Gynecological cancers include neoplasias of internal female genital organs, mainly ovarian, endometrial and cervical tumors, and cancers of the external female genital structures. Current scientific evidence indicates that both up- and down-regulation of the expression of PCs are part of the multiple changes occurring in these gynecological tumors. Nevertheless, the physiological significance of this puzzling pattern of PC expression remains elusive. The fact that PCs can activate both pro- and anticarcinogenic substrates may indicate that the nature of the overexpressed substrates in certain cancer types could determine the final outcome; i.e., slowing or accelerating cancer development.
The expression of PCs in gynecological cancers and the correlation of this expression with other markers may facilitate preventive and therapeutic interventions in at-risk populations. Several studies single out furin as the main PC overexpressed in ovarian and endometrial cancers. For instance, furin expression has been associated with five-year survival in ovarian cancer, and measurements of furin activity in cells obtained by lavage constitute a non-invasive diagnostic tool for endometrial cancer. The other ubiquitously expressed PCs, PC5, PACE4, and PC7 do not show any changes with respect to normal controls or are decisively silenced, as indicated by studies on PACE4 expression and regulation in both ovarian and endometrial tumors.
PCs activate crucial substrates implicated in the progression of gynecological cancers, including adhesion molecules, metalloproteinases, and viral proteins. In the first place, furin, and possibly the other PCs, process both E- and N-cadherin. Processing of these molecules results in variations of cell adhesiveness. The pattern of expression of N- and especially E-cadherin varies during tumor development, as well as in the stages of either epithelial to mesenchymal or mesenchymal to epithelial transitions. E-cadherin is up-regulated during initial steps in ovarian tumor development, whereas N-cadherin follows a more complex expression pattern. Nevertheless, cadherin processing requires fully functional PC activity, a feature that may be explored for future therapeutics applications. Furthermore, PCs drive the activation of metalloproteinases, especially the membrane-type metalloproteases MMP-14 and MMP-15, and also possibly MMP-9. The activity of these metalloproteases promotes the invasion into the omentum and other peritoneal structures, facilitating the degradation of collagens and other extracellular components. Finally, the role of furin in enabling papilloma virus infection, one of the main etiological factors in the development of exocervical cancer, and possibly vaginal and vulvar carcinoma, cannot be overemphasized.
These experimental evidences suggest that careful targeting of PCs in gynecological cancer may represent a feasible strategy to deter tumor progression.
Table of Contents
Expression of PCS in Gynecological Cancers
PCs and Associated Substrates as Markers for Gynecological Cancers
Role of PCs in Tumor Progression
Inhibition of Furin as Therapeutic Strategy
Senior Author Biography
Titles of Related Interest
About the Author(s)Andres J.P. Klein-Szanto
, Department of Pathology, Fox Chase Cancer Center
Andres Klein-Szanto was born in Buenos Aires, Argentina. He worked as a student assistant and histotechnologist in the Departments of Histology and Pathology during his medical student years. He graduated from the University of Buenos Aires Medical School in 1965 (Medico or Physician, M.D.) and after training in pathology and further postgraduate experimental pathology work that resulted in his doctorate thesis, he was awarded the Doctor in Medicine degree (1970). His role models and mentors during these formative years were Professors E. De Robertis, R. Mancini, F. Schajowicz, M. E. Itoiz, and especially Romulo L. Cabrini who consolidated his interest in the fascinating world of science and pathology. He worked as an Instructor and then Chief Instructor of Pathology in the Medical and Dental Schools of the University of Buenos Aires and the University of Zurich, Faculty of Medicine, Switzerland (1965-1977). Since 1978, he was employed as a Senior Medical Scientist at the Oak Ridge National Laboratory, Oak Ridge, TN and as Professor of Biology and Molecular Carcinogenesis at the M.D. Anderson Cancer Center of the University of Texas. Currently, Dr. Klein-Szanto is Professor and Director of the Histopathology Facility at the Fox Chase Cancer Center, Philadelphia. His laboratory focuses on mechanisms of tumor progression and has developed several models to study the development of human cancer using xeno-transplanted normal and precancerous human tissues exposed in vivo to carcinogens. His laboratory was the first to describe in an in vivo model the signature p53 mutations seen in tumors produced by benzo(a)pyrene, the most ubiquitous human carcinogen present in tobacco smoke. Recently, his work on proprotein convertases and cancer has highlighted the role of these proteases in cancer progression. Dr. Klein-Szanto has published more than 350 scientific papers and four books on these topics. He serves on several scientific journal editorial boards and has been a committee and study section member of the National Institute of Health and other funding and professional agencies and associations. Jirong Zhang
, Department of Pathology, Fox Chase Cancer CenterDaniel 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.