| First Author | Gibbons AV | Year | 2013 |
| Journal | Cancer Res | Volume | 73 |
| Issue | 22 | Pages | 6654-66 |
| PubMed ID | 24085786 | Mgi Jnum | J:205053 |
| Mgi Id | MGI:5543961 | Doi | 10.1158/0008-5472.CAN-13-0887 |
| Citation | Gibbons AV, et al. (2013) Intestinal GUCY2C prevents TGF-beta secretion coordinating desmoplasia and hyperproliferation in colorectal cancer. Cancer Res 73(22):6654-66 |
| abstractText | Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-beta secretion, activating fibroblasts through TGF-beta type I receptors and Smad3 phosphorylation. In turn, activating TGF-beta signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through cMET-dependent signaling. Elimination of GUCY2C signaling in mice (Gucy2c(-/-)) produces intestinal desmoplasia, with increased reactive myofibroblasts, which is suppressed by anti-TGF-beta antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-beta and HGF. In that context, GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. The recent regulatory approval of oral GUCY2C ligands to treat chronic gastrointestinal disorders underscores the potential therapeutic opportunity for oral GUCY2C hormone replacement to prevent remodeling of the microenvironment essential for colorectal tumorigenesis. |
