Cancer Gene Therapy with Adenovirally or Immunogene TM4SF

在跨膜4超家族（TM4SF）中，至少有19个成员在各种组织中表达，MRP-1/CD9和KAI1/CD82因参与肿瘤进展和转移而闻名。MPR-1/CD9与其他TM4SF成员CD81和ME491/CD63相关。此外，CD81和KAI1/CD82通过相互结合以及与整合素α3 α4 α6和β6结合形成多分子膜复合物。MRP-1/CD9也是如此。因此，TM4SF成员可能在大的多组分复合物中起作用，并作为受体相关离子通道，或可能通过质膜转导信号并调节细胞的激活、发育、增殖和运动。此外，我们可以通过评估MRP-1/CD9和KAI1/CD82的表达，更准确地预测肺癌、乳腺癌、食管癌和胰腺癌患者的预后。考虑到恶性肿瘤的进展，KAI1/CD82的减少可能先于MRP-1/CD9的减少。在这些肿瘤的早期，肿瘤抑制基因p53或RB发生突变或缺失，因此KAI1/CD82基因可能处于下降状态。在最后阶段，MRP-1/CD9的水平可能由于启动子的甲基化而降低，因此MRP-1/CD9的正常功能可能丧失。因此，恶性细胞最终获得转移潜能。因此，采用腺病毒介导的MRP-1/CD9和KAI1/CD82编码基因转移联合治疗Balb/c裸鼠黑色素瘤BL6细胞系转移。静脉注射表达MRP-1/CD9的腺病毒载体（rAd-MRP-1/CD9）可使肺转移的数量减少75%。相反，静脉注射表达KAI1/CD82的腺病毒载体（rAd-KAI1/CD82）导致70%的减少。此外，MRP-1/CD9和KAI1/CD82的传递对肺转移的抑制作用最强（92%）。此外，同时使用rAd-MRP-1/CD9和rAd-KAI1/CD82治疗的小鼠的总生存期比其他任何组都要长（p<0.0001）。这些结果支持MRP-1/CD9和KAI1/CD82通过基因转移作为预防转移和延长生存期的治疗策略，并支持基因转移在临床相关环境中的可行性。少

Among the transmembrane 4 superfamily (TM4SF), which includes at least 19 members that are expressed on various tissues, MRP-1/CD9 and KAI1/CD82 are noted for their involvement in tumor progression and metastasis. MPR-1/CD9 is associated with other TM4SF members, CD81 and ME491/CD63. In addition, CD81 and KAI1/CD82 formed multimolecular membrane complexes by associating with each other and with integrin α3 α4 α6 and β6. This is true of MRP-1/CD9. Therefore, TM4SF members may act in large multicomponent complexes, and serve as receptor-associated ion channels or may act to transduce of signals across the plasma membrane and to regulate cell activation, development, proliferation, and motility. Moreover, we can predict the prognosis of patients with lung cancers, breast cancers, esophageal cancers and pancreas cancers more precisely by evaluating the expression of both MRP-1/CD9 and KAI1/CD82. Considering the progression of malignant tumors, the reduction in KAI1/CD82 might precede the r … More eduction in MRP-1/CD9. The tumor suppressor genes, p53 or RB had been mutated or deleted during the early stage of these tumors and thus the KAI1/CD82 gene might be in decline. During the last stage, the levels of MRP-1/CD9 might be diminishing due to methylation of the promoter and therefore the normal functions of MRP-1/CD9 could be lost. Thus, the malignant cells could finally acquire metastatic potential. Therefore, combination therapy involving the adenovirus-mediated transfer of the genes encoding MRP-1/CD9 and KAI1/CD82 was used to treat the metastases from the mouse melanoma BL6 cell line in Balb/c nude mice. The intravenous injection of an adenovirus vector (rAd-MRP-1/CD9) expressing MRP-1/CD9 resulted in an 75% reduction in the number of pulmonary metastases. In contrast, intravenous injection of an adenovirus vector (rAd-KAI1/CD82) expressing KAI1/CD82 resulted in a 70% reduction. Furthermore, the delivery of both MRP-1/CD9 plus KAI1/CD82 resulted in the strongest suppression against pulmonary metastasis (92%). Moreover, the overall survival of mice treated with both rAd-MRP-1/CD9 and rAd-KAI1/CD82 was much longer than any of the other groups (p<0.0001). These results support the expression of MRP-1/CD9 and KAI1/CD82 through gene transfer as a therapeutic strategy for preventing metastases and for prolonging survival, and support the feasibility of gene transfer in a clinically relevant setting. Less