GUCY2C ligand replacement to prevent colorectal cancer

Abstract

Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading 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™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).

Keywords: Chemoprevention; colorectal cancer; guanylin; guanylyl cyclase C; linaclotide.

Figure 1.

Preventing colorectal cancer by exploiting the paracrine hormone hypothesis of colorectal cancer. Colorectal cancer is a stepwise disease whereby a normal epithelium is transformed over a period of years into first an adenoma until finally becoming an adenocarcinoma. Importantly, guanylin expression is lost early and universally in this transformative continuum and contributes to disease progression as depicted in the diagram. Insets to this cartoon show adapted immunohistochemistry images (guanylin depicted in purple, nuclei/hematoxylin depicted in black) of normal human colonic epithelium as contrasted with human adenocarcinoma which demonstrate complete loss of guanylin staining in the adenocarcinoma (inset images adapted from Wilson etal. Biomarkers & Prevention, 2014). Importantly, GUCY2C ligand loss in colorectal cancer provides a therapeutic opportunity for chemoprevention through exogenous administration of GUCY2C ligands.