The effects of inhibition of PDGFR-β in retinal endothelial cells within the retinoblastoma tumor microenvironment

Abstract

Purpose : Retinoblastoma (Rb) is a highly angiogenic tumor, for which anti-VEGF therapies have shown limited success in clinical setting. This illustrates the need for more novel therapeutics. Previous work from our lab showed inhibition of PDGFR-β inhibited Rb cell proliferation in vitro. However, novel therapies must not only target tumor cells but also how they affect the tumor microenvironment.

Methods : We investigated the role of the PDGFR-β in the tumor microenvironment and how inhibition of this signaling pathway impacts angiogenesis in human retinal microvascular endothelial cells (hRECs). Rb monocultures and co-cultures with hRECs were evaluated for the production of the angiogenic proteins PDGF and VEGF after treatment with imatinib mesylate, a small molecule kinase inhibitor. We performed tube formation assay in hRECs to investigate if PDGF played a role in structural integrity of the vasculature.

Results : We found that inhibition of the PDGFR-β signaling pathway through imatinib mesylate affects both paracrine and autocrine angiogenic mechanisms in Rb cells. Production of VEGF is also affected by inhibition of this signaling pathway.

Conclusions : More studies are underway to elucidate if the use of imatinib mesylate will also regulate hRECs cell survival. This is of critical importance as success of treatment also depends on the ability of the normal tissues to remain healthy after sensitization and/or killing of the Rb tumor.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.