P-selectin/PSGL-1介导活化血小板促进卵巢癌细胞黏附侵袭的研究

Ovarian cancer with frequent peritoneal dissemination is associated with poor clinical outcomes. High platelet counts and systemic coagulopathy aggravate tumor progression and serve as independent risks for poor prognosis of ovarian cancer. However, the underlying mechanisms for the link between platelets and cancer progression remain poorly understood. Platelets increase production and become hyper-reactive in response to the persistent inflammatory environment of cancer. This increase in hyper-reactive platelets, in turn, promotes the growth and metastasis of ovarian cancer, primarily through platelet-secreted cytokines and adhesion molecules such as P-selectin . .By forming complexes, platelets also facilitate transmigration of cancer cells through the vascular wall. We have detected the activation state of platelets in patients with ovarian cancer by measuring platelet activation markers-- P-selectin and found high level P-selectin in ovarian cancer was associated with metastasis and accompanied by high level of PSGL-1 expression. We hypothesize that the interaction of activated platelets and ovarian cancer cells are mediated by P-selectin/PSGL-1 compand , which is regulated through INTβ1 pathway including PI3K/AKT and Ras/MAPK signal pathway. In order to illustrate the interaction of activated platelet and ovarian cancer cell, We will conduct in vitro and in vivo experiments where ovarian cancer cells are exposed to platelets that are activated by various agonists. Tumor cell proliferation, adhesion, migration and invasion in the presence of these activated platelets will be assayed by experiments. The studie is expected to delineate a novel crosstalk between platelets and tumor cells that propagates cancer invation and identify new therapeutic targets of anti-metastasis therapy in ovarian cancer.

肿瘤转移是卵巢癌患者高病死率的首要原因，研究发现卵巢癌转移常伴血小板增多聚集，肿瘤可以促进血小板增多与活化，活化的血小板则可与肿瘤细胞黏附聚集，促进肿瘤转移。这种血小板与肿瘤细胞的相互作用(Interaction）可能是由活化血小板表面的黏附分子与表达在肿瘤细胞表面上的特异配体介导的。本课题前期证实卵巢癌中血小板明显活化且伴黏附分子P-selectin高表达，而卵巢癌组织中也伴其配体PSGL-1与整合素INTβ1高表达，将进一步研究P-selectin 与PSGL-1结合后介导血小板与卵巢癌细胞之间的黏附作用，探索其作用是否通过PI3K或MAPK信号转导激活整合素INTβ1通路实现的；进而从体内外实验研究P-selectin/PSGL-1介导活化血小板对卵巢癌细胞增殖、黏附、迁移、侵袭的作用。为卵巢癌转移机制研究，预后判断及为寻找不同靶点抑制血小板活化进而抑制肿瘤侵袭转移的研究提供理论依据

肿瘤转移是卵巢癌患者高病死率的首要原因，研究发现卵巢癌转移常伴血小板增多与活化及粘附分子P-selectin的释放，P-selectin与肿瘤细胞表面配体PSGL-1结合后促进肿瘤细胞黏附聚集，促进肿瘤转移。这种由活化血小板表面的黏附分子与表达在肿瘤细胞表面上的特异配体介导的相互作用（Cross Talking）可能是卵巢癌细胞粘附、侵袭、转移的重要环节。.本课题第一部分在上皮性卵巢癌（EOC）患者中研究发现EOC患者外周血血小板明显活化且伴黏附分子P-selectin高表达，进一步分别从mRNA 、蛋白水平和组织中检测到PSGL-1 的高表达。第二部分通过体外实验，P-selectin/PSGL-1 结合后通过活化integrin β1介导卵巢癌细胞粘附，增殖、侵袭与转移，进一步实验证实这一过程与PI3K或MAPK信号转导通路激活有关。第三部分通过动物实验应用卵巢癌裸鼠移植瘤模型研究P-selectin/PSGL-1 对小鼠体内移植瘤生长及转移的影响，发现P-selectin/PSGL-1 促进卵巢癌生长及转移，应用p-selectin阻断剂KF38789和顺铂CDDP治疗具有协同作用，更有效抑制肿瘤生长和转移发生。.本项目为卵巢癌转移机制研究，预后判断以及为寻找不同靶点抑制肿瘤生长转移的研究提供理论依据。