This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-09-0067v1 69/8/3529    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lubbe, W. J. Articles by Pitari, G. M. Search for Related Content PubMed PubMed Citation Articles by Lubbe, W. J. Articles by Pitari, G. M.

Guanylyl Cyclase C Prevents Colon Cancer Metastasis by Regulating Tumor Epithelial Cell Matrix Metalloproteinase-9

¹ Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University; ² Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Requests for reprints: Giovanni M. Pitari, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Suite 348, Philadelphia, PA 19107. Phone: 215-955-5647; Fax: 215-955-7006; E-mail: Giovanni.Pitari{at}jefferson.edu.

Key Words: colorectal cancer • guanylyl cyclase C • cyclic GMP • matrix metalloproteinase-9 • metastasis

Matrix metalloproteinase-9 (MMP-9) produced by colorectal cancer cells is a critical determinant of metastatic disease progression and an attractive target for antimetastatic strategies to reduce colon cancer mortality. Cellular signaling by cyclic GMP (cGMP) regulates MMP-9 dynamics in various cell systems, and the bacterial enterotoxin receptor guanylyl cyclase C (GCC), the principle source of cGMP in colonocytes, which is overexpressed in colorectal cancers, inhibits tumor initiation and progression in the intestine. Here, we show that ligand-dependent GCC signaling through cGMP induces functional remodeling of cancer cell MMP-9 reflected by a compartmental redistribution of this gelatinase, in which intracellular retention resulted in reciprocal extracellular depletion. Functional remodeling of MMP-9 by GCC signaling reduced the ability of colon cancer cells to degrade matrix components, organize the actin cytoskeleton to form locomotory organelles and spread, and hematogenously seed distant organs. Of significance, GCC effects on cancer cell MMP-9 prevented establishment of metastatic colonies by colorectal cancer cells in the mouse peritoneum in vivo. Because endogenous hormones for GCC are uniformly deficient in intestinal tumors, reactivation of dormant GCC signaling with exogenous administration of GCC agonists may represent a specific intervention to target MMP-9 functions in colon cancer cells. The notion that GCC-mediated regulation of cancer cell MMP-9 disrupts metastasis, in turn, underscores the unexplored utility of GCC hormone replacement therapy in the chemoprevention of colorectal cancer progression. [Cancer Res 2009;69(8):3529–36]

This article has been cited by other articles:

				N. Basu, R. Bhandari, V. T. Natarajan, and S. S. Visweswariah Cross Talk between Receptor Guanylyl Cyclase C and c-src Tyrosine Kinase Regulates Colon Cancer Cell Cytostasis Mol. Cell. Biol., October 1, 2009; 29(19): 5277 - 5289. [Abstract] [Full Text] [PDF]