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[Cancer Research 65, 4728-4738, June 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

A Secreted Form of ADAM9 Promotes Carcinoma Invasion through Tumor-Stromal Interactions

Antonio Mazzocca1,4, Roberto Coppari2, Raffaella De Franco4, Je-Yoel Cho3, Towia A. Libermann3, Massimo Pinzani4 and Alex Toker1

Departments of 1 Pathology and 2 Medicine and 3 Genomics Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and 4 Dipartimento di Medicina Interna, Centro di Ricerca, Trasferimento e Alta Formazione MCIDNENT, University of Florence, Florence, Italy

Requests for reprints: Alex Toker, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, RN-237, Boston, MA 02215. Phone: 617-667-8535; Fax: 617-667-3616; E-mail: atoker{at}bidmc.harvard.edu.

Tumor cell invasion is a process regulated by integrins, matrix-degrading enzymes, and interactions with host tissue stromal cells. The ADAM family of proteins plays an important role in modulating various cellular responses. Here, we show that an alternatively spliced variant of ADAM9 is secreted by hepatic stellate cells and promotes carcinoma invasion. ADAM9-S induced a highly invasive phenotype in several human tumor cell lines in Matrigel assays, and the protease activity of ADAM9-S was required for invasion. ADAM9-S binds directly to {alpha}6ß4 and {alpha}2ß1 integrins on the surface of colon carcinoma cells through the disintegrin domain. ADAM9-S was also able to cleave laminin and promote invasion. Analysis of human liver metastases revealed that ADAM9 is expressed by stromal liver myofibroblasts, particularly those that are localized within the tumor stroma at the invasive front. These results emphasize the importance of tumor-stromal interactions in invasion and suggest that ADAM9-S can be an important determinant in the ability of cancer cells to invade and colonize the liver.




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