In Vivo Luminescent Imaging of Cyclosporin A–Mediated Cancer Progression in Rats
In Vivo Luminescent Imaging of Cyclosporin A–Mediated Cancer Progression in Rats
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DOI：
10.1097/01.tp.0000209448.50238.de
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发表时间：
2006-06
期刊：
影响因子：
6.2
通讯作者：
I. Ohsawa;T. Murakami;S. Uemoto;E. Kobayashi
中科院分区：
文献类型：
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作者：
I. Ohsawa;T. Murakami;S. Uemoto;E. Kobayashi
背景。接受器官移植的免疫抑制个体初始癌症复发的风险增加，尽管免疫抑制治疗如何增加早期癌症转移尚不清楚。方法。在免疫抑制剂环孢素A （cyclosporin A, CsA）作用下，用体内发光技术观察了表达荧光素酶的大鼠转移性结肠癌细胞（luc-RCN-H4）静脉注射到同基因和异基因大鼠肝脏的转移命运。对于潜在的肿瘤进展因素，我们利用趋化因子受体和转化生长因子(TGF) -β1特异性的信号抑制剂来评估它们在早期转移中的作用。结果。肝内注射luc-RCN-H4细胞的F344大鼠，在没有CsA的情况下，在接种后长达60天的时间内，并不总是出现肿瘤的形成，并且处于休眠状态。然而，CsA在2周内将早期luc-RCN-H4细胞从肝脏的休眠中释放出来，几乎100%，并优先促进转移到淋巴结（约40%）。类似的传播甚至发生在较小的组织相容性复合体不同的宿主中。作为肿瘤进展因子，RCN-H4细胞异常表达趋化因子受体CXCR4和CCR7。趋化因子受体（CXC） r4特异性拮抗剂AMD3100可降低缺血性肝脏大鼠luc-RCN-H4细胞的早期转移（P<0.05），但CsA处理未增强早期粘附。使用CsA能够促进TGF-β1的表达，随后TGF-β介导的随机迁移被体外特异性信号抑制剂SB431542阻断。结论。即使在CsA介导的免疫抑制下，癌细胞的趋化因子受体表达也与早期嗜器官播散有关，相反，CsA通过TGF-β1的表达促进肿瘤粘附后的晚期进展。
Background. Immunosuppressed individuals undergoing organ transplantation are at increased risk of recurrences of initial cancers, although how immunosuppressive therapy increases early cancer metastasis remains unclear. Methods. The metastatic fate of luciferase-expressing rat metastatic colon cancer cells (luc-RCN-H4) injected intravenously into the liver of syngeneic and allogeneic rats was examined in the presence of the immunosuppressant cyclosporin A (CsA) by in vivo luminescent technique. With respect to potential tumor-progressing factors, contribution of chemokine receptors and transforming growth factor (TGF)–β1 to early metastasis was evaluated using their specific signaling inhibitors. Results. F344 rats injected in the liver with luc-RCN-H4 cells did not always exhibit the formation of tumors and showed a dormant state as long as 60 days after inoculation without CsA. However, CsA released early luc-RCN-H4 cells from dormancy within 2 weeks at nearly 100% in liver and preferentially promoted metastasis to the lymph nodes (approximately 40%). A similar dissemination occurred even in minor histocompatibility complex–disparate hosts. As a tumor-progressing factor, RCN-H4 cells aberrantly expressed chemokine receptors CXCR4 and CCR7. The chemokine receptor (CXC) R4–specific antagonist AMD3100 decreased early metastasis of luc-RCN-H4 cells in rats with ischemic liver conditions (P<0.05), but CsA treatment did not enhance early adhesion. Use of CsA was able to facilitate TGF-β1 expression and the subsequent TGF-β–mediated random migration was blocked by the use of the specific signaling inhibitor SB431542 in vitro. Conclusions. Whereas the chemokine receptor expression by cancer cells is implicated with early organotropic dissemination even under CsA-mediated immune suppression, rather, CsA enhances the late-phase progression after tumor adhesion through TGF-β1 expression.