Guanylyl cyclase C prevents colon carcinoma cell metastasis

Abstract

Background/Aims Of patients with colorectal cancer, >50% die from metastatic progression of their disease. A novel paradigm is emerging in which guanylyl cyclase C (GC-C), the intestinal receptor for the diarrheagenic heat-stable enterotoxin (ST), serves as a tumor suppressor. While the importance of GC-C in regulating tumor cell proliferation has been defined, its role in mechanisms underlying metastasis remains unexplored. Methods The role of ST and cGMP, the intracellular mediator of GC-C, in regulating key in vitro indices of metastasis, including cell spreading, actin polymerization, detachment from collagen substrates, and matrix metalloproteinase-9 (MMP-9) activity was examined. The suitability of MMP-9 as a target for GC-C signaling in human colon tumors was confirmed, ex vivo, by RT-PCR employing laser capture microdissection and electron microscopy. Further, the impact of GC-C activation on the metastatic potential of human colon cancer cells was explored in vivo employing a murine model of lung metastasis. Results ST and cGMP negatively regulated all indices of metastasis examined, including tumor cell MMP-9 activity. Importantly, GC-C activation by ST remarkably reduced “seeding” of colon cancer cell metastases in mouse lung, in part, through an α3β1 integrin-dependent mechanism. Conclusions GC-C and its downstream effectors regulate the malignant progression of human colorectal tumors by inhibiting key processes underlying metastasis. Clinical Pharmacology & Therapeutics (2005) 77, P3–P3; doi: 10.1016/j.clpt.2004.11.016