Faculty Bibliography

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

A number of proteins are found attached to the plasma membrane of mammalian cells by a glycosylphosphatidylinositol (GPI) anchor that can be cleaved by GPI specific phospholipase D (GPI-PLD). There are no known specific inhibitors of GPI-PLD. We examined some inhibitors of phosphatidylinositol specific phospholipase C (PI-PLC) for their ability to inhibit human serum and human bone marrow cell GPI-PLD. Azo analogues of suramin were found to be potent inhibitors of GPI-PLD. One compound had an IC50 of 3.7 microM that was 10-fold lower than the IC50 required to inhibit PI-PLC. The azo suramin analogues inhibited cancer cell growth at concentrations similar to those required to inhibit GPI-PLD, and below concentrations required to inhibit growth factor binding. It is possible that inhibition of cell growth might be related to the ability of the compounds to inhibit GPI-PLD

Chronic lymphocytic leukemia (CLL) is characterized by delayed senescence and slow accumulation of monoclonal, small lymphocytes. Basic fibroblast growth factor (bFGF) is a pleiotropic cytokine that plays a role in hematopoiesis and apoptosis. Elevated bFGF levels have been detected in urine from patients with a variety of neoplastic diseases including various leukemias; however, the cellular source of the bFGF has not been determined. In this study, the intracellular bFGF level in lymphocytes of 36 patients with B-CLL and 15 normal donors was determined using an enzyme-linked immunoassay. In cells derived from patients with high-risk disease, the median level of intracellular bFGF was 381.5 pg/2 x 10(5) cells, compared with a median of 90.5 pg/2 x 10(5) cells in patients with intermediate disease. In patients with low-risk disease, the median bFGF level was 4.9 pg/2 x 10(5) cells, and in normal controls, it was 6.0 pg/2 x 10(5) cells. The difference in the bFGF levels was significant for the comparison between low- and intermediate-risk (P = .00119), low- and high-risk (P < .0001), and intermediate- and high-risk disease (P = .0001). Immunofluorescent stains of peripheral blood mononuclear cells confirmed CLL lymphocytes as a cellular source of bFGF. To evaluate the potential contribution of elevated intracellular bFGF levels to the phenotype of CLL cells, leukemic cells were cultured in vitro with an apoptotic stimulus (fludarabine). CLL cells with high intracellular levels of bFGF appeared to be more resistant to fludarabine treatment. The addition of bFGF to fludarabine-treated CLL cells resulted in a delay of apoptosis and prolonged survival. These data suggest that bFGF may contribute to the resistance of CLL cells to an apoptotic stimulus