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Published on: September 30, 2016
Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis
Moritz Bennecke1, Lydia Kriegl, Monther Bajbouj
12nd Department of Medicine, Klinikum rechts der Isar, Technical University Munich, Germany.
Abstract:
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.
Insights
Oncogenic K-ras drives serrated colorectal cancer through a distinct pathway. Blocking senescence in these KRAS-mutated tumors promotes invasive carcinomas, highlighting RAS-RAF-MEK signaling as a key gatekeeper.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Serrated colorectal cancers may represent a distinct molecular subtype.
- These tumors are thought to arise independently of APC mutations.
Purpose of the Study:
- To investigate the role of oncogenic K-ras in serrated colorectal cancer development.
- To explore the mechanism involving p16INK4a and senescence in this pathway.
Main Methods:
- Mice models with intestinal epithelial cell-specific expression of oncogenic K-ras(G12D).
- Analysis of p16(ink4a) expression and senescence induction.
- Genetic deletion of Ink4a/Arf in K-ras(G12D) expressing mice.
Main Results:
- K-ras(G12D) induced serrated hyperplasia with p16(ink4a) overexpression and senescence.
- Deletion of Ink4a/Arf prevented senescence, leading to invasive, metastasizing carcinomas.
- Tumors showed similarities to human KRAS-mutated serrated colorectal cancers.
Conclusions:
- Oncogenic K-ras is a key driver in an alternative serrated pathway to colorectal cancer.
- RAS-RAF-MEK signaling acts as an additional gatekeeper in colorectal tumor development, independent of APC.
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