Graduation Year

2010

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Pathology and Cell Biology

Major Professor

Santo V. Nicosia, M.D.

Co-Major Professor

Patricia A. Kruk, Ph.D.

Committee Member

Jin Q. Cheng, M.D., Ph.D.

Committee Member

Xiaohong Zhang, Ph.D.

Committee Member

Steven S. Brem, M.D.

Keywords

angiogenesis, angiostatin, biomarker, semaphorin 3F, telomerase

Abstract

Angiogenesis by either normal or neoplastic cells involves a delicate balance of both angiogenic and angiostatic regulators. In the ovary, normal physiological angiogenesis occurs around the developing follicle and corpus luteum in response to hormonal shifts. Interestingly, carcinomas arising from the ovary are usually highly vascularized and are commonly clinically observed to produce cyst fluids or ascites which contain both angiostatic and/or angiogenic regulators. However, in contrast to normal angiogenesis, angiogenesis associated with epithelial ovarian cancer usually produces aberrant vasculature that may promote neoplastic progression. Therefore, the ovary and ovarian cancers provide models to study the mechanisms governing the strict balance of angioregulators in both normal and tumor angiogenesis. While most studies to date have focused on angiogenic regulators for normal and aberrant angiogenesis, we investigated the potential for dysregulation of angiostatic regulators to contribute to the etiology of epithelial ovarian cancer. Therefore, in this study, we examined two angiostatic regulators, angiostatin and semaphorin 3F, in epithelial ovarian cancer.

Angiostatin, a cleavage product of the circulating zymogen plasminogen, was isolated from serum and urine of mice bearing a Lewis lung carcinoma and in vivo studies have demonstrated its potent angiostatic properties. Thus, we investigated the potential prognostic/diagnostic advantage of aberrant angiostatin expression with epithelial ovarian cancer. We found that urinary angiostatin, compared to other angioregulators in plasma or urine, could serve as an effective biomarker for early detection of epithelial ovarian cancer, especially when used in combination with cancer antigen 125. Additionally, urinary angiostatin correlated with both recurrent disease as well as successful tumor ablation further supporting its potential as a disease biomarker.

Alternative biological functions for the axon guidance molecule, semaphorin 3F, have been reported particularly in regard to angiogenesis, tumor progression and metastasis. However, the underlying mechanisms governing semaphorin 3F regulation and dysregulation remain unclear. Therefore, we first investigated the clinical relationship between semaphorin 3F expression and epithelial ovarian cancer progression. These immunohistological studies revealed that, similar to lung cancer, semaphorin 3F expression decreased with progression supporting a tumor suppressor-like role for semaphorin 3F. Additionally, we found that calcium, an essential cellular signaling molecule, could mediate transcriptional suppression of semaphorin 3F expression in a CREB-dependent manner.

Lastly, given the antagonistic relationship between semaphorin 3F and vascular endothelial growth factor, we sought to determine whether semaphorin 3F and vascular endothelial growth factor promoted opposing effects on a common downstream target. In the course of these studies we determined that telomerase is a novel molecular target of semaphorin 3F in ovarian cancer cells such that semaphorin 3F suppresses telomerase activity while vascular endothelial growth factor promotes telomerase activity. In addition, we found that the inverse relationship between semaphorin 3F and telomerase was mediated through transcriptional inhibition of the hTERT promoter by semaphorin 3F.

In conclusion, this research shows that dysregulation of the angiostatic regulators, angiostatin and semaphorin 3F, may contribute to the etiology of epithelial ovarian cancer. In the future, dysregulation of these and other angiostatic regulators may be exploited for therapeutic intervention or as biomarkers for early detection which would allow women more treatment choices and hopefully, reduce the mortality associated with this insidious disease.

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