Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor
Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor
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DOI：
10.1016/s0002-9440(10)63390-1
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Kramer, RH
中科院分区：
文献类型：
--
作者：
Shen, XD;Kramer, RH
鳞状上皮细胞的存活和生长需要整合素-基质相互作用产生的信号。在转化为鳞状细胞癌后，细胞仍然对凋亡诱导的失巢凋亡敏感，但在基质缺陷的肿瘤细胞聚集体中，这些细胞能够在基底层上存活和增殖。它们的存活是通过我们称之为滑膜凋亡的过程来增强的，在这个过程中，相邻细胞之间的连接粘连产生特定的下游存活信号。在这里，我们表明，在鳞状细胞癌细胞，E-钙粘蛋白介导的细胞接触特异性诱导表皮生长因子受体（EGFR）的激活。EGFR激活反过来触发ERK/MAPK信号传导模块，导致抗凋亡Bcl-2的升高。在细胞间粘附后，粘附连接的形成触发E-钙粘蛋白-EGFR复合物的形成，与EGFR反式激活相关。对显性阴性EGFR突变体的过程分析表明，EGFR的激活是配体非依赖性的。我们的数据暗示细胞-细胞粘附诱导的EGFR活化是一种协同机制，产生代偿性生存信号，保护恶性细胞免于凋亡诱导的死亡。
The survival and growth of squamous epithelial cells require signals generated by integrin-matrix interactions. After conversion to squamous cell carcinoma, the cells remain sensitive to detachment-induced anoikis, yet in tumor cell aggregates, which are matrix-deficient, these cells are capable of suprabasal survival and proliferation. Their survival is enhanced through a process we call synoikis, whereby junctional adhesions between neighboring cells generate specific downstream survival signals. Here we show that in squamous cell carcinoma cells, E-cadherin-mediated cell-cell contacts specifically induce activation of epidermal growth factor receptor (EGFR). EGFR activation in turn triggers the ERK/MAPK signaling module, leading to elevation of anti-apoptotic Bcl-2. After intercellular adhesion, formation of adherens junctions triggers the formation of E-cadherin-EGFR complexes, correlating with EGFR transactivation. Analysis of the process with a dominant-negative EGFR mutant indicated that activation of EGFR is ligand-independent. Our data implicate cell-cell adhesion-induced activation of EGFR as a cooperative mechanism that generates compensatory survival signaling, protecting malignant cells from detachment-induced death.