Endothelial colony forming cells (ECFCs) represent a population of truly endothelial precursors that promote the angiogenic switch in solid tumors, such as breast cancer (BC). The intracellular Ca2+toolkit, which drives the pro-angiogenic response to VEGF, is remodelled in tumor-associated ECFCs such that they are seemingly insensitive to this growth factor. This feature could underlie the relative failure of anti-VEGF therapies in cancer patients. Herein, we investigated whether and how VEGF uses Ca2+signalling to control angiogenesis in BC-derived ECFCs (BCECFCs). Although VEGFR-2 was normally expressed, VEGF failed to induce proliferation and in vitro tubulogenesis in BC-ECFCs. Likewise, VEGF did not trigger robust Ca2+oscillations in these cells. Similar to normal cells, VEGF-induced intracellular Ca2+oscillations were triggered by inositol-1,4,5-trisphosphate-dependent Ca2+release from the endoplasmic reticulum (ER) and maintained by store-operated Ca2+entry (SOCE). However, InsP3-dependent Ca2+release was significantly lower in BC-ECFCs due to the down-regulation of ER Ca2+levels, while there was no remarkable difference in the amplitude, pharmacological profile and molecular composition of SOCE. Thus, the attenuation of the pro-angiogenic Ca2+response to VEGF was seemingly due to the reduction in ER Ca2+concentration, which prevents VEGF from triggering robust intracellular Ca2+oscillations. However, the pharmacological inhibition of SOCE prevented BC-ECFC proliferation and in vitro tubulogenesis. These findings demonstrate for the first time that BC-ECFCs are insensitive to VEGF, which might explain at cellular and molecular levels the failure of anti-VEGF therapies in BC patients, and hint at SOCE as a novel molecular target for this disease.
|Digital Object Identifier (DOI):||10.18632/oncotarget.20255|
|Codice identificativo ISI:||WOS:000414937900016|
|Codice identificativo Scopus:||2-s2.0-85033402777|
|Titolo:||VEGF-induced intracellular Ca2+oscillations are down-regulated and do not stimulate angiogenesis in breast cancer-derived endothelial colony forming cells|
|Appare nelle tipologie:||1.1 Articolo in rivista|