Multiple VEGF Family Members are Simultaneously Expressed in Ovarian Cancer: a Proposed Model for Bevacizumab Resistance

Arne      R.M. van der Bilt; Ate      G.J. van der Zee; Elisabeth      G.E. de Vries; Steven      de Jong; Hetty      Timmer- Bosscha; Klaske      A. ten Hoor; Wilfred      F.A. den Dunnen; Harry      Hollema; Anna      K.L. Reyners

doi:10.2174/138161212802002661

Abstract

Objective: Insight into the expression of multiple vascular endothelial growth factor (VEGF) family members can support the implementation of anti-angiogenic therapy. This study aimed to assess VEGF family member expression in ovarian cancers and related omental metastases.

Methods: Tissue microarrays encompassing 270 primary cancers and 112 paired metastases were immunostained for VEGF-A, VEGF-B, VEGF-C and VEGF-D. Staining intensities were categorized as absent, weak, moderate or strong. Expression was related to clinicopathological characteristics and survival.

Results: Immunohistochemical positivity (defined as moderate or strong expression) was observed for VEGF-A in 90%, VEGF-B in 4%, VEGF-C in 41% and VEGF-D in 55% of the primary ovarian cancers. VEGF-A expression correlated with VEGF-C and VEGF-D expression (P < 0.01). Simultaneous positivity for VEGF-A and VEGF-C or VEGF-D was observed in 38% and 54% of the cancers, respectively. Metastases showed positivity for VEGF-A in 78%, VEGF-B in 5%, VEGF-C in 26% and VEGF-D in 45% of cases. VEGF family member expression showed no independent prognostic significance in multivariate survival analysis.

Conclusion: VEGF-A, VEGF-C and VEGF-D are widely and often simultaneously expressed in ovarian cancer, which may contribute to bevacizumab resistance. Measuring their expression could support a rational, individualized choice of anti-angiogenic therapy and might be of predictive value. Studies are warranted to determine whether combinatorial analysis of VEGF family member expression can be used to predict anti-angiogenic drug efficacy.

Keywords: Ovarian cancer, VEGF-A, VEGF-B, VEGF-C, VEGF-D, bevacizumab resistance, anti-angiogenic therapy, survival, Immunohistochemical positivity, Metastases.