Cyclic-GMP–Elevating Agents Suppress Polyposis in ApcMin Mice by Targeting the Preneoplastic Epithelium

Abstract

The cGMP signaling axis has been implicated in the suppression of intestinal cancers, but the inhibitory mechanism and the extent to which this pathway can be targeted remains poorly understood. This study has tested the effect of cGMP-elevating agents on tumorigenesis in the mouse model of intestinal cancer. Treatment of mice with the receptor guanylyl-cyclase C (GCC) agonist linaclotide, or the phosphodiesterase-5 (PDE5) inhibitor sildenafil, significantly reduced the number of polyps per mouse (67% and 50%, respectively). Neither of the drugs affected mean polyp size, or the rates of apoptosis and proliferation. This was possibly due to increased PDE10 expression, as endogenous GCC ligands were not deficient in established polyps. These results indicated that the ability of these drugs to reduce polyp multiplicity was primarily due to an effect on nonneoplastic tissues. In support of this idea, mice exhibited reduced levels of endogenous GCC agonists in the nonneoplastic intestinal mucosa compared with wild-type animals, and this was associated with crypt hyperplasia and a loss of goblet cells. Administration of either sildenafil or linaclotide suppressed proliferation, and increased both goblet cell numbers and luminal apoptosis in the intestinal mucosa. Taken together, the results demonstrate that targeting cGMP with either PDE5 inhibitors or GCC agonists alters epithelial homeostasis in a manner that reduces neoplasia, and suggests that this could be a viable chemoprevention strategy for patients at high risk of developing colorectal cancer..

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis

“…18,19,34 Conversely, luminal replacement of GUCY2C agonists reduces the number and size of tumors driven by Apc mutations in mice. 26,32,33,35 These observations support the hypothesis that guanylin loss and silencing of the GUCY2C axis is one molecular mechanism contributing to the progression of tumorigenesis initiated by mutant APC-β-catenin-TCF signaling.…”

Clinical utility of plecanatide in the treatment of chronic idiopathic constipation

“… 47 , 51 While the underlying mechanism is poorly understood, preclinical evidence suggests that secreted epithelial cGMP has a dampening effect on neural afferents in the lamina propria. 52 – 54 Increasing cGMP in the intestinal epithelium has also been shown by extensive preclinical studies to suppress intestinal carcinogenesis 55 – 58 and promote barrier function in the colon. 59 – 61 These intriguing findings underscore the clinical potential of GC-C agonists for treating post-infectious IBS, ulcerative colitis, and for chemoprevention of colorectal cancer.…”

Are Phosphodiesterase-5 Inhibitors a New Frontier for Prevention of Colorectal Cancer?

“…8,9 Indeed, trial data found that proton pump inhibitor use in this patient population decreased the risk of gastrointestinal events without a detectable increase in cardiovascular risk; thus, avoidance of proton pump inhibitors in this setting was actually associated with overall clinical harm. Residual confounding likely plays some role in these disparate results and, [10][11][12] unfortunately, "positive" findings from small, early studies are also often more memorable (and more often repeated) than later "negative" findings from larger, more definitive evaluations. 10…”