Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs.
Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs.
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DOI：
10.1038/s41598-023-29450-x
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发表时间：
2023-02-17
影响因子：
4.6
通讯作者：
Lee, Norman H.
中科院分区：
文献类型：
--
作者：
Garofano, Kaitlin;Rashid, Kameron;Smith, Michael;Brantner, Christine;Suwunnakorn, Sumanun;Diemert, David;Gordon, Olivia;Horvath, Anelia;Khan, Sikandar;Popratiloff, Anastas;Rhim, Johng;Sidahmed, Alfateh;Maggirwar, Sanjay B.;O'Brien, Travis J.;Perera, Minoli A.;Lee, Norman H.
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-血小板相互作用的受体-配体库和随后的后果尚未完全阐明。从PCa细胞系（RC 77 T/E，MDA PCa 2b）的质膜发出的微绒毛直接接触个体血小板和血小板聚集体。PCa细胞-血小板相互作用与血小板中的钙动员以及P-选择素和整合素αIIbβ3移位到血小板表面相关。PCa细胞-血小板相互作用可促进PCa细胞侵袭和抗凋亡，这些事件对雄激素受体阻断剂比卡鲁胺不敏感。PCa细胞在体外对血小板的活化非常敏感，在PCa细胞：血小板共培养比例低至1：10时发生（而PCa患者血液中含有1：2，000，000/ml）。共培养的条件培养基刺激PCa细胞侵袭，但不诱导凋亡抵抗，也不诱导血小板聚集。通过RNA-Seq鉴定了负责PCa细胞-血小板致癌事件的候选跨膜信号蛋白，并大致分为4个主要类别：（1）整联蛋白-配体，（2）EPH受体-肝配蛋白，（3）免疫检查点受体-配体，和（4）杂项受体-配体相互作用。基于抗体中和和小分子抑制剂测定，发现PCa细胞刺激的血小板中的钙动员由纤连蛋白1（FN 1）-αIIbβ3信号轴介导。CD 55-粘附G蛋白偶联受体E5（ADGRE 5）轴促进了血小板刺激的PCa细胞侵袭，血小板细胞因子CCL 3L 1和IL 32也有贡献。血小板刺激的PCa细胞凋亡抵抗依赖于ephrin-EPH受体和溶血磷脂酸（LPA）-LPA受体（LPAR）信号传导。在参与的信号伴侣中，与正常前列腺相比，在PCa标本中观察到FN 1和LPAR 3过表达，而PCa中CCR 1（CCL 3L 1受体）、EPHA 1和LPAR 5的高表达与患者生存率差相关。这些研究结果强调，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。
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 αIIbβ3 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)-αIIbβ3 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.
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影响因子：
78.5
作者：
Pasquale, Elena B.
通讯作者：
Pasquale, Elena B.
影响因子：
9
作者：
Di Donato M;Zamagni A;Galasso G;Di Zazzo E;Giovannelli P;Barone MV;Zanoni M;Gunelli R;Costantini M;Auricchio F;Migliaccio A;Tesei A;Castoria G
通讯作者：
Castoria G
影响因子：
--
作者：
Lee, Hyun-Ah;Park, Iha;Lee, Hansoo
通讯作者：
Lee, Hansoo
影响因子：
4.8
作者：
Paul, BZS;Daniel, JL;Kunapuli, SP
通讯作者：
Kunapuli, SP
DOI：
10.1091/mbc.1.13.1027
发表时间：
1990-12-01
期刊：
CELL REGULATION
影响因子：
--
作者：
COORSSEN, JR;DAVIDSON, MML;HASLAM, RJ
通讯作者：
HASLAM, RJ