The culprit of tumor spread-EMT

 

Background

Epithelial-mesenchymal transition (EMT) is a kind of polar epithelial cells that lose the basement membrane’s attachment polarity under the action of a number of factors, and the ability to tightly connect and adhere to each other is converted into invasive and Reversible Processes of Migrating Mesenchymal Cells In 1982, Greenburg and Hay first proposed EMT with the characteristics of embryogenesis. Since then, with the deeper and deeper observation of human tumors and experimental animal models by researchers, EMT’s research in organ development, tissue damage repair, and tumor recurrence and metastasis has gradually deepened. EMT of epithelial cells are as follows: ① -the cell morphology changes from cobblestone-like to spindle-like, cell polarity is lost, skeleton changes, and infiltration and migration capabilities are enhanced; ② molecular marker changes-epithelialized molecular marker E -The expression level of molecules such as cadherin decreases, and the expression level of interstitial molecular marker vimentin increases. Let ’s take you into EMT to find out!

1.Classification and inducement of EMT

EMT is mainly divided into the following three types, as shown in Figure 1:

>>>> 1) EMT during biological development:

During early embryonic development, some epithelial cells complete the development of tissues or organs through EMT and its inverse response, namely mesenchymal-epithelial transitions (MET), such as the formation of gastrointestinal embryos, heart valves, and neural crests ;

>>>> 2) EMT in the process of fibrosis:

In the process of repairing tissue damage, repair tissue or organ damage caused by trauma or inflammatory response by generating fibroblasts;

>>>> 3) EMT in tumor migration:

Involved in the genesis and development of tumors, epithelial-derived tumor cells have the ability to move and invade after EMT, and then metastasize to the distal end through blood and lymph circulation.

Studies have shown that a variety of signals can trigger the EMT process, such as growth factors, interactions between tumor cells and interstitial cells, microRNAs and tumor microenvironments (such as hypoxia).

 

figure 1

Picture from Kalluri R, Weinberg RA. J Clin Invest. 2009;119(6):1420–1428.

2.Common marker molecules and related signaling pathways of EMT

The EMT process usually occurs in epithelial cells. This process can be triggered by a variety of signals. Among them, the signals released by interstitial cells that make up normal tissues or neoplastic tissues are the most prominent. The members of the transforming growth factor beta family (TGF-β) are the most important and most thoroughly studied cytokines among all the cytokines that can induce the EMT conversion process in embryonic development. They can treat fibrotic diseases. ) And neoplastic diseases. TGF-β signal can induce EMT conversion process through a number of different signaling mechanisms, such as through the direct phosphorylation of the SMAD transcription factor ligand activated receptor (SMAD transcription factor) pathway (for details, please click the previous tweet: Smads How family proteins precisely regulate TGF-β signal transduction), and trigger the EMT conversion process through certain cytoplasmic proteins that can regulate cell polarity and the formation of tight junctions between cells. TGFβ can also affect the activity of many other EMT trigger signaling pathways, such as Notch, Wnt, and integrin signaling pathways. The Wnt signaling pathway can induce EMT conversion by inhibiting glycogen synthase kinase -3β (GSK3β) -mediated phosphorylation and inhibiting degradation of β-catenin in the cytoplasm (details) Please click on previous tweets: an article takes you to understand what the Wnt / β-Catenin signaling pathway is). Notch signaling pathway can also induce the EMT process, which mainly works by activating the NF-κB signaling pathway or regulating the activity of the TGFβ signaling pathway.

Hypoxia (For details, please click the previous tweet: Why does the HIF pathway win the Nobel Prize?) It is also a physiological mechanism that can induce the EMT process. It is also through a variety of mechanisms, such as upregulating hypoxia-inducible factor 1α (Hypoxia-inducible factor-1α, HIF1α), hepatocyte growth factor (HGF), SNAI1 and TWIST1 protein expression, activate Notch or NF-κB signaling pathway, and induce DNA methylation and other mechanisms to induce EMT process. A large number of tyrosine protein kinase receptors (RTKs) also activate important roles of EMT in related embryonic development processes, such as embryonic branch morphogenesis, through PI3K / AKI and Ras-Raf-MAPK pathways. ) And embryonic heart valve formation (cardiac valve formation) and so on. (See Figure 2)

 

figure 2

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