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Cancer Cell. 2010 Aug 9;18(2):135-46. doi: 10.1016/j.ccr.2010.06.013.

Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis.

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2nd Department of Medicine, Klinikum rechts der Isar, Technical University Munich, Germany.


Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. We demonstrate that intestinal epithelial cell specific expression of oncogenic K-ras(G12D) in mice induces serrated hyperplasia, which is characterized by p16(ink4a) overexpression and induction of senescence. Deletion of Ink4a/Arf in K-ras(G12D) expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras represents a key player during an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development.

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