Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
Cancer Res. 2011 Feb 1;71(3):976-87. doi: 10.1158/0008-5472.CAN-10-3396. Epub 2010 Dec 8.
It is well known that tumor-derived proangiogenic 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 underinvestigated. 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 data sets 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.
众所周知，肿瘤来源的促血管生成因子诱导新生血管形成，以促进肿瘤生长和恶性进展。然而，“血管分泌”信号的概念已经被提出，即内皮细胞产生的信号引发不同于血管功能的肿瘤细胞反应，但仍未得到充分研究。在这里，我们报告内皮细胞分泌的血管分泌因子调节肿瘤生长和运动性。我们发现，Slit2 是一种受内皮 EphA2 受体负调控的肿瘤抑制性血管分泌因子。EphA2 缺陷的内皮细胞中 Slit2 活性升高。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 Slit2 则损害生长/运动性。为了将我们的发现转化为人类癌症，我们分析了 EphA2 和 Slit2 在人类癌症中的表达。EphA2 在侵袭性人类导管癌样本的血管中与 Slit2 的表达呈负相关。此外，对大型乳腺癌数据集的分析显示，Slit2 与总生存率和无复发生存率呈正相关，为 Slit2 在人类乳腺癌中的肿瘤抑制功能提供了临床验证。综上所述，这些数据支持了一种新的、具有临床相关性的机制，即 EphA2 通过阻断肿瘤抑制信号来抑制内皮细胞中 Slit2 的表达，从而促进血管分泌介导的肿瘤生长和运动性。
