation by the ligand, has been demonstrated in non small cell lung cancer and colorectal cancer models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and in both breast and gastric cancers resistant toanti-HER-2 agents. Thus, a lot of agents targeting MET signaling are under clinical investigation as single agent or in combination other molecularly 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 latest data on the role and the molecular mechanism of MET in both primary and acquired resistance to biological agents in several types of cancers.
Type of Paper: Review
Title: HGF-Met Pathway in Regeneration, Drug Resistance, and Drug Discovery
Authors: Kunio Matsumoto 1, Hiroshi Funakoshi 2 and Katsuya Sakai 1
Affiliations: 1 Division of Tumor Dynamics and Regulation, Cancer Research Institute,
Kanazawa University, Kanazawa 920-1192, Japan
2 Center for Advanced Research and Education, Asahikawa Medical University,
Asahikawa 078-8510, Japan
Abstract: Activation of HGF-Met pathway evokes dynamic biological responses that support morphogenesis, regeneration, and survival of cells and tissues. Characterization of conditional Met knockout mice indicates that HGF-Met pathway plays important roles in regeneration, protection, and homeostasis in various cells and tissues, including hepatocytes, renal tubular cells, and neurons. Preclinical studies to address therapeutic significance of HGF in disease models have indicated that recombinant HGF protein and expression plasmid for HGF are biological drug candidate for treatment of patients with diseases and injuries with impaired tissue function. The phase-II or phase-III clinical trials of expression plasmid for HGF are ongoing for treatment of patients with critical limb ischemia. The phase I/II clinical trials indicated that intravenous/systemic administration of recombinant HGF protein was well tolerated. The Phase-I clinical trial of the intrathecal administration of HGF protein for treatment of patients with amyotrophic lateral sclerosis and spinal cord injury has been ongoing. On the other hand, biological actions of HGF to promote spreading and survival of cells closely participate in invasion-metasitasis and drug resistance in cancer cells. In tumor microenvironment, HGF confers survival of cancer cells even in the presence of molecular targeted drugs such as epidermal growth factor receptor or BRAF inhibitors. Clinical trials of different types of inhibitors for HGF-Met pathway have been ongoing.
Keywords: amyotrophic lateral sclerosis; critical limb ischemia; HGF; Met; spinal cord injury
Title: HGF/MET Cardio-Protective Effects in Cardiac Injury
Authors: Simona Gallo1 , Valentina Sala 1,2 , Stefano Gatti 1 and Tiziana Crepaldi 1,*
Affiliations: 1 Department of Oncology, Corso Massimo D’Azeglio 52, 10126 Turin, Italy; E-Mails: firstname.lastname@example.org (S.G.); email@example.com (S.G.)
2 Department of Medical Sciences, Corso Dogliotti 14, 10126 Turin, Italy; E-Mail: firstname.lastname@example.org (V.S.)
* Author to whom correspondence should be addressed: email@example.com (T.C.);
Tel.: +39-011-670-7773; Fax: +39-011-236-7773.
Abstract: Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (Met) have been involved for different cardiac functions in physiological and pathological situations. In developing heart, HGF influences cardiomyocyte proliferation and differentiation. In the adult, HGF/Met signalling controls oxidative stress in normal cardiomyocytes. Thus, the physiological role of HGF/Met axis in myocardium has to be taken in consideration in view of current Met-targeted anti-cancer therapies and their possible cardiotoxicity effects. In injured heart, HGF plays important roles in cardioprotection by promoting: (i) prosurvival (anti-apoptotic and anti-autophagic) effects in cardiomyocytes, (ii) angiogenesis, iii) anti-inflammatory signals, (iv) inhibition of fibrosis and (v) regeneration through activation of cardiac stem cells. Finally, we propose Met agonist antibodies as new therapeutic tools which can be exploited in cardiac disease.