Ink4a/Arf and Oncogene-Induced Senescence Prevent Tumor Progression during Alternative Colorectal Tumorigenesis
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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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Colon SSAs are mainly driven by activating BRAF mutations that trigger OIS.
“Colon SSAs are mainly driven by activating BRAF mutations that trigger OIS 31,34,35 .”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [35]
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Self-citation
- Authors
- Bennecke, M., Kriegl, L., Bajbouj, M., Retzlaff, K., Robine, S., Jung, A., Arkan, M. C., Kirchner, T., & Greten, F. R.
- Affiliations
- TUM Klinikum (DE)
- Pathologisches Institut (DE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Greten, Florian R.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 18
- Issue
- 2
- Pages
- 135-146
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2166189096
- Cited by
- 186
- References
- 48
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 12 · 2023: 12 · 2022: 10 · 2021: 5 · 2020: 7 · 2019: 14 · 2018: 9 · 2017: 12 · 2016: 9 · 2015: 14 · 2014: 16 · 2013: 16 · 2012: 17
- FWCI
- 12.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- Ink4a/Arf, oncogene-induced senescence, KRAS G12D, colorectal carcinogenesis, p16INK4a, metastatic colorectal cancer, Ras/Raf/MEK signaling, gatekeeper genes, tumor progression
- MeSH terms
- Animals, Cell Division, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mutation, Oncogenes, Genes, ras, Colorectal Neoplasms, Signal Transduction, Cellular Senescence, Genes, APC, Disease Progression, Cyclin-Dependent Kinase Inhibitor p16, Wnt Proteins, Mice
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