**3.7. Epithelial-mesenchymal transition (EMT): the source of cancer stem-like cells**

**1.** The evolutionarily conserved *Wnt family* of proteins is cysteine-rich, secreted glycoproteins that control tissue homeostasis, and regulate diverse processes during development. Wnt pathway dysregulation has been identified in several hereditary diseases and is associated

**2.** *The Notch pathway* has crucial roles in stem cell control and cell-fate determination. Research has found that a signature of the Notch pathway is found in CSCs identified patients with poorly differentiated lung adenocarcinoma, and was prognostic for poorer overall survival. By inhibiting the Notch pathway, CSCs were prevented from forming tumors when

**3.** *The Hedgehog (Hh) protein family members* turn on the genes that regulate the cell cycle and determine cell fate. They are also known to be key regulators of carcinogenesis. Hh and downstream factors have been shown to have significant roles in pancreatic cancer, gastric cancer, glioma, and basal cell carcinoma. Inhibition of the Hh pathway in pancreatic cancer depressed the self-renewal of CSCs and impaired their resistance to chemotherapy [45]. **4.** *The Hippo pathway* and its related mediators Yes/Yap regulate several tumor suppressor genes to control cellular processes such as survival, proliferation, differentiation, apoptosis, and stem or progenitor cell expansion [46]. Dysregulation of the Hippo pathway has been identified in multiple cancers including liver, lung, colorectal, gastric, ovarian, and prostate [46]. Researchers also found that the expression levels of Yes/Yap genes were

prognostic for survival in patients receiving certain types of chemotherapy [46].

cancer, gastric, prostate cancer, and melanoma [47].

growth and tumor-initiating potential in colon CSCs [48].

and IL-8, all of which function to regulate CSC activity [49].

activated by interleukin-6 (IL-6).

**5.** *NANOG* is a transcription factor involved in the self-renewal and maintenance of pluripotency in normal stem cells. Experimental inhibition of NANOG or related transcription factors has been shown to decrease stem-cell–like activities in breast cancer, colorectal

**6.** *The STAT family* of transcriptional factors cooperates with NANOG to transcribe stemness genes that are required for modulating pluripotency [33]. The STATS are upstream signals

Activated STAT3 has been found in leukemia, squamous cell carcinoma of the head and neck, multiple myeloma, breast cancer, and prostate cancer. Blocking the STAT3 signaling pathway has been shown to inhibit the clonogenic and tumorigenic potential of CSCs in prostate cancer [26]. In addition, it has been shown that blockade of STAT3 activity inhibits both tumor

Cancer-associated cells in the microenvironment may secrete growth factors and cytokines to support CSCs. Examples of these include cytokines such as stromal cell-derived factor-1, IL-6,

During dormancy, micrometastases are somehow able to evolve and acquire a full complement of metastasis-colonization functions that they did not express before. It is difficult to envision how this progression could occur in CSCs (section of micrometastasis) that remain in a state of replicative quiescence. Although CSCs in bone marrow look quiescent, the overall CSCs population is not static. Circulating cancer cells can be detected in blood in the apparent

with gastrointestinal cancers [43].

implanted into mice [44].

252 Gastric Cancer

Elizabeth Hay first described an "epithelial-mesenchymal transformation" [50].

The term "transformation" has been replaced with "transition," pointing to reversibility of the process and the fact that it is different from neoplastic transformation [51].

An epithelial-mesenchymal transition (EMT) is defined as the process that allows a polarized epithelial cell, which normally interacts with basement membrane via its basal surface, to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype, which includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of extracellular matrix (ECM) components [51].

These processes are consistent with the acquisition of a "cancer stem-like cell" phenotype that is also known as "stemness" or cancer stem cell (CSCs) characteristics [52, 53, 37].

EMTs are encountered in three distinct biological settings that carry very different functional consequences:


While the specific signals that delineate the EMTs in the three discrete settings are not yet clear, it is now well accepted that functional distinctions are apparent.

Pathologists have accepted the hypothesis of EMT in carcinogenesis albeit skeptically.

However, increasing evidence have demonstrated that the process of EMT is vitally important in cancer progression and metastasis, where cancer cells acquire a more invasive and metastatic phenotype [54].

Metastatic cancer cells with a mesenchymal phenotype are believed to undergo reverse transition, i.e., mesenchymal-to-epithelial transition (MET) at the site of metastasis to gain the pathology of their corresponding primary tumors [55].

This process is an important step by which metastatic tumor cells grow at the metastatic site.

Epithelial-mesenchymal transition is associated with carcinogenesis, invasion, metastasis, recurrence, and chemoresistance, which have been shown to be tightly linked with the function of CSCs. However, the direct relationship between CSCs and EMT in terms of molecular mechanisms remains to be elucidated.
