Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

Abstract

Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.

CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors

“…One of the conceivable effector mechanisms is the induction of epithelial-mesenchymal transformation (EMT), characterized by invasion and enhanced motility. 52 Indeed, abemaciclib triggered vimentin and N-cadherin expression, especially in Mlh1 −/− mice, but effectively suppressed Fpr2 , which is also involved in invasion and metastasis. 53 , 54 We, therefore, conclude a compensatory mechanism to counteract abemaciclib-driven EMT.…”

LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway

“…However, radioresistance is one of the main challenges for the applications of radiotherapy. At present, a series of studies have pointed out that radioresistance is related to DNA repair capacity, reduced apoptosis, cell cycle status, EMT and other factors, among which EMT is one of the most important factors affecting the sensitivity of cancer cells to ionizing radiation (IR) [39][40][41]. Studies have shown that IR-induced EMT accelerates the invasion, migration, and radioresistance of various tumor cell lines, including lung, liver, and breast cancer, after radiotherapy.…”

LPAR5 confers cancer cells radioresistance associated with EMT activation via ERK/ Snail pathway

“…However, radioresistance is one of the main challenges for the applications of radiotherapy. At present, a series of studies have pointed out that radioresistance is related to DNA repair capacity, reduced apoptosis, cell cycle status, EMT and other factors, among which EMT is one of the most important factors affecting the sensitivity of cancer cells to ionizing radiation (IR) [40][41][42]. Studies have shown that IR-induced EMT accelerates the invasion, migration, and radioresistance of various tumor cell lines including lung, liver, and breast cancer after radiotherapy.…”