Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis

Abstract

The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through only partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with U1snRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.

Fig. 1

Structure of SF/HGF and c-Met (modified, with permission, from Fig. 1 in Matsumoto and Nakamura, Cancer Science 94, 322, 2003).

Fig. 2

c-Met-dependent signal transduction pathways, transcriptional events, and corresponding functional consequences (modified, with permission, from Fig. 6 in Birchmeier et al., Nature Reviews Molecular Cell Biology 4, 921, 2003).

Fig. 3

SF/HGF promotes brain tumor growth in vivo. A–C. Glioma cells engineered to overexpress SF/HGF (SF #5 and SF #55) produce significantly larger xenografts (C) than control clones (A, Neo #2 and Neo #3, and B) (adapted, with permission, from Fig. 3 in Laterra et al., Biochemical and Biophysical Research Communications 235, 745, 1997). D–E. In vivo inhibition of SF/HGF and c-Met expression by systemic injection of liposomes complexed with plasmids expressing anti-SF/HGF U1/ribozymes (pU1/SF) and anti-c-Met U1/ribozymes (pU1/Met) leads to significant growth inhibition of wild-type intracranial glioma xenografts (pU1 = control) (modified, with permission, from Fig. 1B in Abounader et al., FASEB Journal 16, 109, 2002).

Fig. 4

SF/HGF and c-Met are expressed in human brain tumor blood vessels, and SF/HGF expression levels correlate with tumor vessel density (i.e., angiogenesis). A–B. Immunostaining of human gliomas for SF/HGF (A) and c-Met (B). Arrows indicate immunoreactivity of tumor associated-blood vessels. Arrowheads point to immunoreactive tumor cells. (Adapted, with permission, from Fig. 3 in Lamszus et al., International Journal of Developmental Neuroscience 17, 523, 1999.) C. Relationship between intratumoral growth factor levels and microvessel densities in human gliomas. Tumors were divided into groups with low (<100 microvessels/0.95 mm²), medium (100–200 microvessels/0.95 mm²), and high (>200 microvessels/0.95 mm²) microvessel densities. VEGF and SF/HGF concentrations were statistically significantly higher in tumors with high microvessel densities than in those with low or medium microvessel densities. No such difference was detected for bFGF. (Modified, with permission, from Fig. 1 in Schmidt et al., International Journal of Cancer 84, 12, 1999.)

Fig. 5

SF/HGF induces angiogenesis in experimental glioblastoma. A–B. Rat glioma xenografts originating from glioma cells that overexpress SF/HGF (SF #6 and SF #11) exhibit significantly higher vessel densities than control xenografts (adapted, with permission, from Figs. 8A and B in Laterra et al., Laboratory Investigation 76, 572, 1997). C–D. In vivo ition of SF/HGF and c-Met expression by systemic injection of liposomes complexed with plasmids expressing anti-SF/HGF U1/ribozymes (pU1/SF) and anti-c-Met U1/ribozymes (pU1/Met) leads to a significant inhibition of tumor vessel formation (modified, with permission, from Fig. 2 in Abounader et al., FASEB Journal 16, 110, 2002).

Fig. 6

Multifunctional angiogenic effects of SF/HGF.