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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.

Original publication

DOI

10.1158/0008-5472.CAN-09-0067

Type

Journal article

Journal

Cancer Res

Publication Date

15/04/2009

Volume

69

Pages

3529 - 3536

Keywords

Caco-2 Cells, Cell Line, Tumor, Cell Movement, Colonic Neoplasms, Cyclic GMP, Epithelial Cells, Guanylate Cyclase, Humans, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Neoplasm Metastasis, Peritoneal Neoplasms, Receptors, Enterotoxin, Receptors, Guanylate Cyclase-Coupled, Receptors, Peptide, Signal Transduction