Laboratory-Clinic InterfaceEpithelial–mesenchymal transition and breast cancer: Role, molecular mechanisms and clinical impact
Section snippets
Role of EMT in development and in physiological processes
The series of events converting adherent epithelial cells into individual migratory cells able to invade the extracellular matrix are known as epithelial–mesenchymal transition (EMT). The two cell types involved in the EMT process epithelial and mesenchymal cells differ both morphologically and functionally: (a) the epithelial cells are well organized in sheets of cuboidal or columnar cells, they are closely attached by intercellular adhesion complexes laterally, displaying an apico-basal
Molecular mechanisms at the basis of EMT
At the cellular level, physiological and pathological EMTs are very similar as they are governed by similar signaling pathways, regulators, and effector molecules. EMT is triggered by a diverse set of stimuli including growth factor signaling, tumor–stromal cell interactions and hypoxia. There is a significant crosstalk among EMT-inducing signals and transcription factors and multiple positive-feedback loops take place in this complex program of reprograming the epithelial cells to mesenchymal
Markers for the detection of EMT
The acquisition by cancer cells of invasiveness, through the invasion and destruction of the basement membrane, is thought to represent the onset of a multistep process that will eventually lead to a metastatic dissemination with life-treating consequences. Indeed, in many studies the activation of the EMT program has been postulated as the critical mechanism for the acquisition of a malignant phenotype by epithelial cancer cells.95 This type of EMT, defined as type 3 EMT occurs in epithelial
Interplay among EMT, tumor-initiating cells, circulating tumor cells and metastasis in breast tumors
Unlike the EMT occurring physiologically during the embryonic development, the EMT in tumors has been defined as a “transient mesenchymal appearance” since the EMT markers and phenotypes are often not apparent in distant metastases. This apparent paradox has been explained by the fact cells undergoing an EMT process in the primary tumors invade the surrounding stroma, extravase in the circulation and reach distant organ where they re-growth. Once here, they are supposed to shed their
EMT and chemoresistance
Resistance to chemotherapy is one of the major problems the oncologists have to face in the clinical practice. Several mechanisms associated with drug resistance have been widely reported and discussed. The drug resistance is not only related to conventional anticancer agents but is also an important aspect of the emerging targeted therapies.
Recent evidences indicate that EMT is associated to a chemoresistant phenotype in several tumors including breast cancer. Again, the resistant phenotype
Hypothesis for reversal of EMT
Given the general association between EMT and resistance, and having shown that changes in gene expression profile are associated with EMT, a logical approach would be to re-set the gene expression profile in a way to revert EMT (hence to induce MET) and to restore drug sensitivity. In several experimental studies, the knock-down of the expression of genes promoting EMT was found to be an efficient way to revert the EMT phenotype and the resistance in vitro. siRNA-mediated knock-down of Snail
Clinical importance of EMT in breast cancer and future therapeutical perspectives
Tumor cells during their life frequently activate the EMT “program” in order to induce the metastasis process characterized by a complex series of physical and cellular events that results in epithelial cells’ loosing their epithelial traits and acquiring many properties of mesenchymal cells, including increased expression of vimentin, smooth-muscle actin (SMA), fibronectin (FN), matrix metalloproteinases and N-cadherin. The epithelial cells gain increased motility and invasiveness via the
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgments
The authors are grateful to the Italian Association for Cancer Research (AIRC) for support to MB and GD and to Fondazione Banca Popolare di Cremona for supporting CF and DG.
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