Non-invasive in vivo analysis of early metastatic processes

为了阐明肿瘤转移的早期阶段，我们发展了一种非侵入性的方法，利用正电子发射计算机断层扫描来确定转移的肿瘤细胞的转运。我们已经观察到转移潜能和转移细胞在靶组织中聚集之间的相关性。在本研究中，我们首先阐明了选择素在肿瘤细胞早期转运中的作用。我们还观察到选择素的配体硫脂可以抑制肿瘤转移。其次，我们利用整合素转基因细胞研究了整合素在肿瘤转移过程中的作用。将整合素链α-2、α-3、α-4、α-6、α-9和av导入CHO细胞。PET分析表明，整合素αvβ1和α4β1促进了肿瘤细胞在靶组织中的聚集。此外，还为整合素avb3参与肝转移提供了有用的证据。第三，我们研究了免疫监测在抑制肿瘤转移中的作用。如果在实验性转移模型中注射少量肿瘤细胞，由于免疫防御系统将肿瘤细胞从靶点移除，因此没有观察到转移。事实上，即使在注射少量肿瘤细胞的情况下，经过耗尽巨噬细胞预处理的小鼠也观察到了转移。在这种情况下，肿瘤细胞从靶组织中的去除通过PET的测定而被抑制。因此，我们清楚地证明了巨噬细胞在转移过程的早期阶段对抑制转移起着重要的作用。

For elucidating early phase of tumor metastasis, we developed non-invasive method to determine metastatic tumor cell trafficking by PET. We have already observed the correlation between metastatic potential and metastatic cell accumulation in a target tissues. In the present study, we firstly clarified the involvement of selectins in the early tumor cell trafficking. We also observed sulfatide, a ligand for selectins, suppressed tumor metastasis. Secondly, we investigated the role of integrins in tumor metastatic process by using integrin transfectants. CHO cells were transfected with a chain of integrins, I.e., α2, α3, α4, α6, α9 and av. PET analysis indicated that integrin αvβ1 and α4β1 enhanced tumor cell accumulation in a target tissue. Furthermore, useful evidences were obtained about involvement of integrin avb3 in liver metastasis. Thirdly, we investigated the role of immune surveillance on the suppression of tumor metastasis. If small number of tumor cells were injected in experimental metastatic model, metastasis was not observed due to removal of tumor cells from target by immune defense system. In fact, metastasis was observed in mice which were pretreated for the depletion of macrophages even when small number of tumor cells were injected. And, in this case, removal of tumor cells from target tissues was suppressed by the determination of PET. Therefore, we clearly demonstrated that macrophage play an important role for suppressing metastasis in the early stage of metastatic processes.