Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage.
Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage.
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DOI：
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
C. Kari;T. Chan;Marlene Rocha de Quadros;U. Rodeck
中科院分区：
文献类型：
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作者：
C. Kari;T. Chan;Marlene Rocha de Quadros;U. Rodeck
表皮生长因子受体（EGFR）的异常激活在肿瘤中经常观察到，特别是在上皮源性肿瘤中。用EGFR拮抗剂治疗这类肿瘤的尝试已经取得了显著的初步成功，特别是当EGFR拮抗剂与化疗或电离辐射联合使用时。考虑到EGFR在正常上皮组织中几乎无处不在的表达，这些临床试验也揭示了与EGFR阻断相关的不良副作用的惊人低率。这篇综述强调了EGFR激活的抗凋亡作用，因为它们与EGFR阻断的治疗效果有关。我们介绍了通过EGFR激活控制细胞存活是有条件的概念，因为它限制了肿瘤细胞的存活，而不限制正常上皮细胞的存活。具体来说，正常上皮细胞具有完整的生理细胞-细胞接触和细胞-基质相互作用，从而减少了它们对EGFR提供的生存信号的依赖。相比之下，恶性肿瘤细胞面临的细胞-基质接触不足严重依赖于EGFR激活存活，使其更容易受到EGFR阻断诱导的凋亡。EGFR和细胞外基质/细胞粘附受体对细胞存活的冗余控制在一定程度上是通过共享的信号转导途径实现的，这些信号转导途径控制着凋亡调节因子Bcl-2家族成员的表达和激活状态。
Aberrant activation of the epidermal growth factor receptor (EGFR) is frequently observed in neoplasia,notably in tumors of epithelial origin. Attempts to treat such tumors with EGFR antagonists have met with remarkable initial successes, particularly when EGFR antagonists were used in combination with chemotherapy or ionizing radiation. Considering the almost ubiquitous expression of the EGFR in normal epithelial tissues, these clinical trials also revealed a surprisingly low rate of adverse side effects associated with EGFR blockade. This review highlights antiapoptotic effects of EGFR activation as they relate to therapeutic efficacy of EGFR blockade. We introduce the concept that control of cell survival through EGFR activation is conditional in the sense that it is rate limiting to tumor cell survival but not to survival of normal epithelial cells. Specifically, normal epithelial cells are provided with a full complement of physiological cell-cell contacts and cell-matrix interactions that lessen their dependence on survival signals provided by the EGFR. By contrast, malignant tumor cells faced with inadequate cell-matrix contacts critically depend on EGFR activation for survival, rendering them more susceptible to apoptosis induction by EGFR blockade. Redundant control of cell survival by the EGFR and extracellular matrix/cell adhesion receptors is enabled, in part, by shared signal transduction pathways that control expression and activation states of members of the Bcl-2 family of apoptosis regulators.