The Role of Vascular Endothelial Growth Factors in Ovarian Cancer
Ovarian tumors, like many malignancies, overexpress proangiogenic factors including vascular endothelial growth factors (VEGFs), fibroblast growth factors, angiopoietin, platelet-derived growth factors (PDGFs), and pro-angiogenic cytokines such as tumor necrosis factor alpha and interleukins 6 and 8. Of these, members of the VEGF family are the most potent pro-angiogenic factors. VEGF activation promotes endothelial cell proliferation and migration for the formation of new blood vessels and increases permeability of existing blood vessels to allow for the leakage of multiple plasma proteins, including those playing a role in angiogenesis. Also, VEGF inhibits apoptosis of the newly formed hyperpermeable blood vessels. By this mechanism, VEGF also plays a key role in the formation of ascites and pleural effusions.
Additionally, VEGF plays a significant part in the normal function of the ovary, with serum VEGF levels rising and falling in a predictable pattern during the ovulatory cycle. Therefore, it is not surprising that VEGF plays a role in the biology of ovarian cancer. Preclinical studies have demonstrated that animals inoculated with VEGF/green fluorescent protein (GFP)-positive ID8 in vitro transformed C57BL6 murine ovarian epithelial cells developed diffuse peritoneal carcinomatosis and ascites in a pattern similar to metastatic ovarian cancer.
VEGF expression is higher in ovarian cancers than in normal ovarian tissue or benign ovarian neoplasms, and increasing VEGF expression in either cytosolic fractions derived from ovarian cancers or serum VEGF levels in preoperative serum was associated with advanced stage and worse survival.[32–34] Even for patients with early-stage disease, cancers with elevated VEGF expression and preoperative serum VEGF levels were associated with a higher risk of disease recurrence and worse overall and diseasefree survival.[35,36] In a study by Paley et al, multivariate analysis showed that increased VEGF transcript expression was the strongest prognostic factor for a worse prognosis compared with other high-risk features such as stage IC-IIC disease, tumor rupture, poorly differentiated histology, malignant peritoneal cytology, and postoperative adjuvant therapy. For women with advanced-stage cancer, high serum VEGF levels have been associated with a more aggressive disease phenotype and were an independent risk factor for ascites, increased metastases, suboptimal tumor debulking, and decreased survival.[34,36] The strong association between tumor angiogenesis, VEGF expression and serum levels, and clinical outcome in ovarian cancer makes the VEGF pathway an attractive therapeutic target.
Cancer Control. 2011;18(1):31-43. © 2011 H. Lee Moffitt Cancer Center and Research Institute, Inc.
Copyright by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved.
Cite this: Antiangiogenic Therapies in Epithelial Ovarian Cancer - Medscape - Jan 01, 2011.