Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo

ABSTRACT Hepatocyte growth factor/scatter factor (HGF/SF) is a potent mitogen, motogen, and morphogen for epithelial cells expressing its tyrosine kinase receptor, the c-met proto-oncogene product, and is required for normal development in the mouse. Inappropriate stimulation of Met signal transduction induces aberrant morphogenesis and oncogenesis in mice and has been implicated in human cancer. NK1 is a naturally occurring HGF/SF splice variant composed of only the amino terminus and first kringle domain. While the biological activities of NK1 have been controversial, in vitro data suggest that it may have therapeutic value as an HGF/SF antagonist. Here, we directly test this hypothesis in vivo by expressing mouse NK1 in transgenic mice and comparing the consequent effects with those observed for mice carrying an HGF/SF transgene. Despite robust expression, NK1 did not behave as an HGF/SF antagonist in vivo. Instead, NK1-transgenic mice displayed most of the phenotypic characteristics associated with HGF/SF-transgenic mice, including enlarged livers, ectopic skeletal-muscle formation, progressive renal disease, aberrant pigment cell localization, precocious mammary lobuloalveolar development, and the appearance of mammary, hepatocellular, and melanocytic tumors. And like HGF/SF-transgenic livers, NK1 livers had higher levels of tyrosine-phosphorylated complexes associated with Met, suggesting that the mechanistic basis for the effects of NK1 overexpression in vivo was autocrine activation of Met. We conclude that NK1 acts in vivo as a partial agonist. As such, the efficacy of NK1 as a therapeutic HGF/SF antagonist must be seriously questioned.

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Disassociation of Met-Mediated Biological Responses In Vivo: the Natural Hepatocyte Growth Factor/Scatter Factor Splice Variant NK2 Antagonizes Growth but Facilitates Metastasis

Molecular and Cellular Biology ◽

10.1128/mcb.20.6.2055-2065.2000 ◽

2000 ◽

Vol 20 (6) ◽

pp. 2055-2065 ◽

Cited By ~ 45

Author(s):

Toshiyuki Otsuka ◽

John Jakubczak ◽

Wilfred Vieira ◽

Donald P. Bottaro ◽

Diane Breckenridge ◽

...

Keyword(s):

Growth Factor ◽

Transgenic Mice ◽

Hepatocyte Growth Factor ◽

Melanoma Cells ◽

Scatter Factor ◽

Full Spectrum ◽

Critical Determinant ◽

Hepatocyte Growth

ABSTRACT Hepatocyte growth factor/scatter factor (HGF/SF) stimulates numerous cellular activities capable of contributing to the metastatic phenotype, including growth, motility, invasiveness, and morphogenetic transformation. When inappropriately expressed in vivo, an HGF/SF transgene induces numerous hyperplastic and neoplastic lesions. NK1 and NK2 are natural splice variants of HGF/SF; all interact with a common receptor, Met. Although both agonistic and antagonistic properties have been ascribed to each isoform in vitro, NK1 retains the full spectrum of HGF/SF-like activities when expressed as a transgene in vivo. Here we report that transgenic mice broadly expressing NK2 exhibit none of the phenotypes characteristic of HGF/SF or NK1 transgenic mice. Instead, when coexpressed in NK2-HGF/SF bitransgenic mice, NK2 antagonizes the pathological consequences of HGF/SF and discourages the subcutaneous growth of transplanted Met-containing melanoma cells. Remarkably, the metastatic efficiency of these same melanoma cells is dramatically enhanced in NK2 transgenic host mice relative to wild-type recipients, rivaling levels achieved in HGF/SF and NK1 transgenic hosts. Considered in conjunction with reports that in vitro NK2 induces scatter, but not other activities, these data strongly suggest that cellular motility is a critical determinant of metastasis. Moreover, our results demonstrate how alternatively structured ligands can be exploited in vivo to functionally dissociate Met-mediated activities and their downstream pathways.

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Radioimmunoscintigraphy of Tumors Autocrine for Human Met and Hepatocyte Growth Factor/Scatter Factor

Molecular Imaging ◽

10.1162/15353500200200006 ◽

2002 ◽

Vol 1 (1) ◽

pp. 153535002002000

Author(s):

Rick V. Hay ◽

Brian Cao ◽

R. Scot Skinner ◽

Ling-Mei Wang ◽

Yanli Su ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Nuclear Imaging ◽

Region Of Interest ◽

Scatter Factor ◽

Body Activity ◽

Human Solid Tumors ◽

Total Body ◽

Hepatocyte Growth

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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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 ◽

10.1128/mcb.16.3.1115 ◽

1996 ◽

Vol 16 (3) ◽

pp. 1115-1125 ◽

Cited By ~ 212

Author(s):

M Jeffers ◽

S Rong ◽

G F Vande Woude

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Present Report ◽

Metastatic Potential ◽

Tyrosine Kinase Receptor ◽

Scatter Factor ◽

Protein Levels ◽

Hepatocyte Growth

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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Characterization of the Scatter Factor/Hepatocyte Growth Factor Gene Promoter

Journal of Biological Chemistry ◽

10.1074/jbc.270.2.830 ◽

1995 ◽

Vol 270 (2) ◽

pp. 830-836 ◽

Cited By ~ 24

Author(s):

Antje Plaschke-Schlütter ◽

Jürgen Behrens ◽

Ermanno Gherardi ◽

Walter Birchmeier

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Gene Promoter ◽

Scatter Factor ◽

Factor Gene ◽

Growth Factor Gene ◽

Hepatocyte Growth

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Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

Journal of Experimental Medicine ◽

10.1084/jem.185.12.2121 ◽

1997 ◽

Vol 185 (12) ◽

pp. 2121-2131 ◽

Cited By ~ 84

Author(s):

Robbert van der Voort ◽

Taher E.I. Taher ◽

Robert M.J. Keehnen ◽

Lia Smit ◽

Martijn Groenink ◽

...

Keyword(s):

Cell Adhesion ◽

T Cell ◽

B Cells ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Tyrosine Kinase ◽

B Cell ◽

Germinal Center ◽

Scatter Factor ◽

Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

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