Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer

Abstract

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination.

Fig. 1

Vascular endothelial growth factor (VEGF) family and their receptors. VEGF family members bind to specific receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3 and, through activating different cascades, exert their various biologic effects. VEGFR-2 represents the major mediator of VEGF-driven responses in endothelial cells responsible for most VEGF angiogenic activities. Neuropilins (NRP-1 and NRP-2) are known as co-receptors for VEGF

Fig. 2

A proposed model for intraperitoneal dissemination of ovarian cancer [173, 174] with focus on the role of VEGF. Primary tumors are generally confined to the ovaries. To metastasize, tumor cells undergo epithelial–mesenchymal transition (EMT) to attain motility 1 Subsequently, ruptured tumor sheds malignant cells into the peritoneum 2 where they often form spheroids to survive. 3 Spheroids undergo changes into invasive mesenchymal phenotype to maintain survival and motility. 4 These cellular aggregates are transported throughout the peritoneal cavity by normal peritoneal fluid and then adhere to and implant on the peritoneum and mesothelial linings of pelvic and abdominal organs 5, where they undergo a reverse transition (MET) 6 and disaggregation 7 to initiate metastatic growth. Through the activity of MMPs, matrix degradation occurs 8 and invasive tumor cells infiltrate the mesothelial lining and the extracellular matrix 9. Cytokines and growth factors, such as VEGF, TNF-α, IL-6, IL-8, and bFGF, contribute to EMT and invasiveness of spheroids via autocrine and paracrine loops. VEGF is also significantly involved in different steps of the process, including primary tumor angiogenesis, neovascularization at newly seeded sites, MMP-mediated matrix degradation, and malignant ascites formation