Andres J.P. Klein-Szanto MD, PhD
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Andres J.P. Klein-Szanto MD, PhD
Professor
Director, Histopathology Facility
Fox Chase Cancer Center
333 Cottman Ave
Philadelphia, PA 19111
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.
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