Vesicles Secreted by Renal Cell Carcinoma Cells Cause Vascular Endothelial Cells to Express PSMA and Drive Tumor Progression

• Published in: Cells (Basel, Switzerland) Switzerland), 2025-01, Vol.14 (3), p.165
• Main Authors: Watanabe, Ryuta, Kagimoto, Keito, Chosei, Mami, Sakaue, Tomohisa, Kurata, Mie, Miura, Noriyoshi, Kitazawa, Riko, Kikugawa, Tadahiko, Higashiyama, Shigeki, Saika, Takashi
• Format: Article
• Language: English
• Subjects: Aged; Angiogenesis; Antibodies; Antigens, Surface - metabolism; Blood vessels; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cells; Collagen; Culture Media, Conditioned - pharmacology; Disease Progression; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic; Glioma; Glutamate Carboxypeptidase II - genetics; Glutamate Carboxypeptidase II - metabolism; Growth factors; human umbilical vascular endothelial cells; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hypoxia; Kidney cancer; kidney cancer surgically resected specimen; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kinases; Lymphatic system; Male; Mass spectroscopy; Metastases; Metastasis; Middle Aged; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Penicillin; Polymerase chain reaction; Prostate cancer; Prostate carcinoma; prostate-specific membrane antigen; Proteins; Renal cell carcinoma; Renal function; Stains & staining; tube formation; tumor angiogenesis of renal cell carcinoma; Tumor cell lines; tumor endothelial cells; Tumors; Umbilical vein; Vascular endothelial growth factor
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells14030165

Prostate-specific membrane antigen (PSMA) protein expression is induced during prostate cancer progression and metastasis. Recently, we reported that PSMA-positive vesicles released by prostate cancer cell lines enhanced vascular endothelial cell angiogenesis and that PSMA may be involved in tumor angiogenesis. Similarly, it is known that PSMA is upregulated in peritumoral vessels in renal cell carcinoma (RCC). In this study, we investigated the significance and molecular function of PSMA in RCC. PSMA immunohistochemical staining confirmed PSMA presence only in perinephric tumor vessels, and PSMA intensity was strongly correlated with recurrence rate and venous invasion. Spatial gene expression analysis revealed that FOLH1 expression, which codes PSMA, was upregulated in tumor blood vessels around renal cancer, and that angiogenesis-related pathways were enhanced. The 10,000 g pellet fraction of the renal cancer cell lines Caki1- and ACHN-conditioned medium (CM) induced PSMA positivity in human umbilical vein endothelial cells (HUVECs) and enhanced tube formation. Mass spectrometry indicated that the 10,000 g pellet fraction contained various kinds of growth factors, like GDF15 and MYDGF. RNA sequencing showed that supplementing HUVECs with RCC cell CM-enhanced angiogenesis-related signaling pathways. Conclusively, microvesicle components secreted by RCC cells transform vascular endothelial cells into PSMA-positive cells, enhancing angiogenesis.