Lysosome purinergic receptor P2X4 regulates neoangiogenesis induced by microvesicles from sarcoma patients

• DOI: 10.1038/s41419-021-04069-w
• Publication Date: 2021-08-17T14:18:12Z
• Authors: Wulf Palinski; Maria Monti; Rosa Camerlingo; Ilaria Iacobucci; Serena Bocella; Federica Pinto; Clara Iannuzzi; Gelsomina Mansueto; Sara Pignatiello; Flavio Fazioli; Michele Gallo; Laura Marra; Flora Cozzolino; Annarosaria De Ch...; Piero Pucci; Antonio Bilancio; Filomena de Nigris
• Keywords: 0301 basic medicine; Oncology and Carcinogenesis; PROTEIN; Cardiovascular; Animals; Calcium; Cell Movement; Cell-Derived Microparticles; Cytosol; Human Umbilical Vein Endothelial Cells; Humans; Lysosomes; Mice; Mitochondria; Neovascularization, Pathologic; Receptors, Purinergic P2X4; Retina; Sarcoma; Signal Transduction; Viscosity; ANGIOGENESIS; Article; Retina; Mice; 03 medical and health sciences; Cytosol; Clinical Research; Stem Cell Research - Nonembryonic - Human; Cell Movement; Cell-Derived Microparticles; Receptors; GIANT-CELL TUMOR; Human Umbilical Vein Endothelial Cells; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Neovascularization; Cancer; Pathologic; EXOSOMES; GIANT-CELL TUMOR; ANGIOGENESIS; BONE; EXOSOMES; PROTEIN; DIFFERENTIATION; MICROPARTICLES; DEL-1; QH573-671; Neovascularization, Pathologic; Viscosity; MICROPARTICLES; Sarcoma; DEL-1; Stem Cell Research; Mitochondria; DIFFERENTIATION; Purinergic P2X4; Calcium; Biochemistry and Cell Biology; BONE; Cytology; Lysosomes; Receptors, Purinergic P2X4; Signal Transduction

AbstractThe tumor microenvironment modulates cancer growth. Extracellular vesicles (EVs) have been identified as key mediators of intercellular communication, but their role in tumor growth is largely unexplored. Here, we demonstrate that EVs from sarcoma patients promote neoangiogenesis via a purinergic X receptor 4 (P2XR4) -dependent mechanism in vitro and in vivo. Using a proteomic approach, we analyzed the protein content of plasma EVs and identified critical activated pathways in human umbilical vein endothelial cells (HUVECs) and human progenitor hematopoietic cells (CD34+). We then showed that vessel formation was due to rapid mitochondrial activation, intracellular Ca2+ mobilization, increased extracellular ATP, and trafficking of the lysosomal P2XR4 to the cell membrane, which is required for cell motility and formation of stable branching vascular networks. Cell membrane translocation of P2XR4 was induced by proteins and chemokines contained in EVs (e.g. Del-1 and SDF-1). Del-1 was found expressed in many EVs from sarcoma tumors and several tumor types. P2XR4 blockade reduced EVs-induced vessels in angioreactors, as well as intratumor vascularization in mouse xenografts. Together, these findings identify P2XR4 as a key mediator of EVs-induced tumor angiogenesis via a signaling mediated by mitochondria-lysosome-sensing response in endothelial cells, and indicate a novel target for therapeutic interventions.