title: Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor.
abstract: Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchymally derived, multifunctional paracrine regulator possessing mitogenic, motogenic, and morphogenetic activities in cultured epithelial cells containing its tyrosine kinase receptor, Met. c-met has been implicated in oncogenesis through correlation of expression with malignant phenotype in specific cell lines and tumors. Paradoxically, however, HGF/SF can also inhibit the growth of some tumor cells. To elucidate the oncogenic role of HGF/SF in vivo, transgenic mice were created such that HGF/SF was inappropriately targeted to a variety of tissues. HGF/SF transgenic mice developed a remarkably broad array of histologically distinct tumors of both mesenchymal and epithelial origin. Many neoplasms arose from tissues exhibiting abnormal development, including the mammary gland, skeletal muscle, and melanocytes, suggesting a functional link between mechanisms regulating morphogenesis and those promoting tumorigenesis. Most neoplasms, especially melanomas, demonstrated overexpression of both the HGF/SF transgene and endogenous c-met, and had enhanced Met kinase activity, strongly suggesting that autocrine signaling broadly promotes tumorigenesis. Thus, subversion of normal mesenchymal-epithelial paracrine regulation through the forced misdirection of HGF/SF expression induces aberrant morphogenesis and subsequent malignant transformation of cells of diverse origin.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors.forename: H
authors.initials: H
authors.lastname: Takayama
authors.forename: W J
authors.initials: WJ
authors.lastname: LaRochelle
authors.forename: R
authors.initials: R
authors.lastname: Sharp
authors.forename: T
authors.initials: T
authors.lastname: Otsuka
authors.forename: P
authors.initials: P
authors.lastname: Kriebel
authors.forename: M
authors.initials: M
authors.lastname: Anver
authors.forename: S A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: G
authors.initials: G
authors.lastname: Merlino
mesh_terms: D000818:Animals; D004847:Epithelial Cells; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009374:Neoplasms, Experimental / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
chemical_list: D017228:Hepatocyte Growth Factor; D008668:Metallothionein; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases