Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor

The met proto-oncogene is the tyrosine kinase growth factor receptor for hepatocyte growth factor/scatter factor (HGF/SF). It was previously shown that, like the oncogenic tpr-met, the mouse met proto-oncogene transforms NIH 3T3 cells. We have established NIH 3T3 cells stably expressing both human (Met^hu) and mouse (Met^mu) met proto-oncogene products. The protein products are properly processed and appear on the cell surface. NIH 3T3 cells express endogenous mouse HGF/SF mRNA, suggesting an autocrime activation mechanism for transformation by Met^mu. However, the tumor-forming activity of Met^hu in NIH 3T3 cells is very low compared with that of Met^mu, but efficient tumorigenesis occurs when Met^hu and HGF/SF^hu are coexpressed. These results are consistent with an autocrine transformation mechanism and suggest further that the endogenous murine factor inefficiently activates the tumorigenic potential of Met^hu. The tumorigenicity observed with reciprocal chimeric human and mouse receptors that exchange external ligand-binding domains supports this conclusion. We also show that HGF/SF^hu expressed in NIH 3T3 cells produces tumors in nude mice.