Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium.
Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium.
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DOI：
10.1158/0008-5472.can-10-3396
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Brantley-Sieders DM;Dunaway CM;Rao M;Short S;Hwang Y;Gao Y;Li D;Jiang A;Shyr Y;Wu JY;Chen J
众所周知，肿瘤源性促血管生成因子诱导新血管形成以促进肿瘤生长和恶性进展。然而，“血管分泌”信号传导的概念，其中由内皮细胞产生的信号引起不同于血管功能的肿瘤细胞反应，已被提出，但仍在研究中。在这里，我们报告，血管分泌因子分泌的内皮细胞调节肿瘤的生长和运动。我们发现，Slit 2，这是负调控内皮EphA 2受体，是这样一个肿瘤抑制血管分泌因子。Slit 2活性在EphA 2缺陷的内皮中升高。阻断Slit活性可恢复血管分泌诱导的肿瘤生长/运动性，而升高的Slit 2可损害生长/运动性。为了将我们的发现转化为人类癌症，我们分析了EphA 2和Slit 2在人类癌症中的表达。EphA 2表达与浸润性人导管癌样品的脉管系统中的Slit 2负相关。此外，对大型乳腺肿瘤数据集的分析显示，Slit 2与总体和无复发生存率呈正相关，为Slit 2在人类乳腺癌中的肿瘤抑制功能提供了临床验证。总之，这些数据支持一种新的临床相关机制，通过该机制EphA 2抑制内皮中的Slit 2表达，以通过阻断肿瘤抑制信号促进血管分泌介导的肿瘤生长和运动。
It is well known that tumor-derived pro-angiogenic factors induce neovascularization to facilitate tumor growth and malignant progression. However, the concept of `angiocrine' signaling, in which signals produced by endothelial cells elicit tumor cell responses distinct from vessel function has been proposed, yet remains under investigated. Here, we report that angiocrine factors secreted from endothelium regulate tumor growth and motility. We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. Slit2 activity is elevated in EphA2-deficient endothelium. Blocking Slit activity restored angiocrine-induced tumor growth/motility, whereas elevated Slit2 impaired growth/motility. To translate our findings to human cancer, we analyzed EphA2 and Slit2 expression in human cancer. EphA2 expression inversely correlated with Slit2 in the vasculature of invasive human ductal carcinoma samples. Moreover, analysis of large breast tumor datasets revealed that Slit2 correlated positively with overall and recurrence-free survival, providing clinical validation for the tumor suppressor function for Slit2 in human breast cancer. Together, these data support a novel, clinically relevant mechanism through which EphA2 represses Slit2 expression in endothelium to facilitate angiocrine-mediated tumor growth and motility by blocking a tumor suppressive signal.