Bevacizumab induces intraocular tumour growth in mice: an intriguing paradox

Abstract

Purpose Intravitreal bevacizumab, a humanized monoclonal antibody to VEGF‐A, was originally developed as an anti‐tumour treatment, and is used to treat macular edema in radiation retinopathy. As this drug may potentially be used to treat primary uveal melanoma (UM) and/or its metastases, we analyzed the effect of bevacizumab on UM growth. Methods Mice inoculated with B16F10 melanoma cells into the anterior chamber of the eye were monitored for tumour growth and vascularisation after bevacizumab treatment. UM cell proliferation and the expression of VEGF‐A, GLUT‐1, and HIF‐1α were analyzed in vitro. Results Bevacizumab treatment resulted in an acceleration of intraocular tumour growth in mice, but did not induce UM cell proliferation in vitro. Incubation with bevacizumab induced VEGF‐A and GLUT‐1 mRNA expression via the HIF‐1α pathway in UM cell lines and primary cell cultures. Surprisingly, VEGF‐A expression in mice did not result in more vessels, but we did perceive more anterior chamber hemorrhages in vivo. Conclusion Anti‐VEGF treatment with bevacizumab induces intraocular tumour growth in mice. Although bevacizumab did not induce the number of vessels in treated mice, we did observe more anterior chamber hemorrhages. One of the mechanism involved, is the induction of VEGF‐A expression in hypoxic UM cell lines and cultures through the HIF‐1α pathway, resulting in a ‘pseudohypoxic’ condition. This phenomenon has been described in other tumours and maybe the consequence of tumour adaptive or evasive resistance. The use of bevacizumab for treatment of macular edema (due to radiation retinopathy) after irradiation of UM should therefore be carefully considered.