Abstract
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 (BC-ECFCs). 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.
Highlights
Breast cancer (BC) consists in a heterogeneous group of malignancies deriving from the epithelial cells lining the milk ducts and still represents the leading cause of cancer-related mortality in women worldwide [1]
VEGFR2 has long been regarded as the most suitable target to interfere with tumor vascularization and increase overall survival (OS) in patients affected by highly angiogenic tumors, such as renal cell carcinoma (RCC) and breast cancer (BC)
We took advantage from the availability of patients-derived cells to assess whether Vascular endothelial growth factor (VEGF) stimulates proliferation in Endothelial colony forming cells (ECFCs), which are likely to support the angiogenic switch during BC development [19,20,21]
Summary
Breast cancer (BC) consists in a heterogeneous group of malignancies deriving from the epithelial cells lining the milk ducts and still represents the leading cause of cancer-related mortality in women worldwide [1]. Targeting VEGFR2 with either humanized monoclonal antibodies, such as bevacizumab and VEGF-Trap, or tyrosine kinase inhibitors (TKIs), such as sorafenib, sunitinib and pazopanib, halted neovessel formation and caused tumor shrinkage in immunodeficient mouse models of most malignancies [7, 8], including BC. These promising observations did not translate into an effective therapeutic benefit for cancer patients. The effect of VEGF on BC-associated ECFCs (BC-ECFCs) is, still unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
