Imanishi Yorihisha, Hu Bo, Jarzynka Michael J, Guo Ping, Elishaev Esther, Bar-Joseph Ifat, Cheng Shi-Yuan
Cancer Institute, Research Pavilion at the Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Cancer Res. 2007 May 1;67(9):4254-63. doi: 10.1158/0008-5472.CAN-06-4100.
Acquisition of a metastatic phenotype by breast cancer cells includes alternations of multigenic programs that permit tumor cells to metastasize to distant organs. Here, we report that angiopoietin-2 (Ang2), a known growth factor, is capable of promoting breast cancer cell invasion leading to metastasis. Analysis of 185 primary human breast cancer specimens that include 97 tumors showing lymph node and/or distant metastasis reveals a significant correlation between the expression of Ang2 and E-cadherin, Snail, metastatic potential, tumor grade, and lymph-vascular invasion during breast cancer progression. Using a xenograft model, we show that overexpression of Ang2 in poorly metastatic MCF-7 breast cancer cells suppresses expression of E-cadherin and induces Snail expression and phosphorylation of Akt and glycogen synthase kinase-3beta (GSK-3beta) promoting metastasis to the lymph nodes and lung. In cell culture, Ang2 promotes cell migration and invasion in Tie2-deficient breast cancer cells through the alpha(5)beta(1) integrin/integrin-linked kinase (ILK)/Akt, GSK-3beta/Snail/E-cadherin signaling pathway. Inhibition of ILK and the alpha(5)beta(1) integrin abrogates Ang2 modulation of Akt, GSK-3beta, Snail, and E-cadherin and Ang2-stimulated breast cancer cell migration and invasion. Together, these results underscore the significant contribution of Ang2 in cancer progression, not only by stimulating angiogenesis but also by promoting metastasis, and provide a mechanism by which breast cancer cells acquire an enhanced invasive phenotype contributing to metastasis.
乳腺癌细胞获得转移表型包括多基因程序的改变，这些改变使肿瘤细胞能够转移至远处器官。在此，我们报告血管生成素-2（Ang2），一种已知的生长因子，能够促进乳腺癌细胞侵袭并导致转移。对185例原发性人类乳腺癌标本（包括97例出现淋巴结和/或远处转移的肿瘤）进行分析，结果显示在乳腺癌进展过程中，Ang2的表达与E-钙黏蛋白、Snail、转移潜能、肿瘤分级以及淋巴管浸润之间存在显著相关性。利用异种移植模型，我们发现低转移的MCF-7乳腺癌细胞中Ang2的过表达会抑制E-钙黏蛋白的表达，并诱导Snail表达以及Akt和糖原合酶激酶-3β（GSK-3β）的磷酸化，从而促进向淋巴结和肺部的转移。在细胞培养中，Ang2通过α(5)β(1)整合素/整合素连接激酶（ILK）/Akt、GSK-3β/Snail/E-钙黏蛋白信号通路促进Tie2缺陷型乳腺癌细胞的迁移和侵袭。抑制ILK和α(5)β(1)整合素可消除Ang2对Akt、GSK-3β、Snail和E-钙黏蛋白的调节作用以及Ang2刺激的乳腺癌细胞迁移和侵袭。这些结果共同强调了Ang2在癌症进展中的重要作用，不仅通过刺激血管生成，还通过促进转移，并且提供了一种乳腺癌细胞获得增强的侵袭表型从而促进转移的机制。
