Harvey ras induction of metastatic potential depends upon oncogene activation and the type of recipient cell

NIH-3T3 cells and early passage fibroblasts transformed by various members of the rasH gene family were found to express metastatic potential in nude (Nu/Nu) mice. NIH-3T3 cells transformed by either the cloned DNA of the Harvey sarcoma virus or by the T24 human rasH oncogene were both tumorigenic after subcutaneous injection and metastatic after intravenous injection. In contrast, NIH-3T3 cells transformed by elevated levels of the proto-oncogene were tumorigenic but not metastatic. Tumor growth potential by itself, therefore, was not sufficient to induce metastatic behavior. Diploid fibroblasts transformed with the T24 rasH oncogene were tumorigenic and metastatic after intravenous injection and also produced extensive spontaneous metastases. Thus, induction of the complete metastatic phenotype by the T24 rasH oncogene does not require the use of aneuploid recipient cells such as NIH-3T3 cells. An alternative murine recipient cell type C127, when transformed by the cloned DNA of the Harvey sarcoma virus, was tumorigenic but not metastatic. The transformed C127 cells made less of the viral gene product P21 than the NIH-3T3 rasH transformants. To ensure that the decreased levels of P21 were not responsible for the lack of metastatic potential, C127 cells were transformed with altered constructs of the plasmid containing the Harvey sarcoma virus which elicited enhanced levels of P21. The augmented P21 levels, although equivalent to or greater than that seen in the NIH-3T3 transformants, did not confer metastatic potential on the C127 transformants. These results indicate that at least two complementation groups may be required for induction of metastatic capacity in this system, one involving the "activated" oncogenic form of the rasH gene and the second another as yet undefined factor in the cellular background present in NIH-3T3 cells but absent in C127 cells.