Ink4a/Arf and Oncogene-Induced Senescence Prevent Tumor Progression during Alternative Colorectal Tumorigenesis

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-rasG12D in mice indu...

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Bibliographic Details
Published in:Cancer cell 2010-08, Vol.18 (2), p.135-146
Main Authors: Bennecke, Moritz, Kriegl, Lydia, Bajbouj, Monther, Retzlaff, Kristin, Robine, Sylvie, Jung, Andreas, Arkan, Melek C., Kirchner, Thomas, Greten, Florian R.
Format: Article
Language:English
Subjects:
Animals
Carcinoma
Cell Division
CELLCYCLE
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
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Summary: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-rasG12D in mice induces serrated hyperplasia, which is characterized by p16ink4a overexpression and induction of senescence. Deletion of Ink4a/Arf in K-rasG12D 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. ► Expression of oncogenic K-ras in murine enterocytes leads to serrated transformation ► OIS and p16Ink4a upregulation are found in human and murine serrated polyps ► Loss of Ink4a/Arf leads to invasive, metastasizing colon cancer in mice ► p16INK4A expression is lost at the invasion front in human serrated cancer
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2010.06.013