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1
Toiyama, Y., K. Tanaka, H. Yasuda, S. Saigusa, H. Fujikawa, Y. Mohri, Y. Inoue, C. Miki, T. Tabata, and M. Kusunoki. "Use of co-expression of HGF and c-Met to predict peritoneal dissemination established by autocrine HGF/c-Met signaling in gastric cancer." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 40. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.40.
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40 Background: Epithelial mesencymal transition (EMT) promotes facilitates migration and invasion of epithelial tumour cells. EMT is induced by growth factors implicated in theses process such as hepatocyte growth factor (HGF). Our aim of this study is whether HGF/c-Met pathway is associated with metastasis of gastric cancer (GC), especially in peritoneal dissemination (PD). Methods: HGF and c-Met expression and EMT related molecules were evaluated using real-time PCR and immunohistochemistry in GC tissues. The role of HGF/c-Met pathway for EMT and anoikis was determined and c-Met TKI (SU11274) was tested for their ability to block HGF-induced biological effects in vitro and vivo. Results: In HGF(-)c-Met(+) GC cells,recombinant HGF promoted EMT phenotype characterized by morphology, impaired E-cadherin and induction of Vimentin. HGF promoted cell growth, invasiveness, migration ability and inhibition of anoikis. SU11274 blocked HGF-induced EMT and the biological effects in vitro. In contrast of HGF(+)c-Met(+) GC cells, HGF exposure was not affected biological outcome of EMT and anoikis but SU11274 blocked biological effect as same as in HGF(-)c-Met(+) GC cells. In vivo, HGF(+)c-Met(+) GC cell line only established PD and SU11274 intraperitoneally caused an inhibition of PD growth. Clinically, HGF expression was significantly positive correlated with c-Met expression in GC specimens. Increased HGF and c-Met demonstrated a significantly associated with poor prognosis and can predict PD, respectively. Furthermore, HGF was one of the independent factors for predicting PD. Immunohistochemical analysis showed HGF and c-Met were predominantly co-expressed in cancer cell of both primary GC and PD. Conclusions: We have demonstrated that HGF/c-Met pathway as an inducer of EMT and anoikis inhibition in GC cell. Co-expression of HGF and c-Met implicates its potential to promote PD in GC. Blocking the autocrine HGF/c-Met pathway may be clinically useful for the treatment of PD in GC. No significant financial relationships to disclose.
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Zhang, Hongli, Qingqing Feng, Wei-Dong Chen, and Yan-Dong Wang. "HGF/c-MET: A Promising Therapeutic Target in the Digestive System Cancers." International Journal of Molecular Sciences 19, no. 11 (October 23, 2018): 3295. http://dx.doi.org/10.3390/ijms19113295.
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The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.
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Weimar, Iris S., Daphne de Jong, Egbert J. Muller, Toshikazu Nakamura, Joost M.H.H. van Gorp, Gijsbert C. de Gast, and Winald R. Gerritsen. "Hepatocyte Growth Factor/Scatter Factor Promotes Adhesion of Lymphoma Cells to Extracellular Matrix Molecules Via α4β1 and α5β1 Integrins." Blood 89, no. 3 (February 1, 1997): 990–1000. http://dx.doi.org/10.1182/blood.v89.3.990.
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Abstract Hepatocyte growth factor (HGF )/scatter factor (SF ) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET−, c-MET expression was induced by PMA, ConA, HGF/SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non–Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by β1-integrins α4β1 (VLA4) and α5β1 (VLA5) since blocking antibodies against β1- (CD29), α4- (CD49d), or α5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET− cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via β1-integrins α4β1 and α5β1 , and furthermore promoted migration and invasion.
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Gallo, Simona, Valentina Sala, Stefano Gatti, and Tiziana Crepaldi. "Cellular and molecular mechanisms of HGF/Met in the cardiovascular system." Clinical Science 129, no. 12 (November 11, 2015): 1173–93. http://dx.doi.org/10.1042/cs20150502.
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Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.
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De Silva, Dinuka M., Arpita Roy, Takashi Kato, Fabiola Cecchi, Young H. Lee, Kunio Matsumoto, and Donald P. Bottaro. "Targeting the hepatocyte growth factor/Met pathway in cancer." Biochemical Society Transactions 45, no. 4 (July 3, 2017): 855–70. http://dx.doi.org/10.1042/bst20160132.
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Hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase, drives mitogenesis, motogenesis and morphogenesis in a wide spectrum of target cell types and embryologic, developmental and homeostatic contexts. Typical paracrine HGF/Met signaling is regulated by HGF activation at target cell surfaces, HGF binding-induced receptor activation, internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis, tumor angiogenesis and invasiveness, and tumor metastasis in many types of cancer, leading to the rapid growth of pathway-targeted anticancer drug development programs. We review here HGF and Met structure and function, basic properties of HGF/Met pathway antagonists now in clinical development, and recent clinical trial results. Presently, the main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of effective therapy combinations. The wealth of basic information, analytical reagents and model systems available regarding normal and oncogenic HGF/Met signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective cancer treatment.
6
Kauma, Scott, Natalie Hayes, and Shannon Weatherford. "The Differential Expression of Hepatocyte Growth Factor and Met in Human Placenta*." Journal of Clinical Endocrinology & Metabolism 82, no. 3 (March 1, 1997): 949–54. http://dx.doi.org/10.1210/jcem.82.3.3806.
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Abstract Met is the tyrosine kinase receptor for the ligand hepatocyte growth factor (HGF). Met/HGF plays an important role in epithelial cell proliferation, migration, and morphogenesis. HGF also plays a crucial role in placental development in the mouse. To determine whether HGF potentially has a similar role in human placental development, the production and localization of Met and HGF were determined in early second trimester and term placentas. Reverse transcription-PCR using specific primers demonstrated the expression of Met and HGF messenger ribonucleic acid in placental villi. HGF production was determined by enzyme-linked immunosorbent assay. HGF production over 48 h by second trimester placental villous explants in culture (810 pg/mg total protein·h) was 2.1-fold greater than that in term placental villous explants (380 pg/mg total protein·h; P < 0.01). Isolated trophoblast did not produce HGF, whereas isolated villous core tissues and villous core mesenchymal cells did produce HGF. Interleukin-1β treatment of placental villi or coculture of villous core mesenchymal cells with isolated trophoblast cells did not stimulate HGF production. Using immunohistochemistry, HGF localized to the villous core compartment with no localization to the trophoblast. In contrast, Met localized mainly to cytotrophoblast. These findings suggest that HGF produced by the villous core may act in a paracrine fashion to regulate trophoblast development or function through the HGF receptor, Met.
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Yamasaki, Koji, Shoichiro Mukai, Takahiro Nagai, Kozue Nakahara, Masato Fujii, Naoki Terada, Akinobu Ohno, et al. "Matriptase-Induced Phosphorylation of MET is Significantly Associated with Poor Prognosis in Invasive Bladder Cancer; an Immunohistochemical Analysis." International Journal of Molecular Sciences 19, no. 12 (November 22, 2018): 3708. http://dx.doi.org/10.3390/ijms19123708.
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Hepatocyte growth factor (HGF) plays an important role in cancer progression via phosphorylation of MET (c-met proto-oncogene product, receptor of HGF). HGF-zymogen (pro-HGF) must be processed for activation by HGF activators including matriptase, which is a type II transmembrane serine protease and the most efficient activator. The enzymatic activity is tightly regulated by HGF activator inhibitors (HAIs). Dysregulated pro-HGF activation (with upregulated MET phosphorylation) is reported to promote cancer progression in various cancers. We retrospectively analyzed the expression of matriptase, phosphorylated-MET (phospho-MET) and HAI-1 in tumor specimens obtained from patients with invasive bladder cancer by immunohistochemistry. High expression of phospho-MET and increased expression of matriptase were significantly associated with poor prognosis, and high matriptase/low HAI-1 expression showed poorer prognosis. Furthermore, high expression of matriptase tended to correlate with phosphorylation of MET. Increased expression of matriptase may induce the ligand-dependent activation of MET, which leads to poor prognosis in patients with invasive bladder cancer.
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Woolf, A. S., M. Kolatsi-Joannou, P. Hardman, E. Andermarcher, C. Moorby, L. G. Fine, P. S. Jat, M. D. Noble, and E. Gherardi. "Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros." Journal of Cell Biology 128, no. 1 (January 1, 1995): 171–84. http://dx.doi.org/10.1083/jcb.128.1.171.
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Several lines of evidence suggest that hepatocyte growth factor/scatter factor (HGF/SF), a soluble protein secreted by embryo fibroblasts and several fibroblast lines, may elicit morphogenesis in adjacent epithelial cells. We investigated the role of HGF/SF and its membrane receptor, the product of the c-met protooncogene, in the early development of the metanephric kidney. At the inception of the mouse metanephros at embryonic day 11, HGF/SF was expressed in the mesenchyme, while met was expressed in both the ureteric bud and the mesenchyme, as assessed by reverse transcription PCR, in situ hybridization, and immunohistochemistry. To further investigate the expression of met in renal mesenchyme, we isolated 13 conditionally immortal clonal cell lines from transgenic mice expressing a temperature-sensitive mutant of the SV-40 large T antigen. Five had the HGF/SF+/met+ phenotype and eight had the HGF/SF-/met+ phenotype. None had the HGF/SF+/met- nor the HGF/SF-/met- phenotypes. Thus the renal mesenchyme contains cells that express HGF/SF and met or met alone. When metanephric rudiments were grown in serum-free organ culture, anti-HGF/SF antibodies (a) inhibited the differentiation of metanephric mesenchymal cells into the epithelial precursors of the nephron; (b) increased cell death within the renal mesenchyme; and (c) perturbed branching morphogenesis of the ureteric bud. These data provide the first demonstration for coexpression of the HGF/SF and met genes in mesenchymal cells during embryonic development and also imply an autocrine and/or paracrine role for HGF/SF and met in the survival of the renal mesenchyme and in the mesenchymal-epithelial transition that occurs during nephrogenesis. They also confirm the postulated paracrine role of HGF/SF in the branching of the ureteric bud.
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Czyz, Malgorzata. "HGF/c-MET Signaling in Melanocytes and Melanoma." International Journal of Molecular Sciences 19, no. 12 (December 3, 2018): 3844. http://dx.doi.org/10.3390/ijms19123844.
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Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression. HGF and c-MET usually mediate heterotypic cell–cell interactions, such as epithelial–mesenchymal, including tumor–stroma interactions. In the skin, dermal fibroblasts are the main source of HGF. The presence of c-MET on keratinocytes is crucial for wound healing in the skin. HGF is not released by normal melanocytes, but as melanocytes express c-MET, they are receptive to HGF, which protects them from apoptosis and stimulates their proliferation and motility. Dissimilar to melanocytes, melanoma cells not only express c-MET, but also release HGF, thus activating c-MET in an autocrine manner. Stimulation of the HGF/c-MET pathways contributes to several processes that are crucial for melanoma development, such as proliferation, survival, motility, and invasiveness, including distant metastatic niche formation. HGF might be a factor in the innate and acquired resistance of melanoma to oncoprotein-targeted drugs. It is not entirely clear whether elevated serum HGF level is associated with low progression-free survival and overall survival after treatment with targeted therapies. This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes.
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Sato, Hiroki, Ryu Imamura, Hiroaki Suga, Kunio Matsumoto, and Katsuya Sakai. "Cyclic Peptide-Based Biologics Regulating HGF-MET." International Journal of Molecular Sciences 21, no. 21 (October 27, 2020): 7977. http://dx.doi.org/10.3390/ijms21217977.
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Using a random non-standard peptide integrated discovery system, we obtained cyclic peptides that bind to hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor. (MET) HGF-inhibitory peptide-8 (HiP-8) selectively bound to two-chain active HGF, but not to single-chain precursor HGF. HGF showed a dynamic change in its molecular shape in atomic force microscopy, but HiP-8 inhibited dynamic change in the molecular shape into a static status. The inhibition of the molecular dynamics of HGF by HiP-8 was associated with the loss of the ability to bind MET. HiP-8 could selectively detect active HGF in cancer tissues, and active HGF probed by HiP-8 showed co-localization with activated MET. Using HiP-8, cancer tissues with active HGF could be detected by positron emission tomography. HiP-8 seems to be applicable for the diagnosis and treatment of cancers. In contrast, based on the receptor dimerization as an essential process for activation, the cross-linking of the cyclic peptides that bind to the extracellular region of MET successfully generated an artificial ligand to MET. The synthetic MET agonists activated MET and exhibited biological activities which were indistinguishable from the effects of HGF. MET agonists composed of cyclic peptides can be manufactured by chemical synthesis but not recombinant protein expression, and thus are expected to be new biologics that are applicable to therapeutics and regenerative medicine.
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Kentsis, Alex, Takaomi Sanda, Vu Ngo, Scott J. Rodig, Jeffery Kutok, Eleni Tholouli, Richard Byers, et al. "Aberrant Expression of Hepatocyte Growth Factor Induces Autocrine MET Activation Providing a Novel Therapeutic Target In Acute Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 1042. http://dx.doi.org/10.1182/blood.v116.21.1042.1042.
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Abstract Abstract 1042 Despite improvements in the treatment of acute myeloid leukemia (AML), high risk disease such as complex aberrant karyotype AML remains largely refractory to current therapy, and is mostly fatal. Identification of effective therapeutic targets by using candidate gene approaches has been limited by the number and variety of genetic defects associated with AML. Thus, we carried out a genome-wide functional screen in complex karyotype AML using a retroviral library of short hairpin RNAs (shRNAs), and discovered that shRNA-mediated depletion of hepatocyte growth factor (HGF) specifically inhibits growth of AML cells but not a panel of lymphoid cancer cells. HGF was to found to be aberrantly expressed in about 15% of patients with AML, including most patients with complex karyotype disease. In contrast to normal CD34+ cells that express MET (but not HGF), 5 of 7 cell lines derived from patients with complex karyotype AML exhibited aberrant expression of HGF that was associated with autocrine activation of its receptor MET. Depletion of HGF or MET using multiple independent shRNAs profoundly reduced proliferation and induced cell death in AML cells lines that express HGF but not those that lack HGF expression. Inhibition of MET using the tyrosine kinase inhibitor (SU11274) or HGF using neutralizing anti-HGF antibody (R&D Systems) also inhibited growth and induced apoptosis in AML cell lines dependent on HGF/MET activation but not those that lack HGF expression. Thus, aberrant HGF expression causes autocrine MET activation and oncogene dependence in a subset of patients with AML, confers sensitivity to HGF/MET inhibition, and provides a novel therapeutic target for this otherwise lethal disease. Disclosures: No relevant conflicts of interest to declare.
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McInnis, Ian, Theresa Hahn, Anasitasia Ioane, Ashleigh Lamson, Deepika Lal, Laurie Ann Ford, Sheila NJ Sait, et al. "Diverse Roles of Hepatocyte Growth Factor (HGF) in Normal Karyotype Acute Myeloid Leukemia (AML)." Blood 114, no. 22 (November 20, 2009): 3107. http://dx.doi.org/10.1182/blood.v114.22.3107.3107.
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Abstract Abstract 3107 Poster Board III-44 Prior studies have demonstrated that hepatocyte growth factor (HGF) regulates proliferation and differentiation of normal hematopoietic progenitors. HGF activity occurs primarily via interactions with the c-met receptor, a tyrosine kinase receptor found on epithelial and some cancer cells. In solid tumors, HGF/c-met interactions mediate increased neoplastic invasion, metastases, and angiogenesis. However, in vitro, HGF has also been shown to mediate anti-tumor effects in leukemia cell line models. To better elucidate the role of HGF in acute leukemogenesis, we evaluated HGF and c-met gene expression in 91 normal karyotype acute myeloid leukemia (NK-AML) patient samples previously characterized for marrow angiogenesis (CD31+ microvessels), FLT-3/NPM-1 gene mutation, and pro-angiogenic factors and receptors (specifically vascular endothelial growth factors (VEGF-A and C) and their receptors). Median patient age was 66 years (range 21-87) with 49 women and 42 men. AML disease FAB subtypes M2 (37%) and M1 (36%) subtypes were most common. Median presenting white blood cell count (WBC) was 32,000/μL (range 0.43-555,000/μL) with marrow blasts of 70.6% (range 15-95.4%). Fourteen percent presented with extramedullary disease. Median OS was 9.4 months (95% CI 6.7 to 11.5 months), with median EFS of 8 months (95% CI 5.7 to 11.5 months) for all patients. Seventy-nine patients received cytarabine and anthracycline-based induction chemotherapy with 58% (n=46) achieving complete remission (CR). Marrow aspirate samples were evaluated by quantitative real-time polymerase chain reaction with levels expressed relative to normal bone marrow controls (set =1). We found that HGF gene expression was upregulated in most primary NK-AML patient samples, with 88% expressing higher HGF than normal bone marrow. Median HGF expression in AML samples was 7.73 fold higher than normal controls. Multivariate analysis including age, complete remission, marrow blasts, extramedullary disease, and expression of other angiogenic factors and receptors as covariables, showed high HGF expression to be significantly associated with both longer overall and event-free survival. Surprisingly, HGF gene expression was found to be negatively correlated with microvessel density and NPM-1 mutation and positively correlated with the VEGF receptor neuropilin-1 (NRP-1) which has been reported to function as co-mediator of HGF activity. No association between HGF and FLT-3 ITD mutation was noted. The majority of AML samples did not express the HGF receptor, c-met, suggesting that HGF function in AML occurs primarily via paracrine interactions with surrounding vascular and stromal cells and/or HGF/NRP-1 autocrine pathways. Further analysis confirmed no significant correlation between HGF and c-met gene expression in AML samples but did demonstrate a subset of NPM-1+ HGF+ AML samples (n=7) expressing high levels of both HGF and c-met (p=0.0005, r=0.96). To confirm whether HGF/c-met autocrine interactions contributed to leukemogenesis in these cells, we treated immunodeficient mice engrafted with an HGF+ c-met+ human AML cell line (HEL) with vehicle vs. a c-met tyrosine kinase inhibitor, and noted growth inhibitory effects following c-met blockade. Conclusions HGF gene expression was an independent predictive factor for improved clinical outcome and was associated with NRP-1 expression, lower microvessel density, and NPM-1 negative status in normal karyotype AML patients. A subset of AML samples was identified with high concordant HGF and c-met expression consistent with autocrine pathways. Inhibition of HGF/c-met interactions in a preclinical AML model exerted anti-tumor effects. Additional studies of the diverse roles of HGF in myeloid leukemogenesis are warranted. Disclosures No relevant conflicts of interest to declare.
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Borset, M., H. Hjorth-Hansen, C. Seidel, A. Sundan, and A. Waage. "Hepatocyte growth factor and its receptor c-met in multiple myeloma." Blood 88, no. 10 (November 15, 1996): 3998–4004. http://dx.doi.org/10.1182/blood.v88.10.3998.bloodjournal88103998.
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We have examined whether the hepatocyte growth factor (HGF)/c-met receptor-ligand pair is expressed in freshly isolated and highly purified myeloma cells and whether HGF can be found in the sera of myeloma patients. Myeloma cells were purified with an immunomagnetic method using the syndecan 1-specific antibody B-B4. HGF and c-met mRNA in these cells were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). HGF and c-met proteins were detected by enzyme- linked immunosorbent assay (ELISA) and Western blot, respectively. Serum from 13 myeloma patients was obtained at diagnosis and the levels of HGF were determined by ELISA. HGF and c-met mRNA were expressed in all examined samples (n = 7). HGF was detected in the supernatants of 17 of 20 primary cultures of myeloma cells, whereas bone marrow mononuclear cells from normal controls did not produce detectable amounts of HGF (n = 3). The mean HGF level in serum of myeloma patients at diagnosis was more than fourfold higher than the mean level in normal controls. Possible implications of HGF/c-met expression for the pathophysiology of multiple myeloma are discussed.
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Anastasi, Sergio, Silvia Giordano, Olga Sthandier, Giovanna Gambarotta, Rossella Maione, Paolo Comoglio, and Paolo Amati. "A Natural Hepatocyte Growth Factor/Scatter Factor Autocrine Loop in Myoblast Cells and the Effect of the Constitutive Met Kinase Activation on Myogenic Differentiation." Journal of Cell Biology 137, no. 5 (June 2, 1997): 1057–68. http://dx.doi.org/10.1083/jcb.137.5.1057.
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As a rule, hepatocyte growth factor/scatter factor (HGF/SF) is produced by mesenchymal cells, while its receptor, the tyrosine kinase encoded by the met proto-oncogene, is expressed by the neighboring epithelial cells in a canonical paracrine fashion. In the present work we show that both HGF/SF and met are coexpressed by undifferentiated C2 mouse myoblasts. In growing cells, the autocrine loop is active as the receptor exhibits a constitutive phosphorylation on tyrosine that can be abrogated by exogenously added anti-HGF/SF neutralizing antibodies. The transcription of HGF/SF and met genes is downregulated when myoblasts stop proliferating and differentiate. The coexpression of HGF/SF and met genes is not exclusive to C2 cells since it has been assessed also in other myogenic cell lines and in mouse primary satellite cells, suggesting that HGF/SF could play a role in muscle development through an autocrine way. To analyze the biological effects of HGF/SF receptor activation, we stably expressed the constitutively activated receptor catalytic domain (p65tpr-met) in C2 cells. This active kinase determined profound changes in cell shape and inhibited myogenesis at both morphological and biochemical levels. Notably, a complete absence of muscle regulatory markers such as MyoD and myogenin was observed in p65tpr-met highly expressing C2 clones. We also studied the effects of the ectopic expression of human isoforms of met receptor (h-met) and of HGF/SF (h-HGF/SF) in stable transfected C2 cells. Single constitutive expression of h-met or h-HGF/SF does not alter substantially the growth and differentiation properties of the myoblast cells, probably because of a species-specific ligand–receptor interaction. A C2 clone expressing simultaneously both h-met and h-HGF/SF is able to grow in soft agar and shows a decrease in myogenic potential comparable to that promoted by p65tpr-met kinase. These data indicate that a met kinase signal released from differentiation-dependent control provides a negative stimulus for the onset of myogenic differentiation.
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Tahira, Yumiko, Katsuya Sakai, Hiroki Sato, Ryu Imamura, and Kunio Matsumoto. "Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation." International Journal of Molecular Sciences 22, no. 17 (August 26, 2021): 9240. http://dx.doi.org/10.3390/ijms22179240.
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NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been proposed that the NK1 dimer structure participates in this activation. We investigated the NK1 dimer interface’s role in Met activation by HGF. Because N127, V140, and K144 are closely involved in the head-to-tail NK1 dimer formation, mutant NK1 proteins with replacement of these residues by alanine were prepared. In Met tyrosine phosphorylation assays, N127-NK1, V140-NK1, and K144-NK1 showed 8.3%, 23.8%, and 52.2% activity, respectively, compared with wild-type NK1. Although wild-type NK1 promoted cell migration and scattering, N127-NK1, V140-NK1, and K144-NK1 hardly or marginally promoted them, indicating loss of activity of these mutant NK1 proteins to activate Met. In contrast, mutant HGFs (N127-HGF, V140-HGF, and K144-HGF) with the same amino acid replacements as in NK1 induced Met tyrosine phosphorylation and biological responses at levels comparable to those of wild-type HGF. These results indicate that the structural basis responsible for NK1-dependent Met dimer formation and activation differs from, or is at least distinguishable from, the structural basis responsible for HGF-dependent Met activation.
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Chang, Chih-Ching, Jia-Jhen Chiu, Shan-Ling Chen, Hui-Chun Huang, Hui-Fen Chiu, Bo-Huei Lin, and Chun-Yuh Yang. "Activation of HGF/c-Met signaling by ultrafine carbon particles and its contribution to alveolar type II cell proliferation." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 8 (April 15, 2012): L755—L763. http://dx.doi.org/10.1152/ajplung.00350.2011.
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Hepatocyte growth factor (HGF) is a potent mitogen and motogen for various epithelial cells. The present study aimed to explore the role of HGF and c-Met receptor in ultrafine carbon particle-induced alveolar type II epithelial (type II) cell proliferation. ICR mice were intratracheally instilled with 100 μg ultrafine carbon black (ufCB) and killed at 21, 48, and 72 days postexposure to examine type II cell proliferation, HGF release, and c-Met activation. In vivo and in vitro applications of neutralizing anti-HGF antibody were used to investigate the causal role of HGF in cell proliferation. The Met kinase inhibitor SU11274 and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 were used to delineate the involvement of c-Met/ERK1/2 in rat L2 pulmonary epithelial cell proliferation. The results demonstrated that in vivo exposure to 100 μg ufCB caused increased HGF in bronchoalveolar lavage fluid, as well as increased HGF production, c-Met phosphorylation, and cell proliferation in type II cells. In vitro study revealed that ufCB caused a dose-dependent increase in HGF release, c-Met phosphorylation, and cell proliferation. Importantly, treatment with the neutralizing anti-HGF antibody significantly blocked ufCB-induced in vivo and in vitro type II cell proliferation. Moreover, SU11274 and PD98059 significantly reduced ufCB-increased L2 cell proliferation. Results from Western blotting demonstrated that SU11274 successfully suppressed ufCB-induced phosphorylation of c-Met and ERK1/2. In summary, the activation of HGF/c-Met signaling is a major pathway involved in ufCB-induced type II cell proliferation.
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UMITSU, Masataka, and Junichi TAKAGI. "Structural basis of HGF-Met signaling." Japanese Journal of Thrombosis and Hemostasis 27, no. 1 (2016): 77–84. http://dx.doi.org/10.2491/jjsth.27.77.
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Zhou, Hong, Yuen Pon, and Alice Wong. "HGF/MET Signaling in Ovarian Cancer." Current Molecular Medicine 8, no. 6 (September 1, 2008): 469–80. http://dx.doi.org/10.2174/156652408785747933.
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Dedov, I. I., Ye A. Troshina, N. V. Mazurina, and A. Belfiore. "Low expression of Met-hepatocytic growth factor receptor as an indicator of poor prognosis in thyroid tumors." Problems of Endocrinology 47, no. 3 (June 15, 2001): 6–10. http://dx.doi.org/10.14341/probl11467.
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Clinical implication of Met-hepatocytic growth factor receptor (Met/HGF-R) in thyroid adenocarcinoma tissue was studied on 163 operative thyroid samples (129papillary cancers, 21 follicular cancers, and 13 anaplastic cancers). 49 adenomas, 50 nodular goiters and 50 normal thyroids were compared. Expression of Met/HGF-R was estimated using semiquantitative immunohistochemical method including proportion (limits 0-5) and intensity (limits 0-5) of cell staining and calculation of Met/HGF-R total expression (limit 0-10). Met/HGF-R was not found in normal thyroid tissue, was absent or focally expressed in follicular and aplastic tumors, and was present in different amounts in papillary adenocarcinomas. It is suggested that low expression of Met/HGF-R is an indicator of unfavorable prognosis in papillary thyroid cancer.
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You, Jingjing, Li Wen, Athena Roufas, Chris Hodge, Gerard Sutton, and Michele C. Madigan. "Expression of HGF and c-Met Proteins in Human Keratoconus Corneas." Journal of Ophthalmology 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/852986.
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Keratoconus (KC) is a progressive degenerative inflammatory-related disease of the human cornea leading to decreased visual function. The pathogenesis of KC remains to be understood. Recent genetic studies indicate that gene variants of an inflammation-related molecule, hepatocyte growth factor (HGF), are associated with an increased susceptibility for developing KC. However HGF protein expression in KC has not been explored. In this initial study, we investigated late-stage KC and control corneas for the expression of HGF and its receptor mesenchymal-epithelial transition factor (c-Met/Met). KC buttons (~8 mm diameter) (n=10) and whole control corneas (n=6) were fixed in 10% formalin or 2% paraformaldehyde, paraffin embedded and sectioned. Sections were immunolabelled with HGF and c-Met antibodies, visualised using immunofluorescence, and examined with scanning laser confocal microscopy. Semiquantitative grading was used to compare HGF and c-Met immunostaining in KC and control corneas. Overall, KC corneas showed increased HGF and c-Met immunostaining compared to controls. KC corneal epithelium displayed heterogeneous moderate-to-strong immunoreactivity for HGF and c-Met, particularly in the basal epithelium adjacent to the cone area. Taken together with the recent genetic studies, our results further support a possible role for HGF/c-Met in the pathogenesis of KC.
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Boschert, Verena, Nicola Klenk, Alexander Abt, Sudha Janaki Raman, Markus Fischer, Roman C. Brands, Axel Seher, et al. "The Influence of Met Receptor Level on HGF-Induced Glycolytic Reprogramming in Head and Neck Squamous Cell Carcinoma." International Journal of Molecular Sciences 21, no. 2 (January 11, 2020): 471. http://dx.doi.org/10.3390/ijms21020471.
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Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Methigh-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.
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Blanquaert, Frederic, Renata C. Pereira, and Ernesto Canalis. "Cortisol inhibits hepatocyte growth factor/scatter factor expression and induces c-met transcripts in osteoblasts." American Journal of Physiology-Endocrinology and Metabolism 278, no. 3 (March 1, 2000): E509—E515. http://dx.doi.org/10.1152/ajpendo.2000.278.3.e509.
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Hepatocyte growth factor/scatter factor (HGF/SF) is expressed by osteoblasts and has important effects on repair and bone remodeling. Because glucocorticoids regulate these two functions, we tested the effects of cortisol on the expression of HGF/SF and c-met, the protooncogene encoding the HGF/SF receptor, in cultures of osteoblast-enriched cells from 22-day fetal rat calvariae (Ob cells). Cortisol decreased HGF/SF mRNA levels and diminished the induction of HGF/SF transcripts by fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor BB (PDGF BB). Cortisol also decreased FGF-2 and PDGF BB-induced HGF/SF mRNA and polypeptide levels in MC3T3 cells. In contrast, cortisol enhanced the expression of c-met transcripts in Ob cells. Cortisol did not modify the half-life of HGF/SF or of c-met mRNA in transcriptionally arrested cells, and it increased the rate of transcription of c-met. In conclusion, cortisol decreases HGF/SF transcripts in Ob cells and enhances c-met expression transcriptionally. The effects of cortisol on HGF/SF could be relevant to its inhibitory actions on bone formation and repair.
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Cao, Tong, Jing Pan, Xiulian Li, Yanli He, Yifei Jiang, Yajing Chang, Qi Zhang, et al. "Isolation and Characterization of a Chinese Hamster Ovary Heparan Sulfate Cell Mutant Defective in Both Met Receptor Binding and Hepatocyte Growth Factor NK1/Met Signaling." Cellular Physiology and Biochemistry 48, no. 4 (2018): 1480–91. http://dx.doi.org/10.1159/000492258.
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Background/Aims: The up-regulation of hepatocyte growth factor/receptor, HGF/Met, signal transduction is observed in most of human cancers. Specific heparan sulfate structures enhance the HGF/Met signaling at both cell and animal-based model systems. Biochemical studies indicate that heparan sulfate interacts with HGF and a natural occurring splicing variant NK1 of HGF with similar affinity. However, it is currently unknown if cell surface heparan sulfate binds to Met at physiological conditions and if specific cell surface heparan sulfate structures are required for effective HGF/Met or NK1/Met signaling. Methods: An established flow sorting strategy was used to isolate a soluble Met recombinant protein-binding positive or negative CHO cell clones different only in specific heparan sulfate structures. The cell surface bindings were imaged by confocal microscopy and flow cytometry analysis. Glucosamine vs. galactosamine contents from media-, cell surface-, and cell association glycosaminoglycans were quantified by HPLC. 35S-sulfate labeled glycosaminoglycans were characterized by anion exchange and size-exclusion HPLC. Heparan sulfate disaccharide compositions were determined by HPLC-MS analysis. Western blot analyses of MAPK-p42/44 were used to monitor HGF- and NK1-facillated Met signaling. Results: CHO-Positive but not CHO-Negative cell surface heparan sulfate bound to Met recombinant protein and HGF/NK1 further promoted the binding. Overall glycosaminoglycan analysis results indicated that the CHO-Negative cells had reduced amount of heparan sulfate, shorter chain length, and less 6-O-sulfated disaccharides compared to that of CHO-Positive cells. Moreover, CHO-Negative cells were defective in NK1/Met but not HGF/Met signaling. Conclusions: This study demonstrated that soluble Met recombinant protein bound to cell surface HS at physiological conditions and a Met /HGF or NK1/HS ternary signaling complex might be involved in Met signaling. Shorter HS chains and reduced 6-O-sulfation might be responsible for reduced Met binding and the diminished NK1-initiated signaling in the CHO-Negative cells. The unique CHO-Positive and CHO-Negative cell clones established in current study should be effective tools for studying the role of specific glycosaminoglycan structures in regulating Met signaling. Such knowledge should be useful in developing glycosaminoglycan-based compounds that target HGF/Met signaling.
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Hay, Rick V., Brian Cao, R. Scot Skinner, Ling-Mei Wang, Yanli Su, James H. Resau, George F. Vande Woude, and Milton D. Gross. "Radioimmunoscintigraphy of Tumors Autocrine for Human Met and Hepatocyte Growth Factor/Scatter Factor." Molecular Imaging 1, no. 1 (January 1, 2002): 153535002002000. http://dx.doi.org/10.1162/15353500200200006.
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Inappropriate expression of the c-met-protooncogene product (Met) and/or of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), has been correlated with poor prognosis in a variety of human solid tumors. We are developing animal models for nuclear imaging of Met and HGF/SF expression in tumors in vivo. We radioiodinated a mixture of monoclonal antibodies (MAbs) that bind to human HGF/SF and to the external ligand-binding domain of human Met, and then injected the I-125-MAb mixture intravenously into mice bearing tumors either autocrine for human HGF/SF and human Met or autocrine-paracrine for murine HGF/SF and murine Met. Serial total body gamma camera images were obtained, and regional activity was determined by quantitative region-of-interest (ROI) analysis. Tumors autocrine for human HGF/SF and Met demonstrated significantly more rapid uptake and more rapid clearance of the I-125-MAb mixture than tumors expressing one or both murine homologues, reaching a mean tumor to total body activity ratio of > 0.3 by 1 day postinjection. We conclude that radioimmunodetection of tumors autocrine for human HGF/SF and Met is feasible with an I-125-MAb mixture reactive against the ligand-receptor pair.
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Beilmann, Mario, George F. Vande Woude, Hans-Peter Dienes, and Peter Schirmacher. "Hepatocyte growth factor–stimulated invasiveness of monocytes." Blood 95, no. 12 (June 15, 2000): 3964–69. http://dx.doi.org/10.1182/blood.v95.12.3964.
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Abstract Hepatocyte growth factor (HGF) is a pluripotent cytokine with mitogenic, motogenic, and morphogenic activity for mainly epithelial and endothelial target cells. We previously demonstrated that the specific HGF receptor, MET, is induced in stimulated peripheral blood monocytes. In this study, we analyzed the functional consequences of MET activation in primary cultures of peripheral blood monocytes from healthy donors. After stimulation of MET-expressing monocytes with recombinant HGF, the gene-expression profile of peripheral blood mononuclear cells and monocytes was significantly modulated, especially with regard to genes involved in cell movement. After stimulation of primary cultured monocytes with HGF, invasion assays showed a significantly increased matrigel invasion rate that was completely abolished by neutralizing antibodies to HGF. The HGF-activated invasiveness and the altered gene-expression profile suggest a proinflammatory role for HGF stimulation of monocytes and support the hypothesis that the HGF/MET signaling system plays an important part in the activation of the nonspecific cellular inflammatory response.
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Beilmann, Mario, George F. Vande Woude, Hans-Peter Dienes, and Peter Schirmacher. "Hepatocyte growth factor–stimulated invasiveness of monocytes." Blood 95, no. 12 (June 15, 2000): 3964–69. http://dx.doi.org/10.1182/blood.v95.12.3964.012k20_3964_3969.
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Hepatocyte growth factor (HGF) is a pluripotent cytokine with mitogenic, motogenic, and morphogenic activity for mainly epithelial and endothelial target cells. We previously demonstrated that the specific HGF receptor, MET, is induced in stimulated peripheral blood monocytes. In this study, we analyzed the functional consequences of MET activation in primary cultures of peripheral blood monocytes from healthy donors. After stimulation of MET-expressing monocytes with recombinant HGF, the gene-expression profile of peripheral blood mononuclear cells and monocytes was significantly modulated, especially with regard to genes involved in cell movement. After stimulation of primary cultured monocytes with HGF, invasion assays showed a significantly increased matrigel invasion rate that was completely abolished by neutralizing antibodies to HGF. The HGF-activated invasiveness and the altered gene-expression profile suggest a proinflammatory role for HGF stimulation of monocytes and support the hypothesis that the HGF/MET signaling system plays an important part in the activation of the nonspecific cellular inflammatory response.
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Xu, Chuanhui, Anke Van Den Berg, Wouter Plattel, Nele Ruther, Huang Xin, Miao Wang, Gustaaf Van Imhoff, et al. "Expression of the c-Met Oncogene Correlates with Favorable Progression Free Survival In Classical Hodgkin Lymphoma." Blood 116, no. 21 (November 19, 2010): 3880. http://dx.doi.org/10.1182/blood.v116.21.3880.3880.
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Abstract Abstract 3880 Background The HGF/c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Aberrant c-Met activation has been implicated in the pathogenesis of many human cancers. Furthermore, c-Met is of prognostic significance in several types of cancer such as diffuse large B cell lymphoma, bladder cancer, breast cancer, colorectal cancer and ovarian cancer. Expression of c-Met in Hodgkin lymphoma (HL) patients, as well as increased levels of HGF in the urine of HL patients has been reported, but no prognostic studies or functional data have been reported. Methods We studied the prognostic significance of c-Met expression by immunohistochemistry on paraffin sections of classical HL (cHL) patients from two independent patient cohorts. Functional studies were performed on HL cell line L428 that showed high c-Met levels, constitutive phosphorylated c-Met and no HGF expression. The effect of stimulation by HGF and inhibition by c-Met kinase inhibitor SU11274 was investigated by Western blot, cell proliferation and cell cycle progression analysis. Results Expression of c-Met was detected in Hodgkin Reed-Sternberg (HRS) cells in 52% (79/152) of primary cHL tissue samples and expression of its ligand, hepatocyte growth factor (HGF), was detected in HRS cells in 8% (10/120) of the cHL patients. Co-expression of HGF and c-Met in HRS cells was observed in only 3% (4/120) of cHL patients. A variable percentage of infiltrating cells stained positive for HGF, supporting a predominant paracrine activation route. In contrast to its adverse prognostic impact in other cancers, high c-Met expression significantly correlated with favorable 5 year progression free survival in both patient cohorts. To explain these unexpected findings we studied the c-Met/HGF signaling pathway in the L428 cHL cell line. The levels of phosphorylated c-Met, Akt, and Erk1/2 were upregulated upon HGF stimulation and this induction could be blocked by inhibiting c-Met activation with SU11274. Activation with HGF did not effect cell growth, while SU11274 alone suppressed cell growth. SU11274, as well as inhibitors of PI3K, MEK1/2 and Erk1/2 (downstream targets of the HGF/c-Met signaling pathway) induced G2/M cycle arrest. Conclusion Expression of c-Met in tumor cells was observed in 52% of cHL patients. In contrast to its prognostic value in other cancers, expression of c-Met in HRS cells of cHL patients correlated with favorable prognosis in two independent cohorts. Although triggering of c-Met in L428 cells with HGF induced activation of its downstream factors, no effect was observed on proliferation. Remarkably, the c-Met inhibitor did suppress cell growth of L428 cells. Disclosures: No relevant conflicts of interest to declare.
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Sierra, J. Rafael, and Ming-Sound Tsao. "c-MET as a potential therapeutic target and biomarker in cancer." Therapeutic Advances in Medical Oncology 3, no. 1_suppl (November 2011): S21—S35. http://dx.doi.org/10.1177/1758834011422557.
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The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas. Additionally, the current knowledge of small molecule inhibitors (tivantinib [ARQ 197]), c-MET/HGF antibodies (rilotumumab and MetMAb) and mechanisms of resistance to c-MET-targeted therapies are discussed.
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Sweis, Randy F., Petros Grivas, Alexander T. Pearson, Kathleen C. Day, Mark L. Day, and Maha Hussain. "Expression of MET and HGF in bladder cancer tumorigenesis and invasion." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4573. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4573.
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4573 Background: The human MET gene encodes the hepatocyte growth factor (HGF) tyrosine kinase receptor. Limited studies in human bladder cancer have demonstrated that expression of MET protein is linked with disease progression and survival. We hypothesized that the expression of both MET and its ligand HGF are altered in bladder cancer. Methods: Expression of MET and HGF in human bladder tissues was explored using Oncomine, an online compendium of cancer transcriptome profiles. The largest relevant dataset was identified and contained 157 samples (Sanchez-Carbayo, et al. 2006). Normalized and log2 transformed mRNA expression values for Affymetrix U133 microarray probe sets corresponding to the genes of interest were compiled and averaged for each gene. Mann-Whitney U testing was used to compare means. Nominal and standard least squares logistic regression was used to evaluate the predictive significance of, and relevance of clinicopathologic variables on, gene expression. Statistical analyses were carried out using JMP 9.0.2. Results: Expression of MET and HGF was compared across subsets of normal bladder tissue (n=48), superficial tumors (n=28), and invasive tumors (n = 81). Relative to normal tissue, MET expression was greater in superficial (p = 0.0008) and invasive tumors (p<0.0001). HGF expression was reduced in both invasive and superficial tumors vs. normal tissue (both p< 0.0001), but was higher in invasive vs. superficial tumors (p= 0.0007). In a logistic regression model of tumor samples, both MET and HGF correlated with tumor invasion (model p=0.0003). Interaction between MET and HGF was not significant (p=0.55). Neither MET nor HGF expression was predicted by regression using age, gender, grade, or nodal stage (p=0.16 and 0.27, respectively). Conclusions: Decreased HGF expression and MET over-expression are strongly associated with tumorigenesis and invasion in bladder cancer. The reduction in HGF expression is blunted in invasive vs. superficial tumors, suggesting a potential loss of negative feedback in more aggressive tumors. Expression of both genes could not be predicted by modeling clinicopathologic variables. MET signaling represents a potential therapeutic target in bladder cancer.
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Tonomura, Hitoshi, Masateru Nagae, Ryota Takatori, Hidenobu Ishibashi, Tomonori Itsuji, and Kenji Takahashi. "The Potential Role of Hepatocyte Growth Factor in Degenerative Disorders of the Synovial Joint and Spine." International Journal of Molecular Sciences 21, no. 22 (November 18, 2020): 8717. http://dx.doi.org/10.3390/ijms21228717.
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This paper aims to provide a comprehensive review of the changing role of hepatocyte growth factor (HGF) signaling in the healthy and diseased synovial joint and spine. HGF is a multifunctional growth factor that, like its specific receptor c-Met, is widely expressed in several bone and joint tissues. HGF has profound effects on cell survival and proliferation, matrix metabolism, inflammatory response, and neurotrophic action. HGF plays an important role in normal bone and cartilage turnover. Changes in HGF/c-Met have also been linked to pathophysiological changes in degenerative joint diseases, such as osteoarthritis (OA) and intervertebral disc degeneration (IDD). A therapeutic role of HGF has been proposed in the regeneration of osteoarticular tissues. HGF also influences bone remodeling and peripheral nerve activity. Studies aimed at elucidating the changing role of HGF/c-Met signaling in OA and IDD at different pathophysiological stages, and their specific molecular mechanisms are needed. Such studies will contribute to safe and effective HGF/c-Met signaling-based treatments for OA and IDD.
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Beilmann, Mario, Margarete Odenthal, Waltraud Jung, George F. Vande Woude, Hans-Peter Dienes, and Peter Schirmacher. "Neoexpression of the c-met/Hepatocyte Growth Factor-Scatter Factor Receptor Gene in Activated Monocytes." Blood 90, no. 11 (December 1, 1997): 4450–58. http://dx.doi.org/10.1182/blood.v90.11.4450.
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Abstract Hepatocyte growth factor-scatter factor (HGF-SF ) mediates mito-, moto-, and morphogenic effects through the MET receptor, a membrane bound tyrosine kinase. HGF-SF/MET signaling is mitogenic for a large number of epithelial and endothelial cells and activates organ regeneration. HGF-SF transcripts have been detected in various myeloid cell lines. Therefore, the potential role of HGF-SF/MET signaling for circulating cells of the immune system, especially under conditions of inflammation, was evaluated. Several B-lymphoid and myeloid cell lines were found to express HGF-SF or c-met transcripts, while activity of both genes was mutually exclusive with the exception of low level coexpression in two B-cell lines. HGF-SF transcripts were present in low quantities in freshly isolated peripheral blood mononuclear cells (PBMNCs). In contrast, c-met expression was not detected in freshly isolated cells from peripheral blood, but was induced in monocytes by activation of monocytic or T-cell function. HGF-SF incubation led to an increased c-fos steady state transcript level in myeloblastic K562 cells and moderately promoted cell viability of freshly isolated preactivated monocytes. c-met expression is thus established in activated monocytes, in particular under conditions resembling inflammation, making these cells accessible to functional effects of HGF-SF.
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Beilmann, Mario, Margarete Odenthal, Waltraud Jung, George F. Vande Woude, Hans-Peter Dienes, and Peter Schirmacher. "Neoexpression of the c-met/Hepatocyte Growth Factor-Scatter Factor Receptor Gene in Activated Monocytes." Blood 90, no. 11 (December 1, 1997): 4450–58. http://dx.doi.org/10.1182/blood.v90.11.4450.4450_4450_4458.
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Hepatocyte growth factor-scatter factor (HGF-SF ) mediates mito-, moto-, and morphogenic effects through the MET receptor, a membrane bound tyrosine kinase. HGF-SF/MET signaling is mitogenic for a large number of epithelial and endothelial cells and activates organ regeneration. HGF-SF transcripts have been detected in various myeloid cell lines. Therefore, the potential role of HGF-SF/MET signaling for circulating cells of the immune system, especially under conditions of inflammation, was evaluated. Several B-lymphoid and myeloid cell lines were found to express HGF-SF or c-met transcripts, while activity of both genes was mutually exclusive with the exception of low level coexpression in two B-cell lines. HGF-SF transcripts were present in low quantities in freshly isolated peripheral blood mononuclear cells (PBMNCs). In contrast, c-met expression was not detected in freshly isolated cells from peripheral blood, but was induced in monocytes by activation of monocytic or T-cell function. HGF-SF incubation led to an increased c-fos steady state transcript level in myeloblastic K562 cells and moderately promoted cell viability of freshly isolated preactivated monocytes. c-met expression is thus established in activated monocytes, in particular under conditions resembling inflammation, making these cells accessible to functional effects of HGF-SF.
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Tjin, Esther P. M., Richard W. J. Groen, Irma Vogelzang, Patrick W. B. Derksen, Melanie D. Klok, Helen P. Meijer, Susanne van Eeden, Steven T. Pals, and Marcel Spaargaren. "Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma." Blood 107, no. 2 (January 15, 2006): 760–68. http://dx.doi.org/10.1182/blood-2005-05-1929.
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AbstractInappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent α4β1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL. (Blood. 2006;107:760-768)
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Borset, Magne, Hakon Hov, Randi U. Holt, Torstein B. Ro, Unn-Merete Fagerli, Henrik Hjorth-Hansen, Vadim Baykov, James G. Christensen, Anders Waage, and Anders Sundan. "A Selective Inhibitor of c-Met Blocks an Autocrine HGF Growth Loop in ANBL-6 Cells and Prevents Migration and Adhesion of Myeloma Cells." Blood 104, no. 11 (November 16, 2004): 2358. http://dx.doi.org/10.1182/blood.v104.11.2358.2358.
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Abstract We examined the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small-molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor. Four biological sequels of HGF related to multiple myeloma were studied: (1) proliferation of myeloma cells; (2) secretion of interleukin-11 from osteogenic cells; (3) migration of myeloma cells; and (4) adhesion of myeloma cells to fibronectin. We also examined effects of the c-Met inhibitor on intracellular signaling pathways in myeloma cells. PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50 % inhibition at 5-15 nM concentration and complete inhibition at around 100 nM. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Y1003, Y1230/1234/1235, and Y1349), blocked HGF-mediated activation of Akt and p44/42 Mitogen-activated protein kinase (MAPK), and prevented the adaptor molecule Gab1 from complexing with c-Met. In the HGF-producing myeloma cell line ANBL-6, PHA-665752 revealed an autocrine HGF/c-Met-mediated growth loop. The inhibitor also blocked proliferation of purified primary myeloma cells, suggesting that autocrine HGF/c-Met-driven growth loops are important for progression of multiple myeloma. Conclusions: Collectively, these findings support the role of c-Met and HGF in the proliferation, migration, and adhesion of myeloma cells and identify c-Met kinase as a therapeutic target for treatment of patients with multiple myeloma.
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Miranda, Oshin, Mariya Farooqui, and Jill Siegfried. "Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer." Cancers 10, no. 9 (August 21, 2018): 280. http://dx.doi.org/10.3390/cancers10090280.
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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.
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Uzumcu, Mehmet, Zui Pan, Yi Chu, Peter E. Kuhn, and Rob Zachow. "Immunolocalization of the hepatocyte growth factor (HGF) system in the rat ovary and the anti-apoptotic effect of HGF in rat ovarian granulosa cells in vitro." Reproduction 132, no. 2 (August 2006): 291–99. http://dx.doi.org/10.1530/rep.1.00989.
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Hepatocyte growth factor (HGF) regulates granulosa cell (GC) steroidogenesis and suppresses apoptosis in non-ovarian cells. The hypothesis was thus developed that intraovarian HGF supports folliculogenesis by mediating steroidogenesis and suppressing apoptosis. To investigate the latter, the anti-apoptotic actions of HGF were tested in GCs and follicles isolated from immature rats. Results showed that HGF suppressed apoptosis in GC and follicle cultures as visualized using apoptosis indicator dye, YO-PRO-1. Immunohistochemistry was used to investigate the distribution of HGF, c-met, and HGF activator (HGFA) protein during folliculogenesis in equine chorionic gonadotropin (eCG)-primed rats. Immunoreactive HGF content was the greatest in GCs within preantral follicles. Following eCG, large antral follicles showed elevated HGF staining in theca and interstitial cells when compared with GCs. Intense c-met staining was observed in GCs within non-primed small preantral follicles; following eCG, the level of c-met was diminished in GCs, but increased within theca and interstitial cells. Theca, interstitium, and GCs in non-primed and primed ovaries contained HGFA. Following eCG, HGFA was more apparent in theca cells and the interstitium when compared to that in GCs within large antral follicles. The presence of HGF, c-met, and HGFA in preantral follicles would potentially enable the anti-apoptotic effects of HGF that were observed in vitro to occur in vivo. Advanced folliculogenesis led to a change in the cellular distribution of the HGF, c-met, and HGFA, suggesting that the ovarian HGF system is hormonally regulated in vivo.
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Ricci, G., A. Catizone, and M. Galdieri. "Expression and functional role of hepatocyte growth factor and its receptor (c-met) during fetal mouse testis development." Journal of Endocrinology 191, no. 3 (December 2006): 559–70. http://dx.doi.org/10.1677/joe.1.06879.
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The hepatocyte growth factor (HGF) is a pleiotropic cytokine able to regulate different cellular functions. HGF action is mediated by its receptor, c-met, a glycoprotein with tyrosine kinase activity. We previously demonstrated that c-met is expressed in the newly formed seminiferous cords of the mice embryonic testes and that HGF acts as a morphogenetic factor. In this paper, we report that at 15.5 days post-coitum (dpc) c-met is expressed in the testicular cords, whereas at 18.5 dpc c-met expression is almost exclusively localized in the interstitial tissue of the testis in particular in the fetal Leydig cells. In addition, we demonstrate that HGF gene is expressed during the fetal period of testis development, heavily detectable in the interstitial compartment of 18.5 dpc testes. Interestingly, HGF is not expressed in the Leydig cells that, as above reported, express the HGF receptor. Looking for the functional role of HGF on Leydig cells, we evaluated the amount of testosterone secreted by testes isolated from 18.5 dpc embryos and cultured in the presence of HGF. The results of the in vitro organ culture show that, at this age, HGF increases the amount of testosterone secreted in the culture medium. On the contrary, HGF does not modulate the amount of testosterone secreted by testes isolated from 15.5 dpc embryos. In conclusion, we report that HGF is produced in the interstitial compartment of the developing testis but not by the Leydig cells. Conversely, the HGF receptor c-met is expressed in the Leydig cells and HGF modulates Leydig cell function during the late period of prenatal development.
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Xu, Chuanhui, Anke Van Den Berg, Arjan Diepstra, Miao Wang, Debora Jong, Hans JTWM Vos, Peter Moller, Sibrand Poppema, and Lydia Visser. "The HGF/c-Met Signaling Pathway in Hodgkin Lymphoma." Blood 114, no. 22 (November 20, 2009): 1551. http://dx.doi.org/10.1182/blood.v114.22.1551.1551.
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Abstract Abstract 1551 Poster Board I-574 Introduction Hodgkin lymphoma (HL) is a B-cell neoplasm characterized by a minority of neoplastic cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells, which are located within an extensive infiltrate of reactive cells. Aberrant signaling of various receptor tyrosine kinases (RTKs) via autocrine or paracrine mechanisms contributes to the survival and proliferation of HRS cells. Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway has been implicated in the pathophysiology of many cancers, but its role in HL is poorly investigated. In this study, we investigated the expression of c-Met and HGF in HL patient tissues and studied the cell physiological effects of the HGF/c-Met signaling pathway using a c-Met tyrosine kinase inhibitor SU11274 in HL cell lines. Methods The expression of c-Met and HGF in HL patient tissues was studied by immunohistochemistry on a HL tissue microarray. The c-Met expression level was determined by Western blotting, while HGF mRNA and protein levels were measured by quantitative (q)RT-PCR and ELISA in four HL cell lines, i.e. L428, KMH2, L1236 and U-HO1. The effects of SU11274 treatment on the activity of the HGF/c-Met signaling pathway was determined by detection of phosphorylated downstream targets by Western blotting. Effects on cell growth and cell cycle were determined by 3-(4,5- Dimethylthiazol -2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and by flow cytometry with Propidium iodide (PI), respectively. Results C-Met was detected in HRS cells in 55% (26/47) of HL patient tissues. Expression of HGF was detected in HRS cells in 5 c-Met positive and 2 c-Met negative HL patient tissues. C-Met was highly expressed in L428 compared to three other HL cell lines, whereas HGF was highly expressed in KMH2 and not or only weakly in the other three HL cell lines. Detectable levels of phosphorylated c-Met (p-Met) were observed only in L428 consistent with the high basal expression level of c-Met. Phosphorylation of c-Met, Akt and Erk1/2 were upregulated upon HGF stimulation of L428 cells. This activation could be blocked by inhibiting c-Met activation with SU11274. In functional studies, SU11274 suppressed cell growth in L428, promoted G2/M cell cycle arrest after 24h incubation, and induced tetraploidy after 48h. Washing of the cells after induction of G2/M arrest resulted in normal cell cycle progression indicating that the G2/M cell cycle arrest was reversible. Inhibition of PI3K, MEK1/2 and Erk1/2, three downstream targets of the HGF/c-Met signaling pathway, also induced G2/M cell cycle arrest in L428, indicating that these factors are involved in the G2/M cell cycle arrest induced by SU11274. Conclusion Co-expression of c-Met and HGF in HRS cells was observed in 11% of the HL patient tissues and HGF/c-Met signaling pathway regulates cell growth and cell cycle progression in L428 cells. Disclosures No relevant conflicts of interest to declare.
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Elliott, Bruce E., Wesley L. Hung, Alexander H. Boag, and Alan B. Tuck. "The role of hepatocyte growth factor (scatter factor) in epithelialmesenchymal transition and breast cancer." Canadian Journal of Physiology and Pharmacology 80, no. 2 (February 1, 2002): 91–102. http://dx.doi.org/10.1139/y02-010.
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North American women have a one in eight lifetime risk of developing breast cancer, and approximately one in three women with breast cancer will die of metastases. We, and others, have recently shown that high levels of expression of hepatocyte growth factor (HGF) and its receptor Met are associated with invasive human breast cancer and may be causally linked to metastasis. This high level of HGF and Met expression has been considered as a possible indicator of earlier recurrence and shortened survival in breast cancer patients. In contrast, HGF expression (but not Met) is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention in the treatment of breast cancer. We have recently demonstrated that sustained activation or hyper-activation of c-Src and Stat3, which occurs in invasive breast cancer, can stimulate strong expression of HGF in carcinoma cells. In contrast, transient induction of Stat3 occurs in normal epithelium and promotes mammary tubulogenesis. We hypo thesize that increased autocrine HGFMet signaling is a critical downstream function of c-SrcStat3 activation in mammary tumorigenesis. Future studies will identify novel Stat3 consensus sites that regulate HGF promoter activity and HGF expression preferentially in carcinoma cells and could lead to novel therapeutic drugs that specifically block HGF expression in mammary carcinoma cells, and which could be used in combined treatments to abrogate metastasis.Key words: HGF, SrcStat3 signaling, epithelialmesenchymal transition, breast cancer.
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Tsubaki, Masanobu, Shiori Seki, Tomoya Takeda, Akiko Chihara, Yuuko Arai, Yuusuke Morii, Motohiro Imano, Takao Satou, Kazunori Shimomura, and Shozo Nishida. "The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells." International Journal of Molecular Sciences 21, no. 21 (October 24, 2020): 7905. http://dx.doi.org/10.3390/ijms21217905.
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Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor κB (NF-κB) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-κB inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met/NF-κB signaling pathway, and Met and NF-κB inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-κB inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF.
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Jalili, Ali, Neeta Shirvaikar, Sara Ilnitsky, A. Robert Turner, Mariusz Z. Ratajczak, and Anna Janowska-Wieczorek. "G-CSF Induces Expression of Both Hepatocyte Growth Factor (HGF) and Its Receptor (c-Met) in Human Hematopoietic Stem/Progenitor Cells and Mature Myeloid Cells - Novel Evidence That during Mobilization the HGF-c-Met Axis Counterbalances G-CSF-Induced Attenuation of the SDF-1-CXCR4 Axis." Blood 110, no. 11 (November 16, 2007): 2203. http://dx.doi.org/10.1182/blood.v110.11.2203.2203.
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Abstract The stromal-derived factor-1 (SDF-1)-CXCR4 axis plays an important role in stem cell trafficking, and G-CSF- induced mobilization decreases SDF-1 expression in the bone marrow (BM) microenvironment and CXCR4 expression by CD34+ hematopoietic stem/progenitor cells (HSPC). Alternatively, the tyrosine kinase c-Met receptor-HGF axis was recently postulated to play an important role in the trafficking of non-hematopoietic cells; however, our previous research demonstrated that while HGF is an important constituent of the BM microenvironment, c-Met is not expressed by BM-derived steady state HSPC (Br J Haem1997;99:228). Recently we observed that both c-Met and HGF are upregulated during tissue organ/injury in a hypoxia-inducible factor-1α-dependent manner (Circ Res2004;95:1191). To determine whether G-CSF-induced mobilization affects the c-Met-HGF axis in HSPC, we isolated human CD34+ cells from BM and mobilized peripheral blood (mPB), mature myeloid cells and stromal cells and evaluated expression of c-Met and HGF by hematopoietic and BM-derived stromal cells without and after exposure to G-CSF, and the chemotactic responses of steady state and mobilized hematopoietic cells to HGF. We confirmed using RT-PCR and FACS analysis that the c-Met receptor is not expressed by steady-state BM CD34+ cells and mature mononuclear cells (MNC), but to our surprise we found that c-Met is expressed in G-CSF-mobilized CD34+ cells and MNC obtained from leukapheresis products. Supporting this was our finding that mPB but not steady state CD34+ cells responded to HGF stimulation by phosphorylation of MAPKp42/44 and AKT. HGF was found to highly expressed in mPB CD34+ cells and MNC but in steady state BM MNC. Moreover, G-CSF stimulation induced HGF expression in steady state BM MNC and BM-derived fibroblastic and mesenchymal stem cells. Importantly, when we compared c-Met expression on circulating PB leukocytes from patients during early and late stages of G-CSF mobilization we found that it increases in the later stages. When we compared the expression of CXCR4 and c-Met on leukocytes from the leukapheresis product vs circulating PB from the same patient we found that CXCR4 expression is similar but expression of c-Met is higher in the leukapheresis product. HGF was also found to be a strong chemoattractant for mPB leukocytes, but not for steady state leukocytes, and the chemotactic activity of HGF was totally inhibited by a c-Met antagonist. Additionally, we demonstrated that c-Met is incorporated into lipid rafts as shown by confocal microscopy and that G-CSF stimulation increases the secretion of matrix metalloproteinase (MMP)-9 from BM MNC, which was inhibited by the c-Met antagonist. A combination of G-CSF and HGF also upregulated membrane-type (MT)-MMPs such as MT1-MMP and MT6-MMP on leukocytes. Thus we demonstrate for the first time that G-CSF induces expression of functional c-Met and HGF in HSPC and leukocytes, and that the HGF-c-Met axis could play an important role in their mobilization and maintenance of high expression of matrix-degrading enzymes, allowing egress of HSPC from the BM.
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Chattopadhyay, Naibedya, R. J. MacLeod, Jacob Tfelt-Hansen, and Edward M. Brown. "1α,25(OH)2-vitamin D3inhibits HGF synthesis and secretion from MG-63 human osteosarcoma cells." American Journal of Physiology-Endocrinology and Metabolism 284, no. 1 (January 1, 2003): E219—E227. http://dx.doi.org/10.1152/ajpendo.00247.2002.
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Several mesenchymally derived cells, including osteoblasts, secrete hepatocyte growth factor (HGF). 1α,25(OH)2-vitamin D3[1,25(OH)2D3] inhibits proliferation and induces differentiation of MG-63 osteoblastic cells. Here we show that MG-63 cells secrete copious amounts of HGF and that 1,25(OH)2D3inhibits HGF production. MG-63 cells also express HGF receptor (c-Met) mRNA, suggesting an autocrine action of HGF. Indeed, although exogenous HGF failed to stimulate cellular proliferation, neutralizing endogenous HGF with a neutralizing antibody inhibited MG-63 cell proliferation; moreover, inhibiting HGF synthesis with 1,25(OH)2D3followed by addition of HGF rescued hormone-induced inhibition of proliferation. Nonneutralized cells displayed constitutive phosphorylation of c-Met and the mitogen-activated protein kinases mitogen/extracellular signal-regulated kinase (MEK) 1 and extracellular signal-regulated kinase (Erk) 1/2, which were inhibited by anti-HGF antibody. Constitutive phosphorylation of Erk1/2 was also abolished by 1,25(OH)2D3. Addition of HGF to MG-63 cells treated with neutralizing HGF antibody induced rapid phosphorylation of c-Met, MEK1, and Erk1/2. Thus endogenous HGF induces a constitutively active, autocrine mitogenic loop in MG-63 cells. The known antiproliferative effect of 1,25(OH)2D3on MG-63 cells can be accounted for by the concomitant 1,25(OH)2D3-induced inhibition of HGF production.
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Liu, Y., E. M. Tolbert, A. M. Sun, and L. D. Dworkin. "Primary structure of rat HGF receptor and induced expression in glomerular mesangial cells." American Journal of Physiology-Renal Physiology 271, no. 3 (September 1, 1996): F679—F688. http://dx.doi.org/10.1152/ajprenal.1996.271.3.f679.
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The c-met protooncogene encodes a transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF). It has been widely suggested that HGF and its receptor constitute a paracrine signaling system, in which mesenchymally derived cells produce ligand that binds to the receptor predominantly expressed on cells of epithelial origin. In this study, we have isolated and completely sequenced the entire coding region of c-met cDNA from the rat kidney. The nucleotide sequence of the rat c-met cDNA revealed that the HGF receptor is encoded within single open-reading frame as 190 kDa of a transmembrane glycoprotein consisting of 1,382 amino acids. Determination of c-met mRNA levels in various tissues revealed a widespread expression of c-met with the highest levels in kidney, lung, and liver. We found simultaneous induction of both HGF and its receptor gene expression by interleukin-6 (IL-6) in primary cultured rat glomerular mesangial cells. The expression of HGF and c-met was remarkably stimulated following incubation of rat mesangial cells with IL-6, in a time- and dose-dependent manner Our data suggest that autocrine action of HGF may be achieved in vivo through simultaneous induction of both HGF and its receptor expression in renal mesenchymal cells.
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Jeffers, M., S. Rong, and G. F. Vande Woude. "Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network." Molecular and Cellular Biology 16, no. 3 (March 1996): 1115–25. http://dx.doi.org/10.1128/mcb.16.3.1115.
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Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector of cells expressing the Met tyrosine kinase receptor. Although HGF/SF is synthesized by mesenchymal cells and acts predominantly on epithelial cells, we have recently demonstrated that human sarcoma cell lines often inappropriately express high levels of Met and respond mitogenically to HGF/SF. In the present report we show that HGF/SF-Met signalling in the human leiomyosarcoma cell line SK-LMS-1 enhances its in vivo tumorigenicity, an effect for which the mitogenicity of this signalling pathway is likely to play a role. In addition, we found that HGF/SF-Met signalling dramatically induces the in vitro invasiveness and in vivo metastatic potential of these cells. We have studied the molecular basis by which HGFSF-Met signalling mediates the invasive phenotype. A strong correlation has previously been demonstrated between the activation of the urokinase plasminogen activator (uPA) proteolysis network and the acquisition of the invasive-metastatic phenotype, and we show here that HGF/SF-Met signalling significantly increases the protein levels of both uPA and its cellular receptor in SK-LMS-1 cells. This results in elevated levels of cell-associated uPA and enhanced plasmin-generating ability by these cells. These studies couple HGF/SF-Met signalling to the activation of proteases that mediate dissolution of the extracellular matrix-basement membrane, and important property for cellular invasion-metastasis.
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Awad, Ahmed J., Terry C. Burns, Ying Zhang, and Roger Abounader. "Targeting MET for glioma therapy." Neurosurgical Focus 37, no. 6 (December 2014): E10. http://dx.doi.org/10.3171/2014.9.focus14520.
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Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing clinical trials targeting this pathway.
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Ghanaatgar-Kasbi, Sadaf, Shadi Khorrami, Amir Avan, Seyed A. Aledavoud, and Gordon A. Ferns. "Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma." Current Pharmaceutical Design 24, no. 39 (March 14, 2019): 4619–25. http://dx.doi.org/10.2174/1381612825666190110145855.
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The c-mesenchymal-epithelial transition factor (c-MET) is involved in the tumorigenesis of various cancers. HGF/Met inhibitors are now attracting considerable interest due to their anti-tumor activity in multiple malignancies such as pancreatic cancer. It is likely that within the next few years, HGF/Met inhibitors will become a crucial component for cancer management. In this review, we summarize the role of HGF/Met pathway in the pathogenesis of pancreatic cancer, with particular emphasize on HGF/Met inhibitors in the clinical setting, including Cabozantinib (XL184, BMS-907351), Crizotinib (PF-02341066), MK-2461, Merestinib (LY2801653), Tivantinib (ARQ197), SU11274, Onartuzumab (MetMab), Emibetuzumab (LY2875358), Ficlatuzumab (AV- 299), Rilotumumab (AMG 102), and NK4 in pancreatic cancer.
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Zachow, Rob, and Mehmet Uzumcu. "The hepatocyte growth factor system as a regulator of female and male gonadal function." Journal of Endocrinology 195, no. 3 (September 13, 2007): 359–71. http://dx.doi.org/10.1677/joe-07-0466.
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The hepatocyte growth factor (HGF) system comprises HGF, its receptor (the c-met tyrosine kinase), HGF activator (HGFA) protein, and HGFA inhibitor (HAI). The components of the HGF system have been identified in a plethora of tissues to include the ovary and testis. In its traditional context, the HGF system works via paracrine- and autocrine-mediated feedback in which HGF (of mesenchymal origin) binds and activates c-met (within epithelial cells); target cells then respond to HGF via any number of morphogenic and functional changes. The concomitant presence of HGFA and HAI suggests that HGF bioactivity can be locally modulated. A number of studies have collectively shown that the mammalian ovary and testis contain HGF, c-met, and HGFA; very little is currently known regarding HAI within the gonad. Within the ovary, HGF controls numerous key functions which collectively regulate the growth and differentiation of ovarian follicles; these include cell growth, steroidogenesis, and apoptosis within theca cells and/or granulosa cells. Comparatively, less is known about the function of HGF within the testicular Leydig and Sertoli cells, but evidence is emerging that HGF may regulate somatic cell function, including Leydig cell steroidogenesis. Changes in the cellular origin of HGF and c-met during fetal and postnatal testicular development suggest that HGF, in collaboration with other growth factors, may regulate important aspects of testicular cell morphogenesis and differentiation which enable male sexual viability. Likewise, experimental evidence showing that HGF can modulate many vital processes which enable ovarian follicle growth, differentiation, and function indicate the importance of HGF in female reproduction. This review presents what is currently known regarding the expression of the HGF system and its function within the ovary and testis.
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Accordi, Benedetta, Serena Pillozzi, Marta Campo Dell’Orto, Annarosa Arcangeli, Gertruuy te Kronnie, and Giuseppe Basso. "c-Met Oncogene Enhances Fas-Mediated Apoptosis in B-ALL t(12;21) Cells." Blood 106, no. 11 (November 16, 2005): 858. http://dx.doi.org/10.1182/blood.v106.11.858.858.
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Abstract c-Met, the tyrosine-kinase receptor for HGF, has been related to cell motility, proliferation and protection from apoptosis in epithelial cancers (Cytokine Growth Factor Rev2002; 13:41). On the other hand it has been proposed that c-Met could also stimulate apoptosis: association with the pro-apoptotic protein FAS has been shown in some cell types (Biochem Biophys Res Commun1997;230:89). So far no data are available on a conceivable role of c-Met in pediatric B-ALL. We observed that c-Met is expressed at higher levels in pediatric t(12;21) B-ALL, that better respond to therapy, and in normal B cells compared to B-ALL t(12;21)-, while the latter leukemias do not differ for Fas expression (Haematologica2004;89:113). Here, we studied c-MET/FAS association in t(12;21) B-ALL, and the role of this complex in drug-induced apoptosis. We performed IP/WB experiments in REH (B-ALL t(12;21)) cells and in healthy CD19+ cells: for the first time we observed in B cells the co-precipitation of c-MET and FAS. To investigate if the HGF/c-MET pathway could be activated, we stimulated REH cells with HGF for 48 hours. The phosphorylation of c-MET increased 5 minutes after stimulation, and lasted after 48 hours. In HGF stimulated cells we observed a higher proliferation rate compared to non-stimulated cells (p=0.01). We also observed that the c-MET/FAS complex was preseved during HGF stimulation. These results indicate that HGF stimulation does not disrupt the protein complex, while HGF activates the c-MET signaling pathway despite of FAS binding. To investigate the role of complex formation on FAS activity, REH cells were stimulated with HGF and then treated with Doxorubicin that acts specifically through the FAS apoptosis pathway. After 24 hours of Doxorubicin treatment, we observed in HGF pretreated cells an apoptotic rate higher than in not-pretreated cells (p=0.03). These results indicate that the complex c-MET/FAS does not inhibit c-MET or FAS functions, and importantly show that c-MET activation enhances FAS-mediated apoptosis. To demonstrate that the higher apoptotic sensibility after HGF stimulation is not related to the increased proliferation rate, we treated cells with L-Asparaginase that does not act through the FAS pathway: we did not find an increase of apoptosis after pre-stimulating c-MET with HGF. This is an important result because it confirms that the higher apoptotic rate observed after Doxorubicin treatment in pre-stimulated cells is directly related to increased activation of the FAS pathway. We also verified that the c-MET/FAS complex remains stable after 24 hours from Doxorubicin treatment in apoptotic cells, and results show that it is even more pronounced in HGF treated cells. To confirm FAS involvement in Doxorubicin treated cells, we checked the cleavage of Caspase-8: cleavage is more apparent in HGF pre-treated cells, demonstrating that the FAS pathway is more effective in c-MET activated cells. After L-Asparaginase treatment Caspase-8 is not cleaved. The observation that the activation of the c-MET pathway results in increased FAS mediated apoptosis strongly suggests that the c-MET/FAS complex has functional implications for understanding drug mechanisms. The finding that the c-MET/FAS complex is present in normal B cells and in the leukemia cell line model for patients that better respond to therapy implies that this protein complex may have an important role in cellular homeostasis and in enhanced pharmacological response of tumoral cells during therapy.
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Stakenborg, Michelle, Bram Verstockt, Elisa Meroni, Gera Goverse, Veronica De Simone, Sare Verstockt, Mario Di Matteo, et al. "Neutrophilic HGF-MET Signalling Exacerbates Intestinal Inflammation." Journal of Crohn's and Colitis 14, no. 12 (June 17, 2020): 1748–58. http://dx.doi.org/10.1093/ecco-jcc/jjaa121.
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Abstract Background and Aims Ulcerative colitis [UC] is associated with excessive neutrophil infiltration and collateral tissue damage, but the link is not yet completely understood. Since c-MET receptor tyrosine kinase [MET] is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor [HGF], we aimed to identify the function of HGF-MET signalling in neutrophils in UC patients and in mice during intestinal inflammation. Methods Serum and colonic biopsies from healthy controls and UC patients with active [Mayo endoscopic subscore 2–3] and inactive [Mayo endoscopic subscore 0–1] disease were collected to assess the level of serum and colonic HGF. Disease progression and immune cell infiltration were assessed during dextran sodium sulphate [DSS] colitis in wild-type and MRP8-Cre MET-LoxP mice. Results Increased mucosal HGF expression was detected in patients with active UC, and in mice during the inflammatory phase of DSS colitis. Similarly, serum HGF was significantly increased in active UC patients and positively correlated with C-reactive protein and blood neutrophil counts. Flow cytometric analysis also demonstrated an upregulation of colonic MET+ neutrophils during DSS colitis. Genetic ablation of MET in neutrophils reduced the severity of DSS-induced colitis. Concomitantly, there was a decreased number of TH17 cells, which could be due to a decreased production of IL-1β by MET-deficient neutrophils. Conclusions These data highlight the central role of neutrophilic HGF-MET signalling in exacerbating damage during intestinal inflammation. Hence, selective blockade of this pathway in neutrophils could be considered as a novel therapeutic approach in UC.
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Reid, Janet C., Nigel C. Bennett, Carson R. Stephens, Melanie L. Carroll, Viktor Magdolen, Judith A. Clements, and John D. Hooper. "In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B." Biological Chemistry 397, no. 12 (December 1, 2016): 1299–305. http://dx.doi.org/10.1515/hsz-2016-0163.
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Abstract Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5–10 nm, KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, KLK14 generates HAI-1A and HAI-1B fragments known to inhibit pro-HGF activating serine proteases. These in vitro data suggest that increased KLK14 activity could contribute at multiple levels to HGF/Met-mediated processes in prostate and other cancers.