K-ras proto-oncogene exhibits tumor suppressor activity as its absence promotes tumorigenesis in murine teratomas

Ras proteins transduce signals from membrane-bound receptors via multiple downstream effector pathways and thereby affect fundamental cellular processes, including proliferation, apoptosis, and differentiation. K- ras activating mutations play a key role in neoplastic progression and are particularly prevalent in colorectal, pancreatic, and lung cancers. The present study addressed whether the K- ras proto-oncogene displays a tumor suppressor function by comparative analysis of mouse teratomas derived from wild-type embryonic stem (ES) cells, K- ras null (K- ras −/− ) ES cells, and K- ras −/− ES cells that stably reexpress either wild-type K- ras gly12 or oncogenic K- ras val12 . K- ras −/− and K- ras val12 teratomas were significantly larger than teratomas that expressed wild-type K- ras , contained significantly higher proportions of undifferentiated embryonal carcinoma-like cells, and showed significantly increased mitotic activity. However, K- ras val12 but not K- ras −/− teratomas exhibited significantly higher levels of apoptosis than wild-type teratomas. K- ras −/− and K- ras val12 ES cells showed a higher capacity for stem cell self-renewal in vitro compared with wild-type ES cells, and reexpression of K- ras gly12 in K- ras −/− ES cells restored the K- ras −/− phenotype to wild-type values. Thus, in view of evidence that tumors can derive from tissue stem cells and that tumors harbor “cancer stem cells,” aberrant K- ras expression could promote neoplastic progression by increasing their capacity for self-renewal.