Hepatocyte growth factor (HGF) is a multifunctional cytokine with effects on the proliferation, motility, and differentiation of cells that express its receptor Met. The co-expression of HGF and Met is common among nonsmall-cell lung cancers, especially adenocarcinoma. However, the biologic consequences of this putative HGF-Met autocrine signaling remain speculative. We have used retroviral gene transduction technique to express high levels of HGF in the NCI-H358 lung adenocarcinoma cells that have functionally active cell surface Met receptor. The activation of autocrine HGF-Met signaling was confirmed by the induction of spontaneous cell scattering activity. Compared to the parent and control cells transduced with the retroviral vector alone, 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 changes in their growth rate in monolayer culture condition, or in the expression of vascular endothelial growth factor. The tumors formed by HGF overexpressing cells also showed more prominent glandular cell arrangement and functional activity. This report provides the direct in vivo evidence that autocrine HGF-Met signaling plays significant roles in the growth and differentiation of human lung adenocarcinoma cells.