Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Sep 8;15(1):129.
doi: 10.1186/s13045-022-01347-8.

The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis

Yuhe Huang #  1 , Weiqi Hong #  1 , Xiawei Wei  2
Affiliations
Review

The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis

Yuhe Huang et al. J Hematol Oncol. .

Abstract

Epithelial-mesenchymal transition (EMT) is an essential process in normal embryonic development and tissue regeneration. However, aberrant reactivation of EMT is associated with malignant properties of tumor cells during cancer progression and metastasis, including promoted migration and invasiveness, increased tumor stemness, and enhanced resistance to chemotherapy and immunotherapy. EMT is tightly regulated by a complex network which is orchestrated with several intrinsic and extrinsic factors, including multiple transcription factors, post-translational control, epigenetic modifications, and noncoding RNA-mediated regulation. In this review, we described the molecular mechanisms, signaling pathways, and the stages of tumorigenesis involved in the EMT process and discussed the dynamic non-binary process of EMT and its role in tumor metastasis. Finally, we summarized the challenges of chemotherapy and immunotherapy in EMT and proposed strategies for tumor therapy targeting EMT.

Keywords: Circulating tumor cells; Epithelial–mesenchymal transition; Metastasis; Tumor stemness.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Changes in the cytoskeleton and properties between epithelial and mesenchymal during the EMT process. Epithelial cells exhibit apical–basal polarity with cell–cell and cell–matrix attachment. Three multi-protein complexes (Scribble complex, Crumbs complex, and PAR complex) interact to regulate the spatial separation of apical and basal structural domains together to establish cell polarity. Intercellular adhesion and communication are provided by intercellular junctions and maintain tissue stability and integrity. Tight junctions (TJs) form strips around cells that help separate apical and basal regions and form sealed spaces between adjacent cells, preventing the flow of material. Adherens junctions (AJs) are located below TJs, surround cells, and provide intercellular adhesion, but they are relatively permeable. Gap junctions are gaps located on the outer surface of cells and are hydrophilic ion transport channels between adjacent cells. Bridging granules provide sites of cell adhesion and intermediate filament binding to disklike structures located on the outer surface of the cell. The occurrence of EMT leads to the dissolution of intercellular junctions and loss of cell polarity allowing cytoskeletal rearrangements that alter the shape of the cell, transforming the cell into a mesenchymal phenotype and promoting cell motility and invasion. Based on a synthesis of the literature, we conclude that as the EMT progresses, the cell characteristics are changed, including reduces in drug sensitivity, proliferation, and response to apoptosis signals and increases in drug efflux, invasion, and immune evasion. The partial EMT with intermediate state has properties of enhanced stemness and tumor initiation capacity, and stronger ability to adapt to the changes in immune microenvironment and metabolism
Fig. 2
Fig. 2
Regulatory network of EMT. EMT is tightly regulated by a complex network which is composed of several factors, including transcription regulation, posttranslational control, epigenetic modifications, and noncoding RNA-mediated regulation. Snail, Twist, Zeb, and other EMT-related transcription factors are regulated by multiple signaling pathways at post-transcriptional and posttranslational level and orchestrate with other epigenetic factors to regulate downstream transcriptional networks, further mediating the biological effects of EMT
Fig. 3
Fig. 3
Role of EMT in the tumor metastasis. Tumor cells in situ are induced by EMT to initiate the metastatic cascade process. Intermediate state and mesenchymal stem cells (MCSCs) lose intercellular junctions, detach from tumor tissue, and invade surrounding tissues. Metastatic tumor cells enter the circulation through the endothelial barrier by active or passive trans-endothelial migration (TEM), invading the surrounding mesenchyme and disrupting endothelial junctions. After entering the circulation, single or clustered circulating tumor cells (CTCs) can bind to coagulation factors on platelets by expressing thrombin, forming a unique immune mechanism that protects metastatic cells from immune escape. Neutrophils are also recruited and bind to CTCs to promote tumor cells survival and proliferation. CTCs move slowly, roll along the endothelium, and then arrest. MCSCs anchor with endothelial cells for extravasation and then colonize distal organs via the MET process
Fig. 4
Fig. 4
Features of partial EMT. The partial EMT as an intermediate state is not only phenotypically different from the epithelial and mesenchymal states, but also has greatly altered cellular properties. There is a synthesis of the literature; it has intermediate polarity and loose intercellular junctions compared to the two and has metastatic potential, but the response to treatment is not clear. In addition, partial EMT has plasticity and can differentiate into different cells and move in clusters within the body
Fig. 5
Fig. 5
Therapeutic strategies for targeting EMT. EMT may be resistant to various treatments such as chemotherapy and radiotherapy, and the activation of EMT after treatment leads to further acceleration of the disease process by mechanisms including increased proliferation, decreased apoptosis, immunosuppression, stemness, and increased metastasis. There are three main strategies for targeted EMT treatment: I) inhibiting tumorigenesis by blocking upstream signaling pathways, II) targeting the molecular drivers of EMT, and III) targeting mesenchymal cells and outer stroma or inhibiting the MET process
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–273. doi: 10.1038/nrc2620. - DOI - PubMed
    1. Gros J, Tabin CJ. Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition. Science. 2014;343:1253–1256. doi: 10.1126/science.1248228. - DOI - PMC - PubMed
    1. Correa-Costa M, Andrade-Oliveira V, Braga TT, Castoldi A, Aguiar CF, Origassa CS, Rodas AC, Hiyane MI, Malheiros DM, Rios FJ, et al. Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis. Lab Invest. 2014;94:455–466. doi: 10.1038/labinvest.2013.155. - DOI - PubMed
    1. Ruscetti M, Quach B, Dadashian EL, Mulholland DJ, Wu H. Tracking and functional characterization of epithelial-mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Can Res. 2015;75:2749–2759. doi: 10.1158/0008-5472.CAN-14-3476. - DOI - PMC - PubMed
    1. Chen T, You Y, Jiang H, Wang ZZ. Epithelial-mesenchymal transition (EMT): a biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol. 2017;232:3261–3272. doi: 10.1002/jcp.25797. - DOI - PMC - PubMed

Publication types

LinkOut - more resources