GUCY2C ligand replacement to prevent colorectal cancer

Abstract

Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the secondleading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess TM , Forest Laboratories and Ironwood Pharmaceuticals, Inc.).

ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice

“…Further, transgenic guanylin expression that cannot be suppressed eliminated tumors in carcinogen-induced mouse models of colorectal cancer [ 11 ]. Taken together, these observations suggest a pathophysiological hypothesis that guanylin loss silencing GUCY2C signaling is an essential step in colorectal tumorigenesis [ 15 ]. Moreover, it suggests the correlative therapeutic hypothesis that oral GUCY2C ligand replacement may be a tractable approach to prevent colorectal cancer in patients [ 16 ].…”

“…Beyond secretion, GUCY2C regulates intestinal epithelial homeostasis, including key component processes canonically disrupted in cancer [ 4 , 10 , 11 , 12 , 14 , 15 ]. Thus, guanylin loss expands the proliferating crypt compartment in colon, and silencing GUCY2C produces crypt hyperplasia by accelerating the enterocyte cell cycle [ 10 , 11 , 12 , 13 , 14 , 26 , 41 ].…”

“…Moreover, GUCY2C ligand replacement opposed mutational or carcinogen-induced intestinal carcinogenesis in mice [ 9 , 12 ]. In that context, GUCY2C ligand replacement is emerging as a novel paradigm for colorectal cancer chemoprevention [ 15 , 16 ].…”

“…These studies support the hypothesis of an environmental contribution to the disparity in colorectal cancer incidence in developed and developing countries, mediated by chronic exposure to ST-producing bacteria [ 14 ]. Moreover, it underscores the emerging paradigm of oral GUCY2C ligand replacement as a novel approach to the chemoprevention of colorectal cancer [ 9 , 11 , 15 ].…”

Intestinal Enteroids Model Guanylate Cyclase C-Dependent Secretion Induced by Heat-Stable Enterotoxins

“…Beyond ST-induced intestinal secretion, corruption of the GUCY2C paracrine hormone axis is a key step in initiating transformation in sporadic colorectal cancer (39,40). Similarly, silencing the GUCY2C endocrine axis plays a role in the pathophysiology of obesity, while the GUCY2C paracrine axis contributes to the evolution of tumorigenesis associated with hyperphagia and morbid adiposity (30).…”