Tumor progression is a chain of cellular and molecular events that occur gradually during the development of neoplasia. We are studying the role of pro-protein convertases (PCs) such PACE-4 and furin during the early and late stages of tumor progression because these enzymes activate cancer related biomolecules. Over-expression of PCs correlates with aggressive tumor features both in mouse models and in human tumors. This has been demonstrated in our laboratory using tumor cells derived from lung, ovarian and oral malignant tumors. Inhibition of PCs can be obtained by using competitive inhibitors such as chloro-methyl-ketone (CMK). This inhibitor decreases and even abolishes the invasive/malignant phenotype of tumor cells by inhibiting the activation of invasion and metastasis-associated gene products such as MT1-MMP, stromelysin 3, TGF-β and IGFR1. CMK was also used in vivo by topical skin administration. Using this modality we were able to decrease 40% the number of chemically-induced mouse skin cancers as well as diminish 60% the respective tumor volumes.

Another unrelated gene, discovered during our PCs studies is Vsnl-1, a member of the neuronal Ca++ sensor protein family. Vsnl-1, also known as VILIP-1 is able to act as a tumor suppressor in mouse skin squamous carcinoma cells by inhibiting cell proliferation, adhesion and invasion. The effects are a consequence of VILIP-1 modulating cAMP levels as well as inactivating MMP-9 and RhoA activity. Recently, we have found that this gene is silenced in human tumors due to epigenetic changes including promoter hypermethylation and histone modification. Top

Fox Chase Programs

• The Head and Neck Keystone Program
• Cancer Genetics & Signalling
• Histopathology Facility

Extramural Affiliations

• Department of Pathology, Jefferson College of Medicine, Thomas Jefferson University
• Department of Medicine, University of Pennsylvania School of Medicine