HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR INDUCES A VARIETY OF TISSUE-SPECIFIC MORPHOGENIC PROGRAMS IN EPITHELIAL-CELLS

Hepatocyte growth factor/scatter factor (HGF/SF) is the mesenchymal li gand of the epithelial tyrosine kinase receptor c-Met. In vitro, HGF/S F has morphogenic properties, e.g., induces kidney epithelial cells to form branching ducts in collagen gels. Mutation of the HGF/SF gene in mice results in embryonic lethality due to severe liver and placenta defects. Here, we have evaluated the morphogenic activity of HGF/SF wi th a large variety of epithelial cells grown in three-dimensional coll agen matrices, We found that HGF/SF induces SW 1222 colon carcinoma ce lls to form crypt-like structures. In these organoids, cells exhibit a pical/basolateral polarity and build a well-developed brush border tow ards the lumen. Capan 2 pancreas carcinoma cells, upon addition of HGF /SF, develop large hollow spheroids lined with a tight layer of polari zed cells. Collagen inside the cysts is digested and the cells show fe atures of pancreatic ducts, HGF/SF induces EpH4 mammary epithelial cel ls to form long branches with end-buds that resemble developing mammar y ducts. pRNS-1-1 prostate epithelial cells in the presence of HGF/SF develop long ducts with distal branching as found in the prostate, Fin ally, HGF/SF simulates alveolar differentiation in LX-1 lung carcinoma cells. Expression of transfected HGF/SF cDNA in LX-1 lung carcinoma a nd EpH4 mammary epithelial cells induce morphogenesis in an autocrine manner. In the cell lines tested, HGF/SF activated the Met receptor by phosphorylation of tyrosine residues. These data show that HGF/SF ind uces intrinsic, tissue-specific morphogenic activities in a wide varie ty of epithelial cells. Apparently, HGF/SF triggers respective endogen ous programs and is thus an inductive, not an instructive, mesenchymal effector for epithelial morphogenesis.