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Tumor Epithelial Cell Matrix Metalloproteinase 9 Is a Target for Antimetastatic Therapy in Colorectal Cancer

Authors' Affiliations: ¹ Division of Clinical Pharmacology, Departments of Pharmacology and Experimental Therapeutics and Medicine, Thomas Jefferson University; ² Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and ³ Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan

Requests for reprints: Giovanni M. Pitari, Division of Clinical Pharmacology, Thomas Jefferson University, MOB Suite 810, 1100 Walnut Street, Philadelphia, PA 19107. Phone: 215-955-5647; Fax: 215-955-7006; E-mail: Giovanni.Pitari{at}jefferson.edu.

Background: The current paradigm suggests that matrix metalloproteinase 9 (MMP-9) expressed by stromal cells is a therapeutic target in human colorectal tumors which presumably regulates metastatic disease progression. Conversely, whereas cancer cells within those tumors may induce stromal cells to produce MMP-9 and may be targets for MMP-9 activity, they are not the source of MMP-9 underlying metastasis.

Methods: MMP-9 expression in matched colorectal tumors and normal adjacent mucosa from patients and human colon cancer cell lines was examined by real-time reverse transcription-PCR, laser capture microdissection, immunoelectron microscopy, and immunoblot analysis. The role of colon cancer cell MMP-9 in processes underlying metastasis was explored in vitro by examining degradation of extracellular matrix components by gelatin zymography and formation of locomotory organelles by cell spreading analysis and in vivo by quantifying hematogenous tumor cell seeding of mouse lungs.

Results: Primary colorectal tumors overexpress MMP-9 compared with matched normal adjacent mucosa. In contrast to the current paradigm, MMP-9 is expressed equally by cancer and stromal cells within human colon tumors. Cancer cell MMP-9 regulates metastatic behavior in vitro, including degradation of extracellular matrix components and formation of locomotory organelles. Moreover, this MMP-9 critically regulates hematogenous seeding of mouse lungs by human colon cancer cells in vivo.

Conclusions: These observations reveal that MMP-9 produced by human colon cancer, rather than stromal, cells is central to processes underlying metastasis. They underscore the previously unrecognized potential of specifically targeting tumor cell MMP-9 in interventional strategies to reduce mortality from metastatic colorectal cancer.

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