Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer.
Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer.
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DOI：
10.1158/0008-5472.can-07-6603
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Pal, Soumitro
中科院分区：
文献类型：
--
作者：
Basu, Aninda;Contreras, Alan G.;Datta, Dipak;Flynn, Evelyn;Zeng, Liling;Cohen, Herbert T.;Briscoe, David M.;Pal, Soumitro
癌症是实体器官移植后日益严重的主要问题。在某种程度上，癌症风险的增加与免疫抑制剂的使用有关，尤其是钙调神经磷酸酶抑制剂。我们认为钙调神经磷酸酶抑制剂对血管内皮生长因子（VEGF）表达的影响会导致有利于肿瘤生长的血管生成环境。在这里，我们使用 786-0 人肾癌细胞来研究环孢素 (CsA) 对 VEGF 表达的影响。利用全长 VEGF 启动子-荧光素酶构建体，我们发现 CsA 通过 PKC 信号通路显着诱导 VEGF 转录激活，特别是涉及 PKC z 和 PKC δ 亚型。此外，通过免疫沉淀实验观察到，CsA 促进了 PKCδ 和 PKCδ 与转录因子 Sp1 的关联。使用启动子缺失构建体，我们发现 CsA 介导的 VEGF 转录主要依赖于 Sp1。此外，CsA 诱导和 PKC-Sp1 介导的 VEGF 转录激活被 pVHL 部分抑制。 CsA 还在体内促进人肾肿瘤的进展，其中 VEGF 过度表达。最后，为了评估 CsA 诱导的 VEGF 过表达对移植后肿瘤发展的体内意义，我们将 CT26 鼠癌细胞（已知形成血管生成肿瘤）注射到 MHC 完全不匹配的心脏移植小鼠体内。我们观察到治疗剂量的 CsA 增加了肿瘤大小、VEGF mRNA 表达，并且还增强了肿瘤血管生成。然而，共同施用阻断性抗 VEGF 抗体抑制了这种 CsA 介导的肿瘤生长。总的来说，这些发现将 PKC 介导的 VEGF 转录激活定义为 CsA 诱导的移植后癌症进展的关键组成部分。
Cancer is an increasing and major problem following solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of Cyclosporine (CsA) on VEGF expression. Utilizing a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the PKC signaling pathway, specifically involving PKCζ and PKCδ isoforms. Moreover, CsA promoted the association of PKCζ and PKCδ with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1-dependent. Furthermore, CsA-induced and PKC-Sp1-mediated VEGF transcriptional activation was partially inhibited by pVHL. CsA also promoted the progression of human renal tumors in vivo, where VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size, VEGF mRNA expression, and also enhanced tumor angiogenesis. However, co-administration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer.