Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice

Janssen, Klaus–Peter; Marjou, Fatima El; Pinto, Daniel; Sastre, Xavier; Rouillard, Dany; Fouquet, Coralie; Soussi, Thierry; Louvard, Daniel; Robine, Sylvie

doi:10.1053/gast.2002.34786

Cited by 116 publications

(109 citation statements)

References 68 publications

(82 reference statements)

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“…Thus, overexpression of oncogenic K-ras may yield very different phenotypes to simple mutation. When overexpressed from the villin promoter, mice developed tumors from 8 months of age, although no effects were seen on normal epithelium (7). As with in vitro studies, activation of Raf-MEK-ERK was observed in both normal and adenomatous tissue.…”

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confidence: 60%

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Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

Sansom

Méniel²,

Wilkins³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

177

160

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Oncogenic mutations in the K-ras gene occur in Ϸ50% of human colorectal cancers. However, the precise role that K-ras oncogenes play in tumor formation is still unclear. To address this issue, we have conditionally expressed an oncogenic K-ras V12 allele in the small intestine of adult mice either alone or in the context of Apc deficiency. We found that expression of K-ras V12 does not affect normal intestinal homeostasis or the immediate phenotypes associated with Apc deficiency. Mechanistically we failed to find activation of the Raf͞MEK͞ERK pathway, which may be a consequence of the up-regulation of a number of negative feedback loops. However, K-ras V12 expression accelerates intestinal tumorigenesis and confers invasive properties after Apc loss over the long term. In renal epithelium, expression of the oncogenic Kras V12 allele in the absence of Apc induces the rapid development of renal carcinoma. These tumors, unlike those of intestinal origin, display activation of the Raf͞MEK͞ERK and Akt signaling pathways. Taken together, these data indicate that normal intestinal and kidney epithelium are resistant to malignant transformation by an endogenous K-ras oncogene. However, activation of K-ras V12 after Apc loss results in increased tumorigenesis with distinct kinetics. Whereas the effect of K-ras oncogenes in the intestine can been observed only after long latencies, they result in rapid carcinogenesis in the kidney epithelium. These data imply a window of opportunity for anti-K-ras therapies after tumor initiation in preventing tumor growth and invasion.colorectal cancer ͉ renal carcinoma ͉ Wnt signaling

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confidence: 60%

“…Most have relied on transgenic overexpression of oncogenic K-ras mutants (7). A key difficulty in interpreting these studies is that K-ras is normally mutated but not overexpressed in tumors.…”

mentioning

confidence: 99%

Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

Sansom

Méniel²,

Wilkins³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

177

160

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“…CRC is considered the paradigm of the multistep progression cancer model, where genetic alterations accompany tumorigenesis (Fearon and Vogelstein, 1990), although alternative genetic pathways may contribute to the progression of the disease (Janssen et al, 2002;Smith et al, 2002). Crucial molecular events involve alteration and mutation of adenomatous polyposis coli (APC) and Kirsten-ras (K-ras) genes.…”

Section: Discussionmentioning

confidence: 99%

Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

et al. 2004

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“…All lesions were reviewed by a single, experienced pathologist. Immunofluorescence staining was performed as described before, 30 for details see supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

Holtorf

Conrad²,

Holzmann³

et al. 2018

OncoImmunology

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The signal adapter MyD88, an essential component of Toll-like receptor (TLR) signaling, is important for gut-microbiome interactions. However, its contribution to cancer and its cell-type specific functions are controversially discussed. Therefore, we generated new tissue-specific mouse models and analyzed the clinical importance in human colorectal cancer. A gene-trap was inserted into the murine Myd88 gene (Myd88LSL), yielding MyD88-deficient background with Cre-mediated re-expression in myeloid (MYEL) or intestinal epithelial cells (IECs). These lines were bred with the Apc1638N model that develops invasive adenocarcinoma and analyzed at 12 months. Further, two patient collectives of colorectal cancer (n = 61, and n = 633) were analyzed for expression of Myd88 and TLRs. MyD88 expression was significantly increased in carcinomas, and increased intratumoral levels of MyD88 and TLR pathway components were associated with significantly shorter disease-free (P = .011), and overall survival (P < .0001). In accordance, fully MyD88-deficient mice showed highly significantly decreased tumor incidence, tumor numbers, increased survival, and, importantly, fully lacked malignant lesions. Thus, MyD88 is essential for tumorigenesis and especially progression to malignancy. Tissue-specific re-expression of MyD88 highly significantly increased tumor initiation by differing mechanisms. In intestinal epithelia, MyD88 enhanced epithelial turnover, whereas in myeloid cells, it led to increased production of tumor- and stemness-enhancing cytokines, significantly associated with altered expression of adaptive immune genes. However, neither re-expression of MyD88 in IECs or myeloid cells was sufficient for malignant progression to carcinoma. Thus, MyD88 crucially contributes to colorectal cancer initiation and progression with non-redundant and cell-type specific functions, constituting an attractive therapeutic target.

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Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice

Cited by 116 publications

References 68 publications

Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K- ras oncogene in vivo

Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy

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