Gold Nanoparticles Disrupt Tumor Microenvironment - Endothelial Cell Crosstalk to Inhibit Angiogenic Phenotypes in vitro.

It is currently recognized that perpetual crosstalk among key players in tumor microenvironment such as cancer associated fibroblasts (CAFs), cancer cells (CCs) and endothelial cells (ECs) play a critical role in tumor progression, metastasis and therapy resistance. Disruption of the crosstalk may be useful to improve the outcome of therapeutics for which limited options are available. In the current study we investigate a use of gold nanoparticles (AuNPs) as a therapeutic tool to disrupt the multicellular crosstalk within the TME cells with an emphasis on inhibiting angiogenesis. We demonstrate here that AuNPs disrupt signal transduction from TME cells (CAFs, CCs and ECs) to ECs and inhibit angiogenic phenotypes in vitro. We demonstrate that conditioned media (CM) from ovarian CCs, CAFs or ECs themselves induce tube formation and migration of ECs in vitro. Migration of ECs is also induced when ECs are co-cultured with CCs, CAFs or ECs. In contrast, CM from the cells treated with AuNPs, or co-cultured cells pre-treated with AuNPs demonstrate diminished effects on ECs tube formation and migration. Mechanistically, AuNPs deplete ̴95% VEGF165 from VEGF single-protein solution, and remove up to ̴45% of VEGF165 from CM, which is reflected on reduced activation of VEGF-Receptor 2 (VEGFR2) as compared to control CM. These results demonstrate that AuNPs inhibit angiogenesis via blockade of VEGF-VEGFR2 signaling from TME cells to endothelial cells.