The Role of Proprotein Convertases in Animal Models of Skin Carcinogenesis

The Role of Proprotein Convertases in Animal Models of Skin Carcinogenesis

Daniel Bassi, Jian Fu, Jirong Zhang, Andres J.P. Klein-Szanto
ISBN: 9781615045082 | PDF ISBN: 9781615045099
Copyright © 2012 | 60 Pages | Publication Date: 07/01/2012

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Many proprotein convertases (PC), especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases. In this chapter, we review mostly our work using animal models of squamous cancers that have been induced by chemical or UV carcinogenesis protocols to highlight the role of PCs in the development and progression of experimental tumors. After demonstrating in wild type mice the role of PACE4 in tumor progression as well as detecting the expression of PACE4 and furin in human non-melanoma skin cancers, we developed transgenic mice that over-express either PACE4 or furin in squamous epithelia, including the epidermis. This was accomplished by targeting the expression of the corresponding PC by using the promoter of the bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed increased susceptibility to a two-stage carcinogenesis protocol of chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice also showed an increased sensitivity to ultraviolet B radiation carcinogenesis. In most of these experiments, we were able to demonstrate that compared to the control wild type mice, the over-expression of the transgene in the epidermis increased the number of benign and malignant skin tumors and also had an effect on tumor progression as evidenced by the presence of less differentiated tumors and more frequent local and distant metastases in many of the transgenic lines. Interestingly, double transgenic mice in which PACE4 and furin are targeted to the epidermis did not show any additive effect, pointing to a probable in vivo overlap of functions at least in cutaneous tissues.

The tumor-enhancing effects of PACE4 and furin further support their possible role as therapeutic targets. Furthermore, a proof of principle for PC inhibition as a therapeutic tool has been substantiated by an in vivo experiment in which the PC-inhibitor, decanoyl-RVKRchloromethylketone, was topically administrated to the skin of wild type and transgenic mice treated with chemical carcinogenesis protocols, resulting in a significant decrease of tumor development and progression.

Table of Contents

Introduction
Proprotein Convertases in Skin
Animal Models of Non-Melanoma Skin Carcinogenesis
Transgenic Models of Proprotein Convertase-Mediated Skin Carcinogenesis
In Vivo Inhibition of Proprotein Convertases
Conclusions
References
Author Biography
Titles of Related Interest

About the Author(s)

Daniel Bassi, Department of Pathology, Fox Chase Cancer Center
Daniel Bassi was born in Buenos Aires, Argentina. He initiated his scientific career working as a graduate student on female reproductive tract pharmacology. He graduated from the University of Buenos Aires, School of Sciences, with a Masters in Chemistry in 1989. He was admitted to the doctoral track at the Institute of Biochemical Investigations, "Luis F. Leloir" where he earned his PhD in Chemistry (Biochemistry) in 1996. During these formative years, his mentor, Dr. Marcelo Dankert and professors Israel Algranati, Clara Krisman, and Osvaldo Podhajcer shaped his scientific interest and widened his scientific horizons. In addition he holds a Master's degree in Clinical Pathology. He pursued post-doctoral studies on proprotein convertases and their role in the progression of squamous cell carcinomas under the direction of Dr. Andres Klein Szanto, at Fox Chase Cancer Center in Philadelphia, in 1998. Effective mentoring and close collaboration resulted in several peer-reviewed papers and literature reviews, which contributed to sharpening his scientific views and expanded his areas of interests. After earning a position as Research Assistant Professor, he expanded his interest to study the role of proprotein convertases in ovarian cancer. His initial contribution centered in the relationship of proprotein convertases expression, activity and clinicopathological outcomes, their inhibition, and possible therapeutic strategies. He also continues the research in animal models of skin carcinogenesis, in collaboration with Dr. Klein-Szanto, and epithelial-mesenchymal relationships in collaboration with Dr. Cukierman. At present, Dr. Bassi is an Associate Professor at Holy Family University, Philadelphia.

Jian Fu, Department of Pathology, Fox Chase Cancer Center

Jirong Zhang, Department of Pathology, Fox Chase Cancer Center

Andres J.P. Klein-Szanto , Department of Pathology, Fox Chase Cancer Center

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