Department of Molecular Genetics, University of Toronto, Donnelly Centre, 160 College Street, Toronto, ON, M5S 3E1, Canada.
Mol Biol Rep. 2020 Oct;47(10):8037-8048. doi: 10.1007/s11033-020-05767-y. Epub 2020 Sep 29.
The Eph (erythropoietin-producing human hepatocellular) receptors form the largest known subfamily of receptor tyrosine kinases. These receptors interact with membrane-bound ephrin ligands via direct cell-cell interactions resulting in bi-directional activation of signal pathways. Importantly, the Eph receptors play critical roles in embryonic tissue organization and homeostasis, and in the maintenance of adult processes such as long-term potentiation, angiogenesis, and stem cell differentiation. The Eph receptors also display properties of both tumor promoters and suppressors depending on the cellular context. Characterization of EphA2 receptor in regard to EphA2 dysregulation has revealed associations with various pathological processes, especially cancer. The analysis of various tumor types generally identify EphA2 receptor as overexpressed and/or mutated, and for certain types of cancers EphA2 is linked with poor prognosis and decreased patient survival. Thus, here we highlight the role of EphA2 in malignant tissues that are specific to cancer; these include glioblastoma multiforme, prostate cancer, ovarian and uterine cancers, gastric carcinoma, melanoma, and breast cancer. Due to its large extracellular domain, therapeutic targeting of EphA2 with monoclonal antibodies (mAbs), which may function as inhibitors of ligand activation or as molecular agonists, has been an oft-attempted strategy. Therefore, we review the most current mAb-based therapies against EphA2 expressing cancers currently in pre-clinical and/or clinical stages. Finally, we discuss the latest peptides and cyclical-peptides that function as selective agonists for EphA2 receptor.
Eph（促红细胞生成素产生的人肝细胞）受体形成了已知最大的受体酪氨酸激酶亚家族。这些受体通过直接的细胞-细胞相互作用与膜结合的 Ephrin 配体相互作用，导致信号通路的双向激活。重要的是，Eph 受体在胚胎组织组织和体内平衡以及成年过程（如长时程增强、血管生成和干细胞分化）的维持中发挥关键作用。Eph 受体还根据细胞环境显示出肿瘤促进剂和抑制剂的特性。EphA2 受体的特征在于 EphA2 失调，与各种病理过程，特别是癌症有关。对各种肿瘤类型的分析通常将 EphA2 受体鉴定为过度表达和/或突变，并且对于某些类型的癌症，EphA2 与预后不良和患者生存时间缩短有关。因此，在这里我们强调 EphA2 在特定于癌症的恶性组织中的作用；这些包括多形性胶质母细胞瘤、前列腺癌、卵巢和子宫癌、胃癌、黑色素瘤和乳腺癌。由于其大的细胞外结构域，用单克隆抗体（mAbs）对 EphA2 进行治疗性靶向，mAbs 可以作为配体激活的抑制剂或作为分子激动剂，这是一种经常尝试的策略。因此，我们综述了目前处于临床前和/或临床阶段的针对表达 EphA2 的癌症的最新型 mAb 疗法。最后，我们讨论了作为 EphA2 受体选择性激动剂的最新肽和环状肽。
