C-型凝集素LSECtin在淋巴瘤淋巴道转移中的作用及其机制

Metastasis is the final step in malignancy progression and the major cause of death in cancer patients. There are firm evidences showing that more than 90% cancer patients died for tumor metastasis. The dissemination of tumor cells is the prerequisite of metastases and tumor metastasis occurs primarily through the lymphatic system instead of blood vessels. Despite advances in treatments for malignant lymphoma, the incidence is increased by 5% per year in our country. About 50 thousand patients were diagnosed each year, 20 thousand patients still die from progressive disease. However, the exact mechanism for invasion and metastasis of malignant lymphoma remains to be elucidated. C-type lectins are found to express on the surface of tumor cells and endothelial cells, involving in the process of migration, adhesion and infiltration of tumor cells. Among them, the new C-type lectin-like molecule, designated liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin), is a type II integral membrane protein with a single C-type lectin-like domain at the COOH terminus, closest in homology to DC-SIGNR, DC-SIGN, and CD23. What is more, LSECtin shows specific expression on sinusoidal endothelial cells of the liver and lymph nodes, and the latter two happen to be target organs with stronger tendency to metastasize. Hepatic sinusoidal endothelial cells can directly communicate with tumor cells to accelerate tumor invasion. Martens et al. found that as alto-frequent metastatic targets, compared to foot pad with low-frequent metastatic tendency, liver and lymph node highly expressed C-type lectins and scavenger receptor through the analysis of genetic differential expression. As an important property of C-type lectins, glycosylation commonly occurs in malignant transformation of tumor cells. Therefore LSECtin, a member of the C-type lectin family of glycan-binding receptors, may play a vital role in tumor metastasis. In addition, LSECtin is a newly found CD44 ligand. Many C-type lectin family members, including selectin, mannose receptor, DC-SIGNR, were proved to combine with tumor cells and participate in tumor metastasis or tumor immunity. Applicants' previous study verified in colorectal tumor LSECtin correlated with the process of hepatic metastasis. All above evidences show an indispensable role of LSECtin in tumor metastasis process. For further investigating the precise mechanism of LSECtin in malignant lymphoma lymphatic metastasis, our laboratory intends to prove that in different levels of molecule, cell and animal models. We believe that this original research could provide a theoretical foundation for clinical treatment and actualize great economic and social benefits in the future.

肿瘤转移并不是随机的，具有器官特异性。研究发现，肿瘤细胞与靶器官内皮细胞的粘附在肿瘤转移中起重要作用。由于对各种内皮细胞的特征粘附分子所知有限。因而，在阐明具体作用和机制时进展缓慢。LSECtin是肝脏和淋巴结窦内皮细胞特异高表达的粘附分子，两者正是肿瘤高转移的靶器官；LSECtin同家族的其他成员如selectin、甘露糖受体等都已证明参与肿瘤转移；申请者研究了肝窦内皮细胞LSECtin参与结肠癌肝转移的作用。证明了：表达在肝窦内皮细胞的LSECtin结肠癌细胞结合；将裸鼠体内LSECtin基因敲除后，结肠癌细胞向肝脏转移率显著降低；LSECtin蛋白通过诱导结肠癌细胞株c-Met高表达而促进结肠癌肝转移等。本项目拟选取LSECtin的另一特异表达部位-淋巴结为对象，通过体内/外粘附、侵袭和迁移及动物整体实验等揭示LSECtin在淋巴瘤淋巴道转移的作用，具有重要的理论意义和临床应用前景。

肿瘤转移并不是随机的，具有器官特异性。研究发现，肿瘤细胞与靶器官内皮细胞的粘附在肿瘤转移中起重要作用。由于对各种内皮细胞的特征粘附分子所知有限。因而，在阐明具体作用和机制时进展缓慢。LSECtin和DC-SIGNR是肝脏和淋巴结窦内皮细胞特异高表达的粘附分子，两者正是肿瘤高转移的靶器官；LSECtin和DC-SIGNR同家族的其他成员如selectin、甘露糖受体等都已证明参与肿瘤转移；申请者研究了肝窦内皮细胞LSECtin参与结肠癌肝转移的作用。证明了：表达在肝窦内皮细胞的LSECtin结肠癌细胞结合；将裸鼠体内LSECtin基因敲除后，结肠癌细胞向肝脏转移率显著降低；LSECtin蛋白通过诱导结肠癌细胞株c-Met高表达而促进结肠癌肝转移等。在此基础上，本项目选取了LSECtin的另一特异表达部位-淋巴结为对象，通过体内/外粘附、侵袭和迁移及动物整体实验等揭示LSECtin和DC-SIGNR在肿瘤转移中的作用。结果初步表明：淋巴瘤患者血清LSECtin和DC-SIGNR水平明显低于正常人。而淋巴瘤伴有转移患者血清中LSECtin的水平与无转移的病例相比，无显著差异。淋巴瘤细胞株P388D1、EL-4 和L5178Y不表达 LSECtin。P388D1、L1210及EL-4细胞能够容易地粘附到淋巴结上，细胞向淋巴窦上粘附可以被LSECtin antibody阻断，LSECtin敲除小鼠的淋巴结上几乎不粘附淋巴瘤细胞，与对照组相比具有显著差异。说明淋巴瘤细胞P388D1、L1210及EL-4细胞淋巴道转移可能与淋巴窦内皮细胞LSECtin表达相关。肝转移和淋巴结转移的结直肠癌患者血清中的DC-SIGNR水平显著升高。已发生肝转移的患者血清中DC-SIGNR水平显著高于未发生肝转移的患者和正常人；已发生淋巴结转移患者血清中DC-SIGNR水平显著高于未发生淋巴结转移的患者和正常人。体外粘附实验及整体实验证明了肝窦内皮细胞DC-SIGNR的表达与结肠癌肝转移相关。