TGF-beta Receptor Inactivation and Mutant Kras Induce Intestinal Neoplasms in Mice via a beta-Catenin-independent Pathway

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Gastroenterology (Impact Factor: 13.93). 02/2009; 136(5):1680-8.e7. DOI: 10.1053/j.gastro.2009.01.066
Source: PubMed

ABSTRACT During colorectal cancer pathogenesis, mutations and epigenetic events cause neoplastic behavior in epithelial cells by deregulating the Wnt, Ras-Raf-extracellular signal-regulated kinase (ERK), and transforming growth factor (TGF)-beta-signaling pathways, among others. The TGF-beta-signaling pathway is often inactivated in colon cancer cells by mutations in the gene encoding the TGF-beta receptor TGFBR2. The RAS-RAF-ERK pathway is frequently up-regulated in colon cancer via mutational activation of KRAS or BRAF. We assessed how these pathways interact in vivo and affect formation of colorectal tumors.
We analyzed intestinal tumors that arose in mice that express an oncogenic (active) form of Kras and that have Tgfbr2 inactivations-2 common molecular events observed in human colorectal tumors. LSL-KrasG12D mice were crossed with Villin-Cre;Tgfbr2E2flx/E2flx mice, which do not express Tgfbr2 in the intestinal epithelium.
Neither inactivation of Tgfbr2 nor expression of oncogenic Kras alone was sufficient to induce formation of intestinal neoplasms. Histologic abnormalities arose in mice that expressed Kras, but only the combination of Tgfbr2 inactivation and Kras activation led to intestinal neoplasms and metastases. The cancers arose via a beta-catenin-independent mechanism; the epidermal growth factor-signaling pathway was also activated. Cells in the resulting tumors proliferated at higher rates, expressed decreased levels of p15, and expressed increased levels of cyclin D1 and cdk4, compared with control cells.
A combination of inactivation of the TGF-beta-signaling pathway and expression of oncogenic Kras leads to formation of invasive intestinal neoplasms through a beta-catenin-independent pathway; these adenocarcinomas have the capacity to metastasize.

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    • "Similar to some of the Apc/K-Ras models, tumorigenesis in Tgfbr2/K- Ras double mutant animals is associated with a lack of Erk activation and an apparent downregulation of PI3K signaling [48]. In addition, increased levels of the EGFR ligand epiregulin were observed in tumors from Tgfbr2/K-Ras double mutant animals, suggesting that mutant K-Ras induces an autocrine feed-forward loop in the absence of Tgfbr2 [48]. This K-RAS Epiregulin EGFR feed-forward loop was also found to play an important role regulating proliferation in HCT-116 cells, which are mutant for TGFBR2 [61]. "
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    • "Previous studies on keratinocyte, mammary, prostate and hepatocyte carcinogenesis models showed a synergistic cooperation of TGF-β and RAS to induce progression to undifferentiated, invasive tumors [30] [31] [32] [33] [34]. TGF-β and RAS signaling also cooperates in the intestinal epithelium where overexpression of K-RAS in combination with deletion of TGFRII generated metastatic adenocarcinomas with activated epidermal growth factor (EGF) signaling independent of Wnt/β-catenin [35]. Neither oncogenic K-RAS nor inactivation of TGFRII on its own was able to induce colorectal tumors. "
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    • "To date no other genetic model addressing the function of oncogenic K-ras in the intestine has addressed the development of serrated tumorigenesis. Recent reports demonstrated the occurrence of colonic hyperplasia in mice expressing the same K-ras G12D mutant, however, serrated tumors or the existence of OIS were not described (Haigis et al., 2008; Trobridge et al., 2009). Furthermore, other studies analyzing the function of intestinal K-ras made use of a transgenic approach (Janssen et al., 2006; Janssen et al., 2002), which—albeit moderate overexpression levels of oncogenic K-ras—might lead to the activation of additional downstream signaling cascades. "
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