Ovarian cancer is the fifth most frequent malignancy in U.S. women and the fourth leading cause of death. Approximately 80-85% of human ovarian neoplasms arise from the ovarian surface epithelium (OSE). The phenotype most frequently observed in such neoplasms is characterized by epithelium-lined fibrovascular structures or papillae. The mechanisms regulating papillogenesis in normal, reactive, and neoplastic human OSE are poorly understood and are currently under investigation by the Ovarian Epithelial Cancer Pathobiology Program under the direction of Dr. Nicosia. Dr. Nicosia and his colleagues have shown that estrogens and repetitive ovulation markedly stimulate papillogenesis in animal models, leading to development of an ovarian surface morphology similar to that seen in low-malignant-potential human serous neoplasms. Papillae are more frequent in human OSE brushings obtained after ovulation or from women with dysfunctional hormonal conditions. Estrogen- and ovulation-stimulated OSE cell growth and papillogenesis are most likely mediated by stromal factors, including morphogenetic and angiogenic cytokines and growth factors.
The research in Dr. Nicosia's laboratory has shown that level of bioactive VEGF is dramatically elevated in the cyst fluid of human OSE cancers. A recently completed study indicates that the seriousness of clinical status correlates significantly with plasma and/or urinary levels of VEGF, hepatocyte growth factor endostatin and angiostatin, and suggests that these cytokines may play an important role in development and progression of human OSE cancers. The researchers are currently manipulating tridimensional assays of angiogenesis to enhance interaction of human OSE cells with sprouting capillaries and to investigate gene and cytokine expression during papillogenesis.
Using DNA microarray a complex and diverse pattern of up- and down-regulated genes has been observed in papillary ferous human ovarian neoplasms. Utilizing a combined gene discovery and cytokine profiling approach, studies in Dr. Nicosia's laboratory are testing the hypothesis that transformation of human OSE from a two-dimensional monolayer to a hierarchical three-dimensional papillary configuration is related to expression of unique repertoires of gene and gene products, including morphogenetic cytokines. Identification of such unique genes and gene products and related mechanisms of action will likely provide molecular tools to better understand, and therefore interfere therapeutically with, the fundamental process of papillogenesis in human OSE cancers.