Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth
Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth
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DOI：
10.1158/0008-5472.can-07-1497
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Nor, Jacques E.
中科院分区：
文献类型：
--
作者：
Kaneko, Tomoatsu;Zhang, Zhaocheng;Nor, Jacques E.
目前对内皮细胞和癌细胞之间相互作用的理解基本上是基于这样的概念，即内皮细胞对源自肿瘤细胞的分化和存活信号有反应。尽管肿瘤细胞分泌的因子对血管生成的影响已得到充分证实，但关于内皮细胞分泌的因子对肿瘤细胞基因表达和肿瘤进展的影响知之甚少。在这里，我们发现，bcl-2基因表达显着较高的肿瘤相关的内皮细胞的患者与头颈部鳞状细胞癌（HNSCC）相比，从正常的口腔粘膜的内皮细胞。Bcl-2通过信号转导和转录激活因子3（STAT 3）介导的途径诱导新生血管内皮细胞表达血管内皮生长因子（VEGF）。内皮细胞衍生的VEGF通过VEGFR 1发出信号并诱导HNSCC细胞中Bcl-2和促血管生成趋化因子CXCL 1和CXCL 8的表达。值得注意的是，用RNA干扰抑制新生血管内皮细胞中Bcl-2的表达下调了HNSCC细胞中Bcl-2、CXCL 8和CXCL 1的表达，并且足以抑制免疫缺陷小鼠中异种移植的HNSCC的生长并降低其微血管密度。总之，这些结果表明，Bcl-2是新生血管内皮细胞和肿瘤细胞之间相互作用的协调者，这对肿瘤生长有直接影响。这项工作确定了Bcl-2在癌症生物学中的新功能，超出了其在细胞存活中的经典作用。
The current understanding of the interaction between the endothelium and cancer cells is fundamentally based on the concept that endothelial cells are responsive to differentiation and survival signals originating from the tumor cells. Whereas the effect of tumor cell-secreted factors on angiogenesis is well established, little is known about the effect of factors secreted by endothelial cells on tumor cell gene expression and tumor progression. Here, we show that bcl-2 gene expression is significantly higher in the tumor-associated endothelial cells of patients with head and neck squamous cell carcinomas (HNSCC) as compared with endothelial cells from the normal oral mucosa. Bcl-2 induces vascular endothelial growth factor (VEGF) expression in neovascular endothelial cells through a signal transducer and activator of transcription 3 (STAT3)mediated pathway. Endothelial cell-derived VEGF signals through VEGFR1 and induces expression of Bcl-2 and the proangiogenic chemokines CXCL1 and CXCL8 in HNSCC cells. Notably, inhibition of Bcl-2 expression in neovascular endothelial cells with RNA interference down-regulates expression of Bcl-2, CXCL8, and CXCL1 in HNSCC cells, and is sufficient to inhibit growth and decrease the microvessel density of xenografted HNSCC in immunodeficient mice. Together, these results show that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct effect on tumor growth. This work identifies a new function for Bcl-2 in cancer biology that is beyond its classic role in cell survival.