Activation of hepatocyte growth factor-Met autocrine loop enhances tumorigenicity in a human lung adenocarcinoma cell line

Hepatocyte growth factor (HGF) is a multifunctional cytokine with effects o n the proliferation, motility, and differentiation of cells that express it s receptor Met. The co-expression of HGF and Met is common among nonsmall-c ell lung cancers, especially adenocarcinoma. However, the biologic conseque nces of this putative HGF-Met autocrine signaling remain speculative. We ha ve used retroviral gene transduction technique to express high levels of HG F in the NCI-H358 lung adenocarcinoma cells that have functionally active c ell surface Met receptor. The activation of autocrine HGF-Met signaling was confirmed by the induction of spontaneous cell scattering activity, Compar ed to the parent and control cells transduced with the retroviral vector al one, HGF overexpressing H358 cells show enhanced capacity to colonize soft agar medium and to form xenograft tumors when implanted in the subcutaneous tissue of immune-deficient mice. These effects were not accompanied by cha nges in their growth rate in monolayer culture condition, or in the express ion of vascular endothelial growth factor. The tumors formed by HGF overexp ressing cells also showed more prominent glandular cell arrangement and fun ctional activity. This report provides the direct in vivo evidence that aut ocrine HGF-Met signaling plays significant roles in the growth and differen tiation of human lung adenocarcinoma cells.