摘要
肿瘤是目前对人类威胁最大的疾病之一，其转移是病人痛苦和致死的主要因素。肿瘤转移是一个多步骤、高度受控的过程，在此过程中，肿瘤细胞在血液中的存活率对其转移效率的影响至关重要。进入血液的肿瘤细胞面临多种免疫攻击，成功逃逸这些攻击的肿瘤细胞才有可能完成转移。自然杀伤细胞(NK细胞)可以发现并杀伤肿瘤细胞，是开启其他免疫系统的关键，其功能的正常发挥对肿瘤免疫至关重要。近年来的研究表明，NK细胞功能的发挥经常受到血小板、纤维蛋白原等凝血因子的阻碍，使得肿瘤细胞有机会逃逸杀伤。为此，研究者做了大量的工作，血小板及纤维蛋白原帮助肿瘤细胞逃逸NK细胞攻击的机制已经被讨论了20多年，然而两者的具体角色和协作机制仍然不清楚。
在本研究中，我们用黑色素瘤细胞系A375和B16F10及淋巴瘤细胞系YAc-1，通过静止黏附、层流、流式细胞术和细胞毒性杀伤等实验证明，肿瘤细胞与纤维蛋白原的黏附能力大于它与血小板的黏附能力，在较高剪切力下肿瘤细胞与血小板的黏附很难发生。纤维蛋白原可介导肿瘤细胞与血小板的黏附，此过程中表达于肿瘤细胞和血小板表面的β_3整合素发挥了关键的作用。凝血酶存在时，纤维蛋白原可被凝集在肿瘤细胞周围形成一层致密的保护罩。血小板被肿瘤细胞激活后可产生凝血酶，因此血小板可以与凝血酶一样帮助纤维蛋白原保护肿瘤细胞，使其免于NK细胞接触及被杀伤。水蛭素是凝血酶的特异抑制物，可以逆转血小板对纤维蛋白原的作用。这些结果显示在保护肿瘤细胞的过程中，纤维蛋白原帮助血小板黏附到肿瘤细胞上，而血小板则通过形成凝血酶使更多的纤维蛋白原凝集在肿瘤细胞周围，它们在此过程中相互协作。
在本研究中，我们还探讨了本实验室制备的化学修饰肝素对纤维蛋白原介导的肿瘤细胞．血小板间接黏附的阻断能力。我们通过采用流式细胞术、层流实验等手段发现，肝素及其修饰物可以干扰纤维蛋白原与表达于肿瘤细胞、血小板表面的β_3，整合素的结合，进而阻断纤维蛋白原介导的肿瘤细胞与血小板的间接黏附。不同修饰物的阻断能力也有所差异，这种差异与其不同的修饰结构相关。
Cancer is one of the most danger diseases of human, as its metastasis, patients suffers a lot and died frequently. Metastasis is a multi-step and highly regulated cascade, which effected by the survival rate of tumor cells in blood mostly. Tumor cell escape form the attacks of immunological factors in blood continue the metastasis. Natural killer cells are essential for the tumor immunity as their special ability to recognize tumor cells from normal cells. However, recent studies show that some tumor cell can escape from the recognition by the help of platelet or fibrinogen. The mechanisms of platelets and fibrinogen in protecting tumor cells from NK cytotoxicity have been discussed for more than 20 years. However, the exact roles and relationships of them in the process are still not clear.
In this study, we demonstrate that tumor cells prefer to adhere to fibrinogen than to platelets, and fibrinogen can enhance the adhesion of tumor cells to platelets.β_3 integrins plays an important role in the adhesion of B16F10 to platelets enhanced by fibrinogen. In the presence of thrombin, fibrinogen forms dense fibrin(ogen) layers around tumor cells. Tumor cells can induce platelets to aggregate and form thrombin. Platelets as well as thrombin can help fibrinogen to protect tumor cells from the lethal contact and NK cytotoxicity. Hirudin, a specific inhibitor of thrombin, can reverse the effect of platelets on fibrinogen in blocking NK cytotoxicity. Our results suggest that fibrinogen help platelets adhere to tumor cells, and platelets in turn promote more fibrinogen to aggregate around tumor cells by forming thrombin. They facilitate each other in protecting tumor cells from NK cytotoxicity.
In this study, we also detect the ability of chemical modified heparins in abolishing the indirect adhesion of tumor cell and platelet mediated by fibrinogen. By flow cytometry and flow chamber assay, we found that the heparins could effect the adhesion of fibrinogen toβ_3 integrins on the surface of tumor cells or platelets, and inhibit the indirect adhesion. The inhibiting abilities of different heparin are correlated with their structure.
引文
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