The multiple roles of VEGF throughout the development of ovarian cancer

High VEGF expression mediates a number of important developments in ovarian cancer tumorigenesis and proliferation.^1,2

As in other cancers, angiogenesis is crucial for ovarian tumor growth.² VEGF is associated with the promotion of angiogenesis in early-stage ovarian cancer, implicating VEGF-induced angiogenesis as an early contributor in ovarian carcinogenesis.³ Additionally, preclinical studies have shown that high VEGF-A expression in surface epithelium can transform normal, functional ovarian epithelium into ascites-producing cancers.^1,4

Correlation of high VEGF expression with tumor volume and survival in murine model⁴

Adapted with permission from Schumacher JJ, Dings RPM, Cosin J, et al. Cancer Res. 2007;67:3683-3690. Figure 2. Mice injected with VEGF-A–excreting cells (VR) showed significantly higher tumor volume and lower survival compared with mice injected with control cells.

Ovarian carcinomas tend to produce vasculature that is structurally and functionally abnormal: vessels are characteristically leaky and immature, and provide poor flow overall.² VEGF has been shown to enhance vessel permeability, and in one study, it regulated the permeability of peritoneal vessels that lead to ascites development.^1,5,6 This is consistent with the findings of Belotti et al that provided direct preclinical evidence that pathways involving the release of VEGF contribute to the formation of ascites through pathways involving MMP9 (and, to a lesser extent, MMP2).⁷

Interestingly, VEGF may also serve as an important survival factor for endothelial cells experiencing chemical or physical stress.⁴ In one ovarian cancer model, cells treated with a chemotherapeutic agent induced a significant increase in VEGF expression that appeared to contribute to cell survival.⁸ In another preclinical study, high exogeneous expression of VEGF has also been shown to reduce chemotherapeutic-induced apoptosis.⁵

References:

1.

Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. Angiogenesis. 2005;8:169-182.

2.

Kumaran GC, Jayson GC, Clamp AR. Br J Cancer. 2009;100:1-7.

3.

Hefler LA, Mustea A, Konsgen D, et al. Clin Cancer Res. 2007;13:898-901.

4.

Schumacher JJ, Dings RPM, Cosin J, et al. Cancer Res. 2007;67:3683-3690.

5.

Zhang L, Yang N, Garcia JR, et al. Am J Pathol. 2002;161:2295-2309.

6.

Trinh XB, Tjama WAA, Vermeulen PB, et al. Br J Cancer. 2009;100:971-978.

7.

Belotti D, Paganoni P, Manenti L, et al. Cancer Res. 2003;63:5224-5229.

8.

Wild R, Dings RPM, Subramanian I, Ramakrishnan S. Int J Cancer. 2004;110:343-351.