INDUCTION OF PRIMARY CUTANEOUS MELANOCYTIC NEOPLASMS IN UROKINASE-TYPE PLASMINOGEN-ACTIVATOR (UPA)-DEFICIENT AND WILD-TYPE MICE - CELLULAR BLUE NEVI INVADE BUT DO NOT PROGRESS TO MALIGNANT-MELANOMA IN UPA-DEFICIENT ANIMALS

Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and me tastasis. We studied the contribution of the PAs to the malignant phen otype through the chemical induction of melanocytic neoplasms in uPA-d eficient mice. Primary tumors were induced and promoted concurrently i n 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single appl ication of 7,12-dimethylbenz(a)anthracene followed by repetitive appli cations of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each anima l were excised, characterized histologically, and evaluated microscopi cally for evidence of invasion. The regional lymph nodes, lungs, and s olid abdominal visceral organs were sectioned and examined microscopic ally for evidence of metastatic disease. Cellular blue nevi were induc ed in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95 % of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted w ild-type mice. These tumors were locally aggressive, produced tissue-t ype PA, but were not metastatic to the regional nodes, lungs, or abdom inal viscera. These results indicate that the invasive capability of m elanocytic lesions may depend more on tissue-type PA than uPA activity . No melanomas were induced in the uPA-/- mice. The resistance of the uPA-/- strain to melanoma induction suggests that uPA contributes to m alignant progression. We propose that the absence of uPA negatively af fects tumorigenesis by decreasing the liberation and availability of g rowth factors such as basic fibroblast growth factor.