Chaperone-mediated autophagy controlling VEGFR1 degradation contributes cross talk between breast cancer cells and endothelial cells triggering tumorigenesis via the VEGF-VEGFR2 axis.

The reciprocal cross talk between breast cancer cells and the endothelial cells, through the secretion of growth factors, plays a vital role in angiogenesis and tumorigenesis. We previously demonstrated that chaperone-mediated autophagy (CMA) promotes breast cancer tumorigenesis. However, whether the cross talk between cancer cells with endothelial cells plays a role in CMA-mediated breast tumor tumorigenesis is unknown. We discovered that the conditioned medium (CM) from breast cancer cells with high CMA activity promoted tube formation of endothelial cells (ECs) via the VEGF-VEGFR2 axis. High CMA activity directly promoted angiogenesis of endothelial cells via the VEGF-VEGFR2 axis. The CM from ECs with high level CMA activity accelerated survival and migration of breast cancer cells in vitro via the VEGF-VEGFR2 axis. Co-injection of breast cancer cells mixed with ECs with high level CMA activity trigged angiogenesis and accelerated tumorigenesis in vivo. CMA activity and microvessel numbers were positively correlated with VEGF-VEGFR2 axis between paired breast tumor and normal adjacent tissue. CMA, a highly selective lysosome-dependent degradation process directly degrades VEGFR1 which can serve as a competitively regulatory factor for VEGFR2 regulating its signaling. Our study showed that the cross talk between breast cancer cells and endothelial cells induced by CMA -mediated degradation of VEGFR1 triggers angiogenesis and tumorigenesis via the VEGF-VEGFR2 axis.