Andres J.P. Klein-Szanto, MD, PhD
Office Phone: 215-728-3154
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.Description of research projects
Fox Chase Programs
- Fu J, Bassi DE, Zhang J, Li T, Nicolas E, Klein-Szanto AJ. Transgenic overexpression of the proprotein convertase furin enhances skin tumor growth. Neoplasia. 2012 Apr;14(4):271-82. PubMed
- Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D, Abramowitz LK, Bartolomei MS, Rambow F, Bassi MR, Bruno T, Fanciulli M, Renner C, Klein-Szanto AJ, Matsumoto Y, Kobi D, Davidson I, Alberti C, Larue L, Bellacosa A. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011 Jul 8;146(1):67-79. PubMed
- Goetz JG, Minguet S, Navarro-LeridaI, Lazcano JJ, Samaniego R, Calvo E, Tello M, Osteso-Ibanez T, Pellinen T, Echarri A, Klein-Szanto A.J, Garcia R, Keely P, Sanchez-Mateos P, Cukierman E, Del Pozo MA. Regulation of the biomechanical properties of the tumor microenvironment by stromal Caveolin-1 promotes invasion. Cell. 2011;146:148-63.
- Stairs, DB, Bayne L, Rhoades B, Vega ME, Waldron T, Kalabis J, Klein-Szanto AJ, Lee S, Katz J, Diehl A, Reynolds A, Vonderheide R, Rustgi AK. Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a bona fide tumor suppressor. Cancer Cell 19, 470-483, 2011.
- Schonrath K, Pan W, Klein-Szanto AJ, Braunewell KH. Involvement of VILIP-1 and opposite roles of cyclic AMP and GMP signaling in in vitro cell migration of murine skin squamous cell carcinoma. Molec. Carcinogenesis 50:319-333, 2011.
- Bassi DE, Zhang J, Cenna J, Litwin S, Cukierman E, Klein-Szanto AJ. Proprotein Convertase Inhibition Results in Decreased Skin Cell Proliferation, Tumorigenesis, and Metastasis. Neoplasia. 2010 Jul;12(7):516-26. PubMed
- Fu J, Jin F, Zhang J, Fong K, Bassi DE, Lopez De Cicco R, Ramaraju D, Braunewell KH, Conti C, Benavides F, Klein-Szanto AJ. VILIP-1 Expression /In Vivo/ Results in Decreased Mouse Skin Keratinocyte Proliferation and Tumor Development. PLoS One. 2010 Apr 15;5(4):e10196. PubMed
- Fu J, Zhang J, Jin F, Patchefsky J, Braunewell KH, Klein-Szanto AJ. Promoter regulation of the visinin-like subfamily of neuronal calcium sensor proteins by nuclear respiratory factor-1. J Biol Chem. 2009 Oct 2;284(40):27577-86. PubMed
- Braunewell K-H & Klein-Szanto AJ. Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca(2 )-sensor proteins. Cell Tissue Res. 2009;335:301-316. PubMed
- Fu J, Fong K, Bellacosa A, Ross E, Apostolou S, Bassi D, Jin F, Zhang J, Cairns P, Iba�ez de Caceres I, Braunewell K, Klein-Szanto AJ. VILIP-1 Downregulation in Non-Small Cell Lung Carcinomas: Mechanisms and Prediction of Survival. PLoS ONE. 2008;3:(2)e1698. PubMed
- L�pez de Cicco R, Bassi D, Benavides F, Conti CJ, Klein-Szanto AJ. Inhibition of Proprotein Convertases: Approaches to Block Squamous Carcinoma Development and Progression. Molec Carcinog. 2007;46:654-659. PubMed
- L�pez de Cicco R, Bassi DE, Zucker S, Seidah NG, Klein-Szanto AJ. Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res. 2005;65:4162-71. PubMed Bassi DE, Lopez de Cicco R, Cenna J, Cukierman E, Klein-Szanto AJ. PACE 4 Expression in Mouse Basal Keratinocytes Results in Basement Membrane Disruption and Acceleration of Tumor Progression. Cancer Res. 2005;65:7310-7319. PubMed
- Bassi B, Lopez De Cicco R, Mahloogi H, Zucker S, Thomas G, Klein-Szanto AJ. Furin Inhibition Results in Absent or Decreased Invasiveness and Tumorigenicity of Human Cancer Cells. Proc Natl Acad Sci. (USA) 2001;98:10326-10331. PubMed
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