Cross talk Initiated by Endothelial Cells Enhances Migration and Inhibits Anoikis of Squamous Cell Carcinoma Cells through STAT3/Akt/ERK Signaling
Cross talk Initiated by Endothelial Cells Enhances Migration and Inhibits Anoikis of Squamous Cell Carcinoma Cells through STAT3/Akt/ERK Signaling
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DOI：
10.1593/neo.09266
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Nor, Jacques E.
中科院分区：
文献类型：
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作者：
Neiva, Kathleen G.;Zhang, Zhaocheng;Nor, Jacques E.
众所周知，癌细胞分泌血管生成因子来招募和维持肿瘤血管网络。然而，内皮细胞分泌因子对肿瘤细胞表型和行为的影响知之甚少。本研究的假设是内皮细胞启动信号通路，增强肿瘤细胞的存活和迁移。在这里，我们观察到来自原代人皮肤微血管内皮细胞的可溶性介质诱导头颈部鳞状细胞癌（OSCC-3, UM-SCC-1, UM-SCC-17B, UM-SCC-74A）细胞信号传导和转录激活因子3 (STAT3)， Akt和细胞外信号调节激酶（ERK）的磷酸化。基因表达分析表明，白细胞介素-6 （IL-6）、白细胞介素-8 （CXCL8）和表皮生长因子（EGF）在与HNSCC共培养的内皮细胞中表达上调。通过基因沉默或中和抗体阻断内皮细胞来源的IL-6、CXCL8或EGF，分别抑制肿瘤细胞中STAT3、Akt和ERK的磷酸化。值得注意的是，内皮细胞激活STAT3、Akt和ERK增强了肿瘤细胞的迁移，抑制了肿瘤细胞的凋亡。我们之前已经证明，Bcl-2在HNSCC患者的肿瘤微血管中表达上调。在这里，我们观察到Bcl-2信号诱导IL-6、CXCL8和EGF的表达，为肿瘤相关内皮细胞中这些细胞因子的上调提供了一种机制。本研究扩大了内皮细胞在肿瘤细胞病理生物学中的作用。它揭示了一个新的机制，其中内皮细胞作为分子串扰的启动器，增强肿瘤细胞的生存和迁移。
It is well known that cancer cells secrete angiogenic factors to recruit and sustain tumor vascular networks. However, little is known about the effect of endothelial cell-secreted factors on the phenotype and behavior of tumor cells. The hypothesis underlying this study is that endothelial cells initiate signaling pathways that enhance tumor cell survival and migration. Here, we observed that soluble mediators from primary human dermal microvascular endothelial cells induce phosphorylation of signal transducer and activator of transcription 3 (STAT3), Akt, and extracellular signal-regulated kinase (ERK) in a panel of head and neck squamous cell carcinoma (HNSCC) cells (OSCC-3, UM-SCC-1, UM-SCC-17B, UM-SCC-74A). Gene expression analysis demonstrated that interleukin-6 (IL-6), interleukin-8 (CXCL8), and epidermal growth factor (EGF) are upregulated in endothelial cells cocultured with HNSCC. Blockade of endothelial cell-derived IL-6, CXCL8, or EGF by gene silencing or neutralizing antibodies inhibited phosphorylation of STAT3, Akt, and ERK in tumor cells, respectively. Notably, activation of STAT3, Akt, and ERK by endothelial cells enhanced migration and inhibited anoikis of tumor cells. We have previously demonstrated that Bcl-2 is upregulated in tumor microvessels in patients with HNSCC. Here, we observed that Bcl-2 signaling induces expression of IL-6, CXCL8, and EGF, providing a mechanism for the upregulation of these cytokines in tumor-associated endothelial cells. This study expands the contribution of endothelial cells to the pathobiology of tumor cells. It unveils a new mechanism in which endothelial cells function as initiators of molecular crosstalks that enhance survival and migration of tumor cells.