靶向血小板膜糖蛋白GPIbα抑制肿瘤转移的作用与分子机制研究

原发性肿瘤微环境对于肿瘤细胞生长及转移的过程具有决定性作用。其中,血小板与肿瘤细胞间的相互作用为肿瘤细胞的转移提供了条件。近来证实GPIbα是引起血小板-肿瘤细胞聚集的重要分子之一，推测靶向GPIbα有望于肿瘤的转移控制。为此，本研究拟首先建立作为肿瘤转移抑制剂的抗GPIbα单克隆抗体的筛选模型，其次通过肺癌模型验证靶向GPIbα对肿瘤转移的抑制作用，随后检测其对血小板或肿瘤细胞与内皮细胞黏附的影响，明确靶向GPIbα抑制肿瘤转移的调控作用，最后借助GPIbα突变株寻找该抑制剂的结合位点，并观察共同注射抗原表位肽对该抑制剂介导肿瘤转移抑制的逆转作用，探讨靶向GPIbα治疗肿瘤转移的机制，通过共结晶抗原结合片段和抗原表位肽复合物，为设计和改造该抑制剂以及其它由此衍生的抗体以得到更高亲和力和更高特异性的抗体提供了理论基础。本研究为阐明靶向GPIbα抗肿瘤转移的作用，机制与应用价值提供实验依据。

Tumor metastasis to distant organs depends on interactions between tumor cells and the host microenvironment within the circulation. Platelets play a supportive role in tumor metastasis. The platelet-specific receptor glycoprotein (GP) Ibα is a major molecule inducing the accumulation of platelets and tumor cells and contributing to tumor metastasis, but the underlying molecular mechanism remains elusive. In our study, we will establish the screening model to select the anti-GPIbα monoclonal antibody that inhibits tumor metastasis, and examine the effect of this anti-GPIbα monoclonal antibody in syngeneic mouse models of experimental metastasis, and each of the following interactions: between activated platelets and tumor cells, platelets and endothelial cells. Furthermore, epitope peptide will be recognized by detect the binding of antibody in GPIbα mutant cell lines. Coinjection of epitope peptide will be used to confirm anti-metastatic activity of this anti-GPIbα monoclonal antibody in the B16 melanoma model. Final, The crystal structure of Fab/epitope peptide complex may facilitate the development of future specific inhibitors by targeting GPIbα. Our study will demonstrate the mechanism of targeting GPIbα on tumor metastasis.