Intestinal GUCY2C prevents TGF-β secretion coordinating desmoplasia and hyperproliferation in colorectal cancer.

Authors

Ahmara V Gibbons, Thomas Jefferson UniversityFollow
Jieru Egeria Lin, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityFollow
Gilbert Won Kim, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityFollow
Glen P Marszalowicz, Drexel UniversityFollow
Peng Li, Thomas Jefferson UniversityFollow
Brian Arthur Stoecker, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson UniversityFollow
Erik S Blomain, Thomas Jefferson UniversityFollow
Satish Rattan, Thomas Jefferson UniversityFollow
Adam E. Snook, Thomas Jefferson UniversityFollow
Stephanie Schulz, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USAFollow
Scott A Waldman, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

11-15-2013

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Research

Volume 73, Issue 22, November 2013, Pages 6654-66.

The published version is available at DOI: 10.1158/0008-5472.CAN-13-0887. Copyright © American Association for Cancer Research

Abstract

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-β secretion, activating fibroblasts through TGF-β type I receptors and Smad3 phosphorylation. In turn, activating TGF-β 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-β antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-β 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.

Recommended Citation

Gibbons, Ahmara V; Lin, Jieru Egeria; Kim, Gilbert Won; Marszalowicz, Glen P; Li, Peng; Stoecker, Brian Arthur; Blomain, Erik S; Rattan, Satish; Snook, Adam E.; Schulz, Stephanie; and Waldman, Scott A, "Intestinal GUCY2C prevents TGF-β secretion coordinating desmoplasia and hyperproliferation in colorectal cancer." (2013). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 58.
https://jdc.jefferson.edu/petfp/58

PubMed ID

24085786