Using human and mouse tumor models, we are studying the cellular and molecular events that characterize gradual malignant changes. Focusing on pro-protein convertases such PACE-4 and furin, we have observed that their overexpression correlates with an aggressive neoplastic phenotype both in mouse models and in human primary tumors. Genetic transfer of furin cDNA into low-grade human squamous cell carcinoma cell lines induced invasiveness and tumorigenicity. These effects can be inhibited by transfecting with the bioengineered serpin alpha1-PDX or using exogenous compounds. This specific inhibition of furin is able to decrease or abolish the invasive/malignant phenotype of ovarian as well as squamous tumor cells by inhibiting the activation of invasion and metastasis-associated gene products. Further studies on pro-protein convertase inhibition are in progress using genetically engineered mice and human tumor cells. In addition, we are evaluating the suppressive role of the gene VILIP-1 in mouse models and in human neoplasia.