Journal
TRANSLATIONAL ONCOLOGY
Volume 13, Issue 11, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.tranon.2020.100845
Keywords
HIF-1 alpha; partial EMT; Collective migration; Inflammatory breast cancer; Metastasis
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Funding
- Ramanujan Fellowship - Science and Engineering Research Board, Department of Science and Technology, Government of India [SB/S2/RJN-049/2018]
- Intramural Research Program of the NIH, National Cancer Institute
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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.
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