title: CD44-independent hepatocyte growth factor/c-Met autocrine loop promotes malignant peripheral nerve sheath tumor cell invasion in vitro.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are invasive peripheral nerve neoplasms that express both the receptor tyrosine kinase c-Met and its ligand hepatocyte growth factor (HGF). The combined expression of these proteins has been implicated in tumor cell growth and metastasis. However, HGF/c-Met autocrine activity requires the presence of a serine protease, the HGF activator (HGFA), and, in some cells, the CD44 transmembrane glycoprotein. Here, we found that HGFA, HGF, c-Met, and CD44 are coexpressed in MPNSTs but their localization did not correlate with increased cell proliferation. The ST8814 MPNST cell line also expresses all of these proteins, can convert pro-HGF to active HGF, and exhibits constitutive c-Met phosphorylation. Blocking c-Met activity or expression inhibits the invasive behavior of these cells but not their proliferation. Interestingly, although a CD44 splice variant contributes to MPNST cell invasion and interacts with c-Met and HGF in ST8814 cells, it is not required for c-Met activation. These data indicate that an HGF/c-Met autocrine loop can promote MPNST invasion through a CD44-independent mechanism and suggest that c-Met, HGFA, and HGF are potential molecular targets to inhibit MPNST metastasis.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Su
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
authors.forename: John
authors.initials: J
authors.lastname: Laterra
authors.forename: Larry S
authors.initials: LS
authors.lastname: Sherman
mesh_terms: D019898:Autocrine Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000502:physiology*
chemical_list: D018960:Hyaluronan Receptors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met