Membrane-derived particles shed by PSMA-positive cells function as pro-angiogenic stimuli in tumors

Cell membrane-derived particles (Mp) are rounded membrane-enclosed particles that are shed from tumor cells. Mp are formed from tumor membranes and are capable of tumor targeting and immunotherapeutic agents because they share membrane homology with parental cells; thus, they are under consideration as a drug delivery vehicle. Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein with enzymatic functionality, is highly expressed in Mp and extracellular vesicles (EV) from prostate cancer (PCa) with poor clinical prognosis. Although PSMA expression was previously shown in EV and Mp isolated from cell lines and from the blood of patients with high-grade PCa, no pathophysiological effects have been linked to PCa-derived Mp. Here, we compared Mp from PSMA-expressing (PSMA-Mp) and PSMA-non-expressing (WT-Mp) cells side by side in vitro and in vivo. PSMA-Mp can transfer PSMA and new phenotypic characteristics to the tumor microenvironment. The consequence of PSMA transfer to cells and increased secretion of vascular endothelial growth factor-A (VEGF-A), pro-angiogenic and pro-lymphangiogenic mediators, with increased 4E binding protein 1 (4EBP-1) phosphorylation. Comparative impact of PSMA-Mp and WT-Mp on tumor microenvironment: PSMA-expressing membrane particles transfer psma, enhancing angiogenesis and 4EBP-1 phosphorylation in PSMA-negative tumors (Figure made with Biorender.com software). [Display omitted] •PSMA-Mp transfer PSMA protein to recipient cells, inducing pro-angiogenic changes in the tumor microenvironment (TME).•PSMA-Mp delivery of PSMA promotes VEGF-A and angiogenin secretion in TME cells, enhancing angiogenesis and lymphangiogenesis.•In vivo experiments show sustained exposure to PSMA-Mp leads to increased microvessel density, altered vascular architecture, and elevated CD68+ cell infiltration in tumors.•PSMA-Mp-mediated AKT activation and 4EBP-1 phosphorylation promote a pro-angiogenic and pro-lymphangiogenic TME, without significant changes in tumor size.•This study suggests that PSMA-Mp may contribute to disease progression in prostate cancer by modulating the TME through enhanced angiogenesis and lymphangiogenesis.