Anti-Platelet-Derived Growth Factor Receptor-Beta Therapy Does Not Trigger Retinal Endothelial Cell Toxicity
*Corresponding author: Zachary K. Goldsmith, Andrew S. Irvine, Matthew W. Wilson and Vanessa M. Morales-Tirado*
Retinoblastoma (Rb) is a highly angiogenic tumor, for which anti-vascular endothelial growth factor (VEGF) therapies have shown limited success in clinical setting. Recent investigations demonstrated upregulation of ancillary axis including the platelet-derived growth factor (PDGF) when VEGF is inhibited. This illustrates the need for novel therapeutics. Previous work from our lab showed inhibition of the platelet-derived growth factor receptor-beta (PDGFR-β) by imatinibmesylate (IM), inhibited Rb cells proliferation in vitro. Novel therapies ideally are tumor-specific, leaving normal non-cancerous cells a stroma to perform their homeostatic functions. Rb treatments induce apoptosis of the retinal endothelial cells, causing the release of pro-inflammatory cytokines and chemokines to the microenvironment.
We investigated the role of the PDGFR-β in the tumor microenvironment and how inhibition of this signaling pathway, as a potential targeted therapy, impacts angiogenesis in human retinal microvascular endothelial cells (hRECs), specialized neurons arborizing the retinal microvasculature.
Our results demonstrated that inhibition of the PDGFR-β signaling pathway by IM affects the proliferation of the Rb cells, but not hRECs. PDGFR-β signaling is not required for hRECs angiogenic activity, although it reduces the percentage of VEGF-Aproducing cells.
These results illustrate a lack of functional activity PDGFR-β signaling in hRECs and points to a more tumor-specific therapeutic option. 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.
Retinoblastoma; Retinal endothelial cells; Ocular oncology; Imatinib mesylate.