SANTO NICOSIA, MD
Chair, College of Medicine, Pathology & Cell Biology University of South Florida
Our basic research focuses on the regulation of cell growth and morphogenesis in the ovarian surface epithelium (OSE), the source of the most frequent and lethal gynecologic malignancy. In particular, our laboratory is interested in the identification of genes and cytokines involved in the morphogenesis of ovarian papillary neoplasms. The underlying hypothesis of the research is that morphogenetic genes regulate transformation of OSE from a flat to a hierarchically branching papillary tissue. Using differential display, approximately 20 genes were discerned a few years ago that were either up-regulated (including microvascular endothelial differentiation gene) or down-regulated in rabbit OSE cells whose architecture had become predominantly papillary after 3 months of exposure to estrogens.
More recently using a DNA microarray approach, a number of angiogenic and epithelial morphogens have been identified as significantly upregulated or down-regulated in the papillary component of well-differentiated human ovarian serous cystadenocarcinomas. Among the upregulated genes were morphogens such as FGF18, FGFR-7, ephrins, Hox B7 and BMP7. Down-regulated genes included IGFBP5, thrombospondin, progesterone and androgen receptors as well as caldesmon.
We are currently in the process of setting up studies to investigate the functional implications of these genes in benign and neoplastic OSE cells via transfection and RNA silencing methodologies. Papillogenesis is also being reproduced in vitro utilizing heterotypic cultures of OSE cancer cells, endothelial cells and fibroblasts grown in collagen and basement membrane-rich matrices.
Previous studies have shown that OSE papillogenesis is stimulated by vascular endothelial growth factor (VEGF) and that VEGF is dramatically elevated in the cyst fluid of human ovarian papillary carcinomas consistent with the hypothesis that this cytokine may play an important role in ovarian cancer related-angiogenesis and tumor progression (1). Translating these results to the bedside, the laboratory has shown that seriousness of clinical status (OEC > benign lesions > healthy status) correlates with plasmatic VEGF, urinary scatter factor or HGF and urinary angiostatin. Angiostatin is the variable that independently discriminates OEC patients from volunteer controls and patients with benign ovarian masses. The diagnostic robustness of angiostatin as a screening or diagnostic tool in ovarian cancer needs to be explored further in a larger cohort of patients.
Recent trends toward conservative surgery for breast cancer and increasing detection of smaller invasive malignancies have shifted the traditional surgical approach from mastectomy to lumpectomy and from complete axillary lymph node dissection to sentinel lymph node biopsy in order to avoid extensive procedures in node-negative women. In collaboration with Dr. Charles Cox, we have developed imprint cytology procedures for the intraoperative analysis of lumpectomy margins and sentinel lymph nodes in breast cancer patients that allow for a rapid analysis of residual and metastatic disease without loss of diagnostic tissue and artifacts associated with pathological evaluation by the traditional frozen section method.