Abstract 1614: Guanylyl cyclase C signaling through vasodilator-stimulated phosphoprotein in lost in colon cancer

Abstract

Abstract The biochemical pathway(s) induced by guanylyl cyclase C (GCC) regulates the intestinal crypt-villus axis by modulating proliferation, maturation and metabolic programming. During colorectal tumorigenesis, GCC signaling through cGMP becomes dysregulated as a consequence of the reduced expression of GCC endogenous hormones guanylin and uroguanylin. However, the significance of the loss of ligand-dependent signaling by GCC for the human disease remains unclear. Here, immunohistochemical examination of tumor specimens from patients compared to respective normal adjacent tissues revealed that the GCC signaling through vasodilator-stimulated phosphoprotein (VASP), a key regulator of actin polymerization and morphogenetic dynamics, is lost in colon cancer. Interruption of GCC signaling through VASP resulted in tumor depletion of the cGMP-dependent VASP phosphorylation species, and presumably reflected complex alterations of the normal initiation and propagation of the ligand-induced GCC signal. In vitro reconstitution of the ligand-dependent GCC signal through VASP induced a functional remodeling of human cancer cells which assumed a rounded, lamellipodia-free morphology with reduced proliferative and invasive abilities. Importantly, GCC ligand therapy in vivo restored the cGMP-dependent VASP phosphorylation circuit in intestinal tumors of APCmin/+ mice. These findings offer a previously undescribed tumor suppressor mechanism, cGMP-dependent VASP phosphorylation, with high translational potential for the diagnosis and therapy of colon cancer. Reactivation of cGMP signaling through VASP by GCC hormone replacement therapy may represent an innovative paradigm for the treatment of colorectal cancer in patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1614.