Targeting the hepatocyte growth factor/Met pathway in cancer

2017 ◽  
Vol 45 (4) ◽  
pp. 855-870 ◽  
Author(s):  
Dinuka M. De Silva ◽  
Arpita Roy ◽  
Takashi Kato ◽  
Fabiola Cecchi ◽  
Young H. Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cancer Treatment ◽  
Target Cell ◽  
Wide Spectrum ◽  
Cell Types ◽  
Receptor Activation ◽  
Model Systems ◽  
Cell Surface Receptor ◽  
Hepatocyte Growth

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.

Increased Engraftment of Hepatic Progenitors After Activation of the Hepatocyte Growth Factor Signaling Pathway by Protein Transduction

2009 ◽  
Vol 234 (9) ◽  
pp. 1102-1108 ◽  
Author(s):  
Guillaume Kellermann ◽  
Lyes Boudechiche ◽  
Anne Weber ◽  
Michelle Hadchouel
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Signaling Pathway ◽  
Cell Types ◽  
Cell Surface Receptor ◽  
Migration And Invasion ◽  
Protein Transduction ◽  
Growth Factor Signaling ◽  
Hepatocyte Growth

Cell transplantation has become a major focus in biomedical research. However, efficient engraftment in solid tissues remains a challenge. Hepatocyte growth factor (HGF) signaling increases survival, proliferation, migration, and invasion of many cell types through Met, its cell surface receptor. Therefore, activation of this signaling pathway may improve the ability of many cells to be transplanted. We constructed a constitutively activated form of Met (Tpr-Met) fused to the protein transduction domain of HIV-TAT to activate the HGF/Met pathway for a few hours following cell injection. Matrix-assisted refolding was used to renature TAT-Tpr-Met protein, which was efficiently delivered into cells and recapitulated several biological functions of Met in vitro. Furthermore, treatment of hepatic progenitors with this molecule for one hour before transplantation significantly improved engraftment efficiency (31% untreated cells, 58% treated cells). These findings suggest that the transient transfer of Tpr-Met may provide a new approach to increase the proportion of successfully engrafted cells.

Hepatocyte Growth Factor and Macrophage-stimulating Protein “Hinge” Analogs to Treat Pancreatic Cancer

2019 ◽  
Vol 19 (10) ◽  
pp. 782-795
Author(s):  
John W. Wright ◽  
Kevin J. Church ◽  
Joseph W. Harding
Keyword(s):  
Pancreatic Cancer ◽  
Signal Transduction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tumor Growth ◽  
Receptor Activation ◽  
Signal Transduction Pathways ◽  
Met Receptor ◽  
Macrophage Stimulating Protein ◽  
Hepatocyte Growth

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the “hinge regions” of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.

scholarly journals Hepatocyte growth factor modulates in vitro survival and proliferation of germ cells during postnatal testis development

2006 ◽  
Vol 189 (1) ◽  
pp. 137-146 ◽  
Author(s):  
A Catizone ◽  
G Ricci ◽  
J Del Bravo ◽  
M Galdieri
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Germ Cell ◽  
Germ Cells ◽  
Cell Types ◽  
Tyrosine Kinase Receptor ◽  
Testis Development ◽  
Pachytene Spermatocytes ◽  
Hepatocyte Growth

The hepatocyte growth factor (HGF) is a pleiotropic cytokine that influences mitogenesis, motility and differentiation of many different cell types by its tyrosine kinase receptor c-Met. We previously demonstrated that the c-Met/HGF system is present and functionally active during postnatal testis development. We found also that spermatozoa express c-Met and that HGF has a positive effect on the maintenance of sperm motility. In the present paper, we extend our study on the germ cells at different stages of differentiation during the postnatal development of the testis. We demonstrate that c-met is present in rat spermatogonia, pachytene spermatocytes and round spermatids and that HGF significantly increases spermatogonial proliferation in 8- to 10-day-old pre-pubertal rats. At this age HGF does not affect Sertoli cells and peritubular myoid cells proliferation. In addition, we studied the effect of the factor on germ cell apoptosis and we show that HGF prevents the germ cell apoptotic process. We also studied the effect of HGF on 18- to 20-day-old and 28- to 30-day-old rat testes. At these ages also the factor significantly increases germ cell duplication and decreases the number of apoptotic cells. However, the effect on programmed cell death is higher in the 8- to 10-day-old rats and declines in the older animals. In conclusion, we report that rat germ cells (spermatogonia, pachytene spermatocytes and round spermatids) express c-met and that HGF modulates germ cell proliferating activity and apoptosis in vitro. These data indicate that the c-Met/HGF system is involved in male germ cell homeostasis and, consequently, has a role in male fertility.

Insights into the structure of hepatocyte growth factor/scatter factor (HGF/SF) and implications for receptor activation

FEBS Letters ◽  
1998 ◽  
Vol 430 (1-2) ◽  
pp. 126-129 ◽  
Author(s):  
Dimitri Y Chirgadze ◽  
Jonathan Hepple ◽  
R.Andrew Byrd ◽  
R Sowdhamini ◽  
Tom L Blundell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Receptor Activation ◽  
Scatter Factor ◽  
Hepatocyte Growth

scholarly journals Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development.

1993 ◽  
Vol 123 (1) ◽  
pp. 223-235 ◽  
Author(s):  
E Sonnenberg ◽  
D Meyer ◽  
K M Weidner ◽  
C Birchmeier
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinase ◽  
Cell Surface Receptor ◽  
Mouse Development ◽  
Scatter Factor ◽  
Rnase Protection ◽  
Hepatocyte Growth

Scatter factor/hepatocyte growth factor (SF/HGF) has potent motogenic, mitogenic, and morphogenetic activities on epithelial cells in vitro. The cell surface receptor for this factor was recently identified: it is the product of the c-met protooncogene, a receptor-type tyrosine kinase. We report here the novel and distinct expression patterns of SF/HGF and its receptor during mouse development, which was determined by a combination of in situ hybridization and RNase protection experiments. Predominantly, we detect transcripts of c-met in epithelial cells of various developing organs, whereas the ligand is expressed in distinct mesenchymal cells in close vicinity. In addition, transient SF/HGF and c-met expression is found at certain sites of muscle formation; transient expression of the c-met gene is also detected in developing motoneurons. SF/HGF and the c-met receptor might thus play multiple developmental roles, most notably, mediate a signal given by mesenchyme and received by epithelial. Mesenchymal signals are known to govern differentiation and morphogenesis of many epithelia, but the molecular nature of the signals has remained poorly understood. Therefore, the known biological activities of SF/HGF in vitro and the embryonal expression pattern reported here indicate that this mesenchymal factor can transmit morphogenetic signals in epithelial development and suggest a molecular mechanism for mesenchymal epithelial interactions.

Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1857-1863 ◽  
Author(s):  
Nadeem Wajih ◽  
David C. Sane
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Cell Surface ◽  
Hepatocyte Growth Factor ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Cell Surface Receptor ◽  
Antiangiogenic Effect ◽  
Soluble C ◽  
Hepatocyte Growth

Angiostatin, an inhibitor of angiogenesis, contains 3 to 4 kringle domains that are derived from proteolytic cleavage of plasminogen. The antiangiogenic effects of angiostatin occur, in part, from its inhibition of endothelial cell surface adenosine triphosphate synthase, integrin functions, and pericellular proteolysis. Angiostatin has structural similarities to hepatocyte growth factor (HGF; “scatter factor”), a promoter of angiogenesis, that induces proliferation and migration of both endothelial and smooth muscle cells via its cell surface receptor, c-met. We hypothesized that angiostatin might block HGF-induced signaling in endothelial and smooth muscle cells. Angiostatin inhibited HGF-induced phosphorylation of c-met, Akt, and ERK1/2. Angiostatin also significantly inhibited proliferation of human umbilical vein endothelial cells (HUVECs) induced by HGF. In contrast, angiostatin did not inhibit vascular endothelial growth factor (VEGF)–or basic fibroblast growth factor (bFGF)–induced signaling events or HUVEC proliferation. Angiostatin bound to immobilized truncated c-met produced by A431 cells and could be immunoprecipitated as a complex with soluble c-met. HGF inhibited the binding of 125I-angiostatin to HUVECs. Soluble c-met, produced by several tumor cell lines, could inhibit the antiangiogenic effect of angiostatin. The disruption of HGF/c-met signaling is a novel mechanism for the antiangiogenic effect of angiostatin.

scholarly journals Expression of Hepatocyte Growth Factor and the Proto-oncogenic Receptor c-Met in Canine Osteosarcoma

2009 ◽  
Vol 46 (5) ◽  
pp. 869-877 ◽  
Author(s):  
H. Fieten ◽  
B. Spee ◽  
J. IJzer ◽  
M. J. Kik ◽  
L. C. Penning ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mrna Expression ◽  
Survival Time ◽  
Receptor Activation ◽  
Disease Free Interval ◽  
Canine Osteosarcoma ◽  
Free Interval ◽  
Hepatocyte Growth ◽  
Disease Free

Hepatocyte growth factor (HGF) and the proto-oncogenic receptor c-Met are implicated in growth, invasion, and metastasis in human cancer. Little information is available on the expression and role of both gene products in canine osteosarcoma. We hypothesized that the expression of c-Met is associated with malignant histologic characteristics, a short survival time, and a reduced disease-free interval in canine osteosarcoma. Quantitative real-time polymerase chain reaction was used to analyze the messenger RNA (mRNA) expression of both HGF and c-Met in 59 canine osteosarcoma samples. The relationship between HGF and c-Met expression, patient outcome, and histologic characteristics of the tumor were studied. Western blot analysis was performed to investigate the presence of active HGF protein. The expression pattern of c-Met in 16 slides of canine osteosarcoma was identified by immunohistochemistry. Coexpression of HGF and c-Met mRNA in all canine osteosarcoma samples suggested autocrine or paracrine receptor activation. A significant, moderately positive correlation was found between c-Met and HGF mRNA expression. c-Met mRNA expression was not associated with survival time or disease-free interval. Expression of c-Met was significantly associated with metastasis via the lymphogenic route. Immunolabeling with c-Met revealed a cytoplasmic staining pattern in all osteosarcoma cell types. In this study, c-Met mRNA expression in canine osteosarcoma was found to be of no influence on survival time and disease-free interval. Further studies are necessary to confirm the involvement of the c-Met pathway in the lymphogenic route of metastasis.

scholarly journals A Natural Hepatocyte Growth Factor/Scatter Factor Autocrine Loop in Myoblast Cells and the Effect of the Constitutive Met Kinase Activation on Myogenic Differentiation

1997 ◽  
Vol 137 (5) ◽  
pp. 1057-1068 ◽  
Author(s):  
Sergio Anastasi ◽  
Silvia Giordano ◽  
Olga Sthandier ◽  
Giovanna Gambarotta ◽  
Rossella Maione ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Myogenic Differentiation ◽  
Biological Effects ◽  
Receptor Activation ◽  
Receptor Interaction ◽  
Scatter Factor ◽  
Autocrine Loop ◽  
Myoblast Cells ◽  
Hepatocyte Growth

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.

Hepatocyte growth factor: Molecular biomarker and player in cardioprotection and cardiovascular regeneration

2012 ◽  
Vol 107 (04) ◽  
pp. 656-661 ◽  
Author(s):  
Rosalinda Madonna ◽  
Cihan Cevik ◽  
Maher Nasser ◽  
Raffaele De Caterina
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Types ◽  
Diagnostic Biomarker ◽  
Scatter Factor ◽  
Molecular Biomarker ◽  
Cardiovascular Regeneration ◽  
Hepatocyte Growth

SummaryThe liver possesses impressive regenerative capacities. Grafts of embryonic liver explants and liver explant-conditioned media have been shown to enhance the mitotic activity of hepatocytes. Hepatocyte growth factor (HGF), also named scatter factor (SF), has been identified as a primary candidate in promoting and regulating liver regeneration. Although initially thought to be a liver-specific mitogen, HGF was later reported to have mitogenic, motogenic, morphogenic, and anti-apoptotic activities in various cell types. By promoting angiogenesis and inhibiting apoptosis, endogenous HGF may play an important role in cardioprotection as well as in the regeneration of endothelial cells and cardiomyocytes after myocardial infarction. Since serum concentration of HGF increases in the early phase of myocardial infarction and in heart failure, HGF may also play a key role as a prognostic and diagnostic biomarker of cardiovascular disease. Here we discuss the role of HGF as a biomarker and mediator in cardioprotection and cardiovascular regeneration.

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