Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes
Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes
复制标题
DOI：
10.1038/onc.2010.518
复制
发表时间：
2011-03-01
期刊：
影响因子：
8
通讯作者：
Siegel, P. M.
中科院分区：
文献类型：
--
作者：
Tabaries, S.;Dong, Z.;Siegel, P. M.
在乳腺癌患者中，肝脏是第三个最常见的转移部位。我们使用4T1乳腺癌细胞进行体内筛选，以鉴定与肝转移表型相关的基因。与许多紧密连接蛋白的缺失同时，我们观察到claudin-2过表达，特别是在肝脏侵袭性乳腺癌细胞中。我们进一步证明，claudin-2对于4T1乳腺癌细胞在肝脏中定植和生长的能力是必要和充分的。肝侵袭性乳腺癌细胞显示出claudin-2介导的细胞外基质（ECM）成分粘附能力的增加，如纤维连接蛋白和IV型胶原。Claudin-2通过增加乳腺癌细胞中α (2) β(1)-和α (5) β(1)-整合素复合物的细胞表面表达来促进这些细胞/基质相互作用。事实上，claudin-2介导的对纤维连接蛋白和IV型胶原的粘附可以被分别靶向α (5) β(1)和α (2) β(1)复合物的中和抗体阻断。免疫组织化学分析显示，虽然claudin-2在原发性人类乳腺癌中表达较弱，但在迄今为止检查的所有肝转移样本中都很容易检测到。总之，这些结果揭示了claudin-2在促进乳腺癌粘附到ECM中的新作用，并确定了其在乳腺癌转移到肝脏中的重要性。中华肿瘤杂志（2011）30 (3):1318-1328；doi: 10.1038 / onc.2010.518;2010年11月15日在线发布
The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of alpha(2)beta(1)- and alpha(5)beta(1)-integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target alpha(5)beta(1) and alpha(2)beta(1) complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver. Oncogene (2011) 30, 1318-1328; doi:10.1038/onc.2010.518; published online 15 November 2010