Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
GW Nanofabrication and Imaging Center, The George Washington University, Washington, DC, 20037, USA.
Sci Rep. 2023 Feb 17;13(1):2864. doi: 10.1038/s41598-023-29450-x.
Platelets play a crucial role in cancer and thrombosis. However, the receptor-ligand repertoire mediating prostate cancer (PCa) cell-platelet interactions and ensuing consequences have not been fully elucidated. Microvilli emanating from the plasma membrane of PCa cell lines (RC77 T/E, MDA PCa 2b) directly contacted individual platelets and platelet aggregates. PCa cell-platelet interactions were associated with calcium mobilization in platelets, and translocation of P-selectin and integrin αβ onto the platelet surface. PCa cell-platelet interactions reciprocally promoted PCa cell invasion and apoptotic resistance, and these events were insensitive to androgen receptor blockade by bicalutamide. PCa cells were exceedingly sensitive to activation by platelets in vitro, occurring at a PCa cell:platelet coculture ratio as low as 1:10 (whereas PCa patient blood contains 1:2,000,000 per ml). Conditioned medium from cocultures stimulated PCa cell invasion but not apoptotic resistance nor platelet aggregation. Candidate transmembrane signaling proteins responsible for PCa cell-platelet oncogenic events were identified by RNA-Seq and broadly divided into 4 major categories: (1) integrin-ligand, (2) EPH receptor-ephrin, (3) immune checkpoint receptor-ligand, and (4) miscellaneous receptor-ligand interactions. Based on antibody neutralization and small molecule inhibitor assays, PCa cell-stimulated calcium mobilization in platelets was found to be mediated by a fibronectin1 (FN1)-αβ signaling axis. Platelet-stimulated PCa cell invasion was facilitated by a CD55-adhesion G protein coupled receptor E5 (ADGRE5) axis, with contribution from platelet cytokines CCL3L1 and IL32. Platelet-stimulated PCa cell apoptotic resistance relied on ephrin-EPH receptor and lysophosphatidic acid (LPA)-LPA receptor (LPAR) signaling. Of participating signaling partners, FN1 and LPAR3 overexpression was observed in PCa specimens compared to normal prostate, while high expression of CCR1 (CCL3L1 receptor), EPHA1 and LPAR5 in PCa was associated with poor patient survival. These findings emphasize that non-overlapping receptor-ligand pairs participate in oncogenesis and thrombosis, highlighting the complexity of any contemplated clinical intervention strategy.
血小板在癌症和血栓形成中起着至关重要的作用。然而，介导前列腺癌（PCa）细胞-血小板相互作用和随之而来的后果的受体-配体谱尚未完全阐明。来自 PCa 细胞系（RC77 T/E、MDA PCa 2b）的质膜微绒毛直接与单个血小板和血小板聚集物接触。PCa 细胞-血小板相互作用与血小板内钙动员以及 P-选择素和整合素αβ向血小板表面的易位有关。PCa 细胞-血小板相互作用互惠促进 PCa 细胞侵袭和抗凋亡，并且这些事件对比卡鲁胺的雄激素受体阻断不敏感。PCa 细胞在体外对血小板的激活极为敏感，在 PCa 细胞：血小板共培养比例低至 1:10 时发生（而 PCa 患者血液中每毫升含有 1:2,000,000）。共培养物的条件培养基刺激 PCa 细胞侵袭，但不刺激抗凋亡或血小板聚集。通过 RNA-Seq 鉴定负责 PCa 细胞-血小板致癌事件的候选跨膜信号蛋白，并广泛分为 4 大类：（1）整合素-配体，（2）EPH 受体-ephrin，（3）免疫检查点受体-配体，和（4）各种受体-配体相互作用。基于抗体中和和小分子抑制剂测定，发现 PCa 细胞刺激的血小板钙动员是由纤维连接蛋白 1（FN1）-αβ信号轴介导的。血小板刺激的 PCa 细胞侵袭是由 CD55-黏附 G 蛋白偶联受体 E5（ADGRE5）轴促进的，血小板细胞因子 CCL3L1 和 IL32 也有贡献。血小板刺激的 PCa 细胞抗凋亡依赖于 ephrin-EPH 受体和溶血磷脂酸（LPA）-LPA 受体（LPAR）信号。在 PCa 标本中观察到参与信号的 FN1 和 LPAR3 过表达与正常前列腺相比，而在 PCa 中 CCR1（CCL3L1 受体）、EPHA1 和 LPAR5 的高表达与患者生存不良相关。这些发现强调了非重叠的受体-配体对参与肿瘤发生和血栓形成，突出了任何预期的临床干预策略的复杂性。
