Background 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 plateletderived 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. Aims 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. Results 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. Conclusion 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.
Computational analysis revealing that K634 and T681 mutations modulate the 3D-structure of PDGFR-β and lead to sunitinib resistance
