Abstract 2368: The vesicle component released from renal cell carcinoma cells transforms tumor blood vessels into PSMA-positive and enhances angiogenic potential
Authors: Ryuta Watanabe, Keito Kagimoto, Mami Chosei, Haruna Arai, Tomohsa Sakaue, Mie Kurata, Noriyoshi Miura, Riko Kitazawa, Tadahiko Kikugawa, Shigeki Higashiyama, Takashi Saika
Journal: Cancer Research (2025)

Abstract Background: Prostate-specific membrane antigen (PSMA) expression rises as prostate cancer progresses and metastasizes. Recently, 68Ga-labeled PSMA PET imaging has been utilized in prostate cancer diagnosis. Previous studies have shown that PSMA-positive vesicles secreted by prostate cancer cells increase angiogenic activity in vascular endothelial cells, suggesting a role for PSMA in tumor-related angiogenesis. This study aims to explore the relationship between PSMA expression in peritumoral vessels and patient outcomes, particularly focusing on tumor recurrence in surgically resected renal cell carcinoma samples. Methods: Immunohistochemistry was performed on renal cell carcinoma tissue from 45 patients who underwent nephrectomy or partial nephrectomy at our institution between January 2018 and December 2022. The intensity of PSMA expression in tumor vessels was compared with recurrence rates. Furthermore, PSMA levels in human umbilical vein endothelial cells (HUVECs) treated with conditioned media (CM) from the renal cancer cell lines Caki1 and ACHN were assessed via Western blotting (WB) and immunofluorescence (IF). Angiogenic activity was measured using a tube formation assay, while RNA sequencing (RNA-seq) was employed to examine gene expression changes in endothelial cells induced by vesicles from renal cancer cells. Spatial gene expression analysis was performed to compare differences in gene expression between tumor vessels near and vessels away from the tumor. Results: Immunohistochemical staining for PSMA and CD31 demonstrated that only the vessels surrounding the tumors were positive for PSMA. The intensity of PSMA expression was classified as weak (18 cases), moderate (11 cases), or strong (16 cases), and was found to correlate with the recurrence rates. When the 10, 000 g pellet fraction of CM from the renal cancer cell lines was applied to HUVECs, the cells became PSMA-positive, and tube formation was enhanced. RNA-seq analysis revealed that HUVECs treated with CM from renal cancer cell lines showed upregulation of pathways linked to angiogenesis. Conclusions: Vesicles secreted by renal cancer cells stimulate PSMA expression in vascular endothelial cells and promote angiogenic activity. Future studies will investigate the mechanisms leading to PSMA expression in normal vascular endothelial cells, with the goal of developing novel anti-angiogenic treatments. Citation Format: Ryuta Watanabe, Keito Kagimoto, Mami Chosei, Haruna Arai, Tomohsa Sakaue, Mie Kurata, Noriyoshi Miura, Riko Kitazawa, Tadahiko Kikugawa, Shigeki Higashiyama, Takashi Saika. The vesicle component released from renal cell carcinoma cells transforms tumor blood vessels into PSMA-positive and enhances angiogenic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2368.