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Constitutive c-Met Signaling through a Nonautocrine Mechanism Promotes Metastasis in a Transgenic Transplantation Model

Molecular Genetics Section, Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4264

Normal cells are dependent on exogenous, receptor-mediated growth stimulation for cell cycle entry and progression, providing a critical homeostatic mechanism regulating cellular proliferation. In contrast, tumor cells acquire some degree of growth signal autonomy, often through their ability to produce growth factors as well as their receptors (autocrine signaling). Recently, data have begun to emerge implicating heterotypic signaling between diverse cell types within a tumor in the genesis and progression of cancer; however, current experimental approaches in vivo have not adequately addressed this critical relationship. Here we used transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF), or its growth antagonist NK2, as genetically modified hosts for transplantation of tumor cells expressing their receptor, c-Met, to directly assess the contribution of heterotypic signaling to metastatic colonization. We demonstrate that metastatic potential under nonautocrine signaling conditions (i.e., where tumor cells expressing c-Met are transplanted into transgenic hosts producing HGF/SF) rivaled that observed under conditions of autocrine signaling (i.e., where tumor cells expressing both HGF/SF and c-Met are transplanted into wild-type hosts). HGF/SF and NK2 were not functionally equivalent in vivo. Attenuation of NK2-associated growth inhibition by the presence of an HGF/SF-Met autocrine loop uncovered a shift in metastatic site preference from lung to liver only in NK2-transgenic hosts, a qualitative behavioral alteration likely detectable only through the genetic approach used here. Our data demonstrate that growth factors not intrinsic to malignant cells can have profound effects on metastatic efficiency in vivo and provide experimental support of a role for heterotypic signaling in tumor progression.

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