**6. EMT in a clinical perspective**

EMT significantly affects metastasis in cancers [63]. This process has attracted increasing attention because metastasis is vital in cancer recurrence and in death caused by cancer [64, 65]. In addition, understanding this process is important to determine medical diagnosis and treatment approach. Notably, sufficient information on biomarkers can lead to accurate forecast and precise therapeutic methods for metastases. Hence, proper diagnostic and therapeutic treatment for patients with early-stage cancer can promote good prognosis and prolong survival time to further improve the quality of life of patients [66, 67]. Furthermore, TBLR1, Sam68, SNAI1, Twist 2, etc. have been diagnosed markers or prognostic factors. This information is clinically important to predict survival and provide promising therapeutic targets for patients with early stage cancer [68, 69].

junctions (connexins 26 and 31), cell polarity markers (Crumbs3, Pals1-associated tight junction protein, and lethal giant larvae homologue 2), desmosomes (plakophilin 3, desmoplakin), and components of tight junctions (claudin 7, occludin, junctional adhesion molecule 1, and zonula occludens protein 3). ZEB proteins activate mesenchymal markers, such as N-cadherin and vimentin [43]. ZEB1 and ZEB2 repress epithelial splicing regulatory proteins-1 and 2, the

ZEB1 inhibits epithelial phenotype, although this factor is found in isolated fibroblasts and immune cells in the interstitial matrix. This factor is not expressed in normal epithelium and well-differentiated carcinomas that express E-cadherin [58, 59]. ZEB1 is highly expressed in invading dedifferentiated cancer cells of many tumors, such as colorectal, breast, liver, endometrial, lung, prostate, and pancreatic carcinomas. ZEB1 and ZEB2 are expressed by stromal cells in epithelial tissues and organs of normal E-cadherin-positive epithelial cells [60]. ZEB-dependent paracrine signaling from the stroma can cooperate in E-cadherin repression

Other transcription factors also induce EMT and tumor invasiveness. The homeobox factor goosecoid induces EMT by activating mesenchymal genes and repressing epithelial markers [62]. TGF-β induces goosecoid in breast epithelial cells, and goosecoid is overexpressed in ductal breast carcinomas and atypical ductal hyperplasia [62]. **Figure 2** shows the main

EMT significantly affects metastasis in cancers [63]. This process has attracted increasing attention because metastasis is vital in cancer recurrence and in death caused by cancer [64,

overexpression of which inhibits EMT [57].

**Figure 2.** The main signaling pathways involved in EMT.

signaling pathways involved in EMT.

**6. EMT in a clinical perspective**

in other parts of the tumor [61].

224 Tumor Metastasis

Sulforaphane or salinomycin treatment changes the stemness properties of cancer stem cells (CSCs), which may have been caused by the regulation of the expression of a special gene or protein. Sulforaphane downregulates Twist-1 and vimentin. By contrast, salinomycin treat‐ ment does not only significantly reduce vimentin level but also induce and upregulate Ecadherin expression in special cancer cell lines. Various reports have indicated a key role of Ecadherin in EMT. Thus, studying these cadherins can be a promising strategy [70, 71].

Epithelial cancer cells tend to differentiate to acquire invasive and stem cell-like properties. Thus, EMT regulators may function as therapeutic targets of cancer progression and recur‐ rence. EMT-TFs, such as Twist, Snail, and ZEB, will be regarded as potent therapeutic targets for pharmacologic inhibition. Traditionally, EMT regulators are nearly impossible to target; however, evidence suggests that molecular links can offer the possibility for targeting regu‐ lation as a therapeutic intervention of EMT among metabolic adaptation, epigenetic alteration, and EMT [4, 72–74].

EMT significantly affects epigenome restructuring. Thus, epigenetic therapies can be used to realize the pharmacologic inhibition of EMT, which makes EMT sensitive to chemotherapy. In recent years, potential EMT inhibitors function as an effective chemotherapeutic sensitive agent, such as HDAC enzymes LBH589 [75]. In addition, histone demethylase LSD1 epigenetic modifiers offer important information on the survival of EMT by reducing invasiveness or inhibiting the transfer function. Thus, inhibiting LSD1 [76] may lead to improved survival because of the inhibition of invasiveness and metastasis [76].

Although epigenetic therapies exhibit considerable potential for clinical applications, the clinical application of epigenetic drugs remains ambiguous because of its unclear mechanism. The mechanism of epigenetic drugs should be investigated further. Therefore, the enhance‐ ment of specificity may solve the potential problem on the treatment of particular epigenetic targets in the future [74].

Drugs are likely to become anti-cancer drugs in clinical applications. Further study on the clinical trials of cancer has shown that metformin arouses attention as a promising anti-cancer agent [77, 78]. Metformin involves systemic effects, such as reducing insulin levels and acting on one-carbon metabolism. This metabolism will be explored with epigenetic alterations based on the connection between metabolism and the epigenetic state of cells [79].

Decitabine, which is a DNA methyltransferase (DNMT) inhibitor, suppresses the migration capacities of SDH-mutant cells. This inhibition is evidently displayed by succinate abnormal accumulation in epigenetic dysregulation and the resultant EMT. Mutant enzymes to directly explore the inhibition approach for SDH- and FH-associated cancers are worthy to be explored [80].
