Tumor dormancy is an important aspect of the etiology of ovarian cancer. Malignant transformation has been linked with ovulation and proliferation of the ovarian epithelium. However the disease rarely appears in women during the reproductive years. At menopause the incidence as well as aggressiveness of the disease increases. Thus it is probable that dormant tumors remain undetected for a few decades before initiation of tumor progression and clinical symptoms. The goal of this work is to increase our understanding of the role of gonadotropins in mediating exit of ovarian carcinoma from dormancy, and specifically, the role of hormone induced tumor angiogenesis in initiation of tumor growth. The project proposed here will include analysis of vascular instability in sustaining tumor dormancy and vascular maturation and stabilization as signals for initiation of tumor progression. The dual role of hyaluronic acid secreted by mesothelial cells in mediating gonadotropin-dependent tumor adhesion and suppression of angiogenesis will be evaluated. In order to study the kinetics of tumor angiogenesis and vascular maturation and their impact on tumor grovvth, we will apply BOLD contrast MRI for differential mapping of mature and functional vasculature from signal changes in response to hypercapaia and hyperoxia. MRI will be used also for mapping changes in vascular density and permeability. The focus of the project for the coming 5 years will be to evaluate the impact growth factors that modulate vascular development and maturation, and the role of hyaluronic acid in implantation and initiation of growth of ovarian tumors.
The specific aims of the project are:
Aim 1. Analysis of vascular maturation and permeability during angiogenesis and vascular regression in ovarian cancer tumors and in the normal ovary.
Aim 2. Evaluation of the role of hypoxic regulation of VEGF expression on vascular instability and vascular regression during experimental dormancy of ovarian carcinoma Aim 3. Analysis of the role of vascular maturation, namely recruitment of pericytes and smooth muscle ceils, in vascular stabilization and initiation of tumor growth.
Aim 4. Analysis of the role of hyaluronic acid and hyaluronidase in angiogenesis in the normal ovary and in ovarian carcinoma.
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