Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis
Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis
复制标题
DOI：
10.1016/j.tranon.2020.100845
复制
发表时间：
2020-11-01
影响因子：
5
通讯作者：
Balamurugan, Kuppusamy
中科院分区：
文献类型：
--
作者：
Saxena, Kritika;Jolly, Mohit Kumar;Balamurugan, Kuppusamy
上皮-间充质转化(EMT)是一种细胞生物学过程，参与原发癌细胞向继发部位的迁移，促进转移。此外，EMT还具有茎性、抗药性和免疫逃避等特性，有助于在遥远的地点成功定居。EMT不是一个二元过程；最近的证据表明，与接受完全EMT的细胞相比，部分EMT或E/M混合表型(S)的细胞可以具有更强的干性和耐药性。此外，部分EMT能够使细胞集体迁移为循环中的肿瘤细胞或栓子，进一步证实E/M混合表型的细胞可能是最适合转移的细胞。在这里，我们回顾了混合E/M表型的机制和意义，包括已报道的与缺氧的关联。缺氧诱导的HIF-1α活化可驱动EMT。此外，与急性或慢性低氧相比，周期性低氧显示出最高水平的活性HIF-1α，并且可以在更大程度上增强癌症的侵袭性，包括丰富部分EMT表型。我们还讨论了低氧、部分EMT和集体细胞迁移是如何影响转移的，并呼吁更好地了解这些机制之间的相互联系。我们讨论了已知的低氧、杂交EMT和集体细胞迁移的调节因素，并强调了连接这三个轴需要填补的空白，这将增加我们对转移动力学的理解，并有助于更有效地控制转移。
Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the 'fittest' for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1 alpha can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1 alpha and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.