HIF-1α调控循环肿瘤微栓子（CTM）形成的机制及相关干预新策略研究

Circulating tumor microemboli (CTM) plays a vital role in tumor metastasis due to the higher metastatic potential compared with single circulating tumor cell (CTC). However, the underlying mechanism of CTM formation is still unknown, and there still no effective targeting strategy. Our previous studies showed that CTM generally expressed high level HIF-1α, and platelets combined with tumor cells can further promote the expression of HIF-1α, which can accelerate tumor metastasis. We speculate that HIF-1α can regulate the formation of primary tumor and circulating CTM, which can be expected as a new target for intervening CTM formation. This project intends to carry out the following researches: (1) Clarify the effect and mechanism of HIF-1α regulating CTM formation; (2) Confirming that HIF-1α can be a new target for CTM targeting therapy; (3) Based on the high adhesion properties between platelets and tumor cells, platelets can be used as the specificity drug carrier targeting CTM, to study the anti-metastasis effect of engineering platelets carried with HIF-1α inhibitor in vitro and in vivo. In sum, this project will clarify the regulation mechanism of CTM formation and establish the method of targeting CTM, providing the theoretical guidance and experimental basis for the development of new tumor metastasis strategies which can be converted to clinical application.

循环肿瘤微栓子（CTM）具有比单个循环肿瘤细胞（CTC）更强的转移潜能，是肿瘤转移的关键，但其形成的调控机制未明，尚无针对性治疗策略。本课题组前期研究发现CTM普遍高表达HIF-1α；血小板可与肿瘤细胞粘附，进一步提高HIF-1α表达水平，促进肿瘤转移，推测HIF-1α可调控原发灶或循环中CTM的形成，有望作为干预CTM形成的新靶点。本项目主要研究内容：⑴HIF-1α对CTM形成的调控作用及其分子机制；⑵确认HIF-1α可作为靶向CTM抗肿瘤转移的新靶点；⑶基于血小板与肿瘤细胞的高粘附特性，将其作为靶向CTM的特异性药物载体，从体内外研究载有HIF-1α抑制剂的工程化血小板的抗肿瘤转移作用。通过上述研究阐明CTM形成的调控机制，并建立靶向CTM的方法，为开发可转化为临床的肿瘤转移治疗新策略奠定理论和实验基础。

目前，关于循环肿瘤细胞的研究 主要集中于肿瘤早期检测、疗效监测以及预后判断等 其形成的相关作用机制尚不明确 。 本文证实了 HIF 2α与胰腺癌循环肿瘤微栓子形成间的关系，并初步阐明其可能的机制，为循环肿瘤微栓子形成的研究提供可行的方向 ，并 为胰腺癌的 临床 治疗提供新药物靶点和干预策略。