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Expression of PACE4 in Chemically Induced Carcinomas Is Associated with Spindle Cell Tumor Conversion and Increased Invasive Ability¹

Department of Pathology [F. C. H., T. L. G., S-C. L., A. J. P. K-S.] and Institute of Cancer Research [M. H. B.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; Institute de Genetique et de Biologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, 67404 Illkirch, France [P. B.]; and Departments of Neuroscience and Physiology, The John Hopkins University School of Medicine, Baltimore, Maryland 21205 [R. E. M.]

Gene expression changes associated with the conversion of squamous cell carcinoma (SCC) to a more advanced malignant spindle cell carcinoma (SPCC) were determined by differential display. Using an animal model of human SCC progression, we provide evidence of increased PACE4 expression in SPCC cell lines and primary tumors induced by chemical carcinogenesis protocols, thus implicating this proprotein convertase in the process of tumor progression. Exogenous overexpression of PACE4 cDNA in mouse SCC cells of low invasive ability resulted in enhanced tumor cell invasiveness that was absent in parental or mock-transfected SCC cells. In addition, the PACE4-transfected cells acquired the ability to process prostromelysin 3 into its active enzyme form. Taken together, these results show that up-regulation of PACE4 expression is associated with SCC conversion to SPCC and suggests that activation of essential PACE4 substrates, such as the metalloproteinase stromelysin 3, is required for tumor cell invasion.

¹ This work was supported by the USPHS Grants CA-53713, CA-06927 (to A. J. P. K-S.), and DA-00266 (to R. E. M.) and an appropriation from the Commonwealth of Pennsylvania.

² These authors contributed equally to this work.

³ Present Address: Magainin Pharmaceuticals, Inc., Plymouth Meeting, PA 19462.

⁴ To whom requests for reprints should be addressed, at Department of Pathology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728.3 154; Fax: (2 15) 728-2899; E-mail: aj_klein-szanto@fccc.edu.

Received 9/ 2/97. Accepted 10/17/97.

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