Regulation of scatter factor (hepatocyte growth factor) production by tumor-stroma interaction

Abstract

Scatter factors (SF) [also known as hepatocyte growth factor (HGF)] is a cytokine produced by stromal cell types that induces dissociation (scattering) of contiguous sheets of epithelial cells into individual motile fibroblast-like cells (Stoker et al., 1987; Rosen et al., 1989). In addition to scattering, SF stimulates the following processes in multiple epithelial and carcinoma cell types: (1) random motility of isolated cells (Li et al., 1994); (2) gradient-directed migration (chemotaxis) (Rosen et al., 1990b, 1991a); (3) migration of cells out of multicellular spheroids onto flat culture surfaces (Rosen et al., 1990a); (4) migration off carrier beads onto flat surfaces (Rosen et al., 1990b, 1990c, 1991a); (5) cell surface expression of urokinase (Pepper et al., 1992; Rosen et al., 1994a); and (6) invasion through extracellular matrix proteins (Weidner et al., 1990; Rosen et al., 1991a, 1994a; Bhargava et al., 1992). Thus, SF appears to activate an entire program of cellular activities required for the invasive phenotype. SF stimulates proliferation of many normal epithelial cell types, including hepatocytes, mammary epithelium, keratinocytes, melanocytes, and renal tubular epithelium (Miyazawa et al., 1989; Nakamura et al., 1989; Rubin et al., 1991; Kan et al., 1991; Halaban et al., 1992). However, SF has little or no effect on the proliferation of most carcinoma cell types. For these cell types, the major in vitro action of SF appears to be stimulation of cell motility.