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-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.
Bennecke
Moritz
M
2nd Department of Medicine, Klinikum rechts der Isar, Technical University Munich, Germany.
Kriegl
Lydia
L
Bajbouj
Monther
M
Retzlaff
Kristin
K
Robine
Sylvie
S
Jung
Andreas
A
Arkan
Melek C
MC
Kirchner
Thomas
T
Greten
Florian R
FR
D000818:Animals; D002455:Cell Division; D016922:Cellular Senescence / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D017491:Genes, APC; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009857:Oncogenes; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D051153:Wnt Proteins