Explaining the preponderance of Kras mutations in human cancer: An isoform-specific function in stem cell expansion

Abstract

Mutationally activated forms of the three closely related Ras isoforms, Kras, Hras, and Nras can each exert oncogenic activity, and activated alleles arise in a variety of human cancers. However, mutant Kras is, by far, the most frequently observed Ras isoform in cancer, and is most frequently detected in tumors derived from endodermal tissues, including pancreas, lung, and colon. We have recently reported findings that may explain this. We observed that activated Kras, but not Hras or Nras, promotes the expansion of an endodermal stem/progenitor cell and blocks its differentiation. Thus, Kras may uniquely contribute to the initiation of tumors in endodermally-derived tissues by expanding a stem/progenitor cell population.