The Role of Thrombospondin-1 (TSP-1) in Epithelial Ovarian Cancer.

Epithelial Ovarian Cancer (EOC) is the fifth leading cause of cancer deaths among U.S. women and represents the most lethal gynecological malignancy. Thrombospondin-1 (TSP-1) has been established as an anti-angiogenic protein and has received interest as a therapeutic target in various cancers. Although the anti-angiogenic role of TSP-1 has been defined its physiologic role in cancers such as EOC is predominantly unknown. It was our goal to determine the role of TSP-1 in epithelial ovarian cancer and its effect on tumour cells. Our laboratory has recently developed an orthotopic syngeneic mouse model of EOC to study the formation and progression of the disease. Morphological and histological characterization revealed that these mice developed large primary tumours, numerous secondary lesions, and widespread ascites which closely resembles the human disease. In order to determine the role of TSP-1 in EOC, we performed various in vitro and in vivo experiments to manipulate TSP-1 expression in ovarian cells. Murine ovarian surface epithelial cells (MOSECs) were stably transfected to overexpress TSP-1 and the proliferative and apoptotic profiles of MOSECs and TSP-1 transfectants were characterized. Control and TSP-1 overexpressing cells were injected into the ovary of wild-type mice to evaluate the role of TSP-1 in tumour development and growth. Preliminary results from these studies have demonstrated that TSP-1 overexpression results in an increase in tumour tissue density compared to animals injected with control MOSECs. Ovarian tumours were also evaluated for expression of various angiogenic and matrix proteins. TSP-1 expression was elevated in primary tumour tissue while metastatic secondary lesions had reduced expression. This suggests that although TSP-1 expression was higher in the primary tumour, the tumour cells developed a mechanism to downregulate its expression in order to enhance metastatic dissemination. An uneven tissue distribution of secondary lesions was observed in mice that had tumours formed from MOSEC cells. There was an increased proportion of secondary lesions in the upper abdominal quadrant, with no apparent tumours below. This distribution pattern may relate to endogenous TSP-1 levels in the peritoneal cavity, which we are currently investigating. Collagen IV was increased in tumours generated from TSP-1 overexpression MOSECs, suggesting that TSP-1 may be an important mediator of extracellular matrix production in ovarian tumours. We have previously demonstrated an inverse relationship between TSP-1 and angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and we will report on the angiogenic profile and expression of angiogenic factors in control and TSP-1 overexpressing ovarian tumours. We have shown that TSP-1 is an important mediator of ovarian angiogenesis and inhibitor of angiogenic factors in the ovary and in ovarian tumours. Results from this study will increase our understanding of the role of TSP-1 in EOC and may identify its potential role as a therapeutic tool in this disease.