title: 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.
abstract: Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced 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 wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic 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 malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.
authors: Department of Surgery, Division of Oncology, New York University Medical Center, New York 10016, USA.
authors: R L
authors: RL
authors: Shapiro
authors: J G
authors: JG
authors: Duquette
authors: D F
authors: DF
authors: Roses
authors: I
authors: I
authors: Nunes
authors: M N
authors: MN
authors: Harris
authors: H
authors: H
authors: Kamino
authors: E L
authors: EL
authors: Wilson
authors: D B
authors: DB
authors: Rifkin
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D008207:Lymphatic Metastasis; D008544:Melanocytes / Q000201:enzymology / Q000473:pathology; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D018329:Nevus, Blue / Q000201:enzymology* / Q000473:pathology*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000378:metabolism
chemical_list: D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator