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Inhibition of Prostate Cancer Neovascularization and Growth by Urokinase-Plasminogen Activator Receptor Blockade¹

Departments of Urology [C. P. E.], Anatomy [F. E., G. C.], Surgery [S. P.], and Medicine [M. C., M. A. S.], University of California, San Francisco, California 94143

Binding of the serine protease urokinase (u-PA) to its receptor on tumor cell surfaces facilitates proteolysis and tumor invasion. We undertook this study to determine whether the role of u-PA in prostate cancer induced angiogenesis and secondary tumor growth by developing a homologous, immunocompetent in vivo model in which the tumors cells secrete an inhibitor of the murine u-PA receptor. A mutant recombinant murine u-PA that retains receptor binding but not proteolytic activity was made by PCR mutagenesis. Mutant u-PA and a reporter gene pRK luciferase were transfected and stably expressed in the highly metastatic rat Dunning MAT-LyLu prostate cancer cell line. Several clones expressing mutant u-PA and luciferase were identified by Western blotting, plasminogen zymography, and reverse transcription-PCR. One of these clones, 5C4, was injected s.c. into Copenhagen rats. Compared to animals injected with clones expressing pRK luciferase alone, tumors in animals injected with 5C4 cells were significantly smaller. Moreover, there were fewer lung micrometastases in the 5C4 animals. Primary tumor angiogenesis was measured by microvessel quantification of tissue stained with antibodies against von Willebrand factor. Mean microvessel density in 5C4 tumors was 4.3-fold lower than that in animals with tumors derived from the control tumor cell line (P < 0.0001). Significant inhibition of tumor growth was also observed for two additional MAT-LyLu cell lines expressing mutant u-PA. These findings suggest that cell surface u-PA contributes to prostate cancer growth by enhancing angiogenesis.

¹ C. P. E. was supported by a research fellowship award from the National Kidney Foundation of Northern California. S. P. was supported by a research grant from the Lucille Markey University of California San Francisco Molecular Medicine Program. M. A. S. was supported by NIH Grant R01 CA59545 and a grant from the Joseph Drown Foundation.

² Present address: Department of Urology, University of Texas, M. D. Anderson Cancer Center, Box 110, 1515 Holcombe Boulevard, Houston, TX 77030.

³ To whom requests for reprints should be addressed, at the Department of Medicine, HSE 1260A, Box 1028, University of California, San Francisco, CA 94143.

Received 2/25/97. Accepted 6/17/97.

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