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Direct Evidence of the Importance of Stromal Urokinase Plasminogen Activator (uPA) in the Growth of an Experimental Human Breast Cancer Using a Combined uPA Gene-Disrupted and Immunodeficient Xenograft Model

The Finsen Laboratory, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark [T. L. F., C. H-H., B. S. N., I. J. C., N. B.]; Stereological Research Laboratory, Bartholin Bygningen, Aarhus University, 8000 Århus C, Denmark [J. R. N.]; and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium [P. C.]

Several studies have indicated an interaction between tumor cells and infiltrating stromal cells regarding the urokinase plasminogen activation (uPA) system. By developing combined uPA gene-disrupted and immunodeficient mice, we have studied the role of stromal uPA for the growth of the MDA-MB-435 BAG human tumor xenograft. Subcutaneous tumor growth and lung metastasis were compared between wild-type immunodeficient mice and mice with the combined deficiencies. Tumor growth was evaluated by volume measurements and plasma ß-galactosidase activity and metastasis was evaluated by counting lung surface metastases. Although no differences appeared in primary tumor take between the two groups of mice, a significant difference was observed in primary tumor growth, with tumors in uPA^-/- mice growing significantly more slowly. In addition, a nonsignificant trend toward fewer lung metastases in uPA^-/- mice was observed. The present data points to a critical role of stromal-derived uPA in the primary tumor growth of MDA-MB-435 BAG xenografts, whereas only a trend toward fewer lung metastases in uPA gene-disrupted mice was found.

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