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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Cellular Senescence / genetics*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology*
  • Disease Progression
  • Genes, APC
  • Genes, ras
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Oncogenes*
  • Signal Transduction
  • Wnt Proteins / metabolism


  • Cyclin-Dependent Kinase Inhibitor p16
  • Wnt Proteins

Associated data

  • GEO/GSE20647