Epithelial-specific programming of the microenvironment by guanylyl cyclase C regulates intestinal architecture
Abstract
In intestine, activated fibroblasts modulate continuous mucosal renewal by depositing extracellular matrix and secreting soluble factors that regulate epithelial cell proliferation, differentiation, and migration, an imbalance of which contributes to neoplasia. GUCY2C, the intestinal epithelial-specific guanylyl cyclase receptor for the paracrine hormones guanylin and uroguanylin, whose early loss characterizes colorectal transformation, has emerged as a component of homeostatic programs organizing spatio-temporal patterning along the crypt-surface axis. Dysregulation of GUCY2C signaling, reflecting hormone loss, promotes tumorigenesis through hyperproliferation, metabolic remodeling and genetic instability. The role of guanylyl cyclases in defining mesenchymal architecture in other systems suggests that heterotypic epithelial-mesenchymal interactions in intestine may be coordinated by GUCY2C, whose dysregulation induces a tumorigenic niche potentiating an environment that promotes the graded progression of neoplasia. Eliminating GUCY2C signaling in mouse epithelial cells induces interstitial fibrosis, with activation of myofibroblasts producing MMP-9 and α-SMA and deposition of collagen I and tenascin C, all characteristic of tumor stroma. Conversely, GUCY2C signaling in human colon cancer cells induces a secretory phenotype that prevents myofibroblast activation and their expression of pro-collagen I, α-SMA, and prolyl-hydroxylase. Eliminating GUCY2C in enterocytes in mice induces TGF-β secretion, known to mediate heterotypic signaling driving myofibroblast activation. In contrast, activating GUCY2C in human colon cancer cells suppresses TGF-β secretion and disrupts heterotypic signaling underlying morphologic, molecular, and functional activation of myofibroblasts. Further, blocking TGF-β signaling by colon cancer cells employing antibody depletion, siRNA gene silencing, or a TGF-β receptor antagonist eliminated the ability of GUCY2C to program epithelial cell secretion opposing myofibroblast activation. Together, these data suggest that GUCY2C coordinates mucosal homeostasis, in part, by directing heterotypic interactions organizing the stromal compartment by restricting epithelial cell secretion of TGF-β. Finally, TGF-β induction by GUCY2C deficiency increases the mesenchymal-derived mitogen HGF, suggesting that absence of GUCY2C signaling enhances a maladaptive epithelial-mesenchymal cross-talk and stromal remodeling characterizing tumorigenesis. Dysregulation of GUCY2C signaling reflecting paracrine hormone loss induces unrestricted secretion of epithelial cell TGF-β contributing to maladaptive epithelial-mesenchymal cross-talk and stromal remodeling characterizing tumorigenesis. In the context of the universal loss of paracrine ligands early in tumorigenesis, but the persistent expression of GUCY2C in nearly all primary and metastatic tumors, these observations suggest a novel therapeutic opportunity for targeted prevention and treatment of colorectal cancer employing oral hormone replacement therapy.
Subject Area
Molecular biology|Cellular biology|Pharmacology
Recommended Citation
Gibbons, Ahmara Vivian, "Epithelial-specific programming of the microenvironment by guanylyl cyclase C regulates intestinal architecture" (2011). ProQuest ETD Collection - Thomas Jefferson University. AAI3449427.
https://jdc.jefferson.edu/dissertations/AAI3449427
