Scatter factor (SF) (also known as hepatocyte growth factor (HGF)) is a stromal cell-derived cytokine that can stimulate epithelial cell motility, proliferation, or morphogenesis, depending upon the cell type and environment. SF is not related to other growth factors but shows significant homology to blood coagulation proteases such as plasminogen. SF disrupts intercellular adhesion and stimulates random motility, directed migration, invasion, and expression of urokinase, a enzyme that mediates cell invasion, in human carcinoma cells. Thus, SF may """"""""switch on"""""""" a program of tumor cell activities for invasion. SF is also a potent angiogenic molecule In vivo. Preliminary data indicate that human breast cancers contain biologically active and immunoreactive SF. Moreover, human mammary tumor cells produce at least two distinct SF-inducing factors (SF- IFs) that up-regulate SF production by human fibroblasts. One of these is a low molecular weight (5-10 kDa), heat stable protein. We partially purified this factor from a high producer cell line. We hypothesize that (I) overexpression of SF contributes to the development of the invasive phenotype of human breast carcinomas; and (2) overproduction of SF is due - to an abnormal epithelial:stromal interaction in which the tumor cells secrete factors that stimulate SF synthesis b fibroblasts or other stromal cell types. To evaluate these hypotheses, we will: (I) study the expression of SF, the SF receptor (the c-met protein), and SF-lF during human breast carcinoma development and progression; (2) purify and definitively characterize the low molecular weight SF-IF; and (3) study the regulation of SF in human mammary cell cultures utilizing early passage normal and tumor-derived fibroblasts, early passage normal and tumor epithelial cells, and established tumor cell lines. The ultimate goal is to understand the mechanism(s) by which SF contributes to human mammary carcinogenesis. These studies may lead to new approaches in breast cancer diagnosis and treatment.
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