Epithelial-mesenchymal, mesenchymal-epithelial, and endothelial-mesenchymal transitions in malignant tumors: An update

Abstract

Epithelial-to-mesenchymal transition (EMT) represents conversion of an epithelial cell in an elongated cell with mesenchymal phenotype, which can occur in physiologic and pathologic processes such as embryogenesis (type 1 EMT), wound healing and/or fibrosis (type 2 EMT) and malignant tumors (type 3 EMT). The proliferation rate, metastasizing and recurrence capacity, as also the individualized response at chemotherapics, in both epithelial and mesenchymal malignant tumors is known to be influenced by reversible switch between EMT and mesenchymal-to-epithelial transition (MET). Although much research work has already been done in these fields, the specific molecular pathways of EMT, relating to the tumor type and tumor localization, are yet to be elucidated. In this paper, based on the literature and personal experience of the authors, an update in the field of EMT vs MET in epithelial and mesenchymal tumors is presented. The authors tried to present the latest data about the particularities of these processes, and also of the so-called endothelial-to-mesenchymal transition, based on tumor location. The EMT-angiogenesis link is discussed as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management. The paper begins with presentation of the basic aspects of EMT, its classification and assessment possibilities, and concludes with prognostic and therapeutic perspectives. The particularities of EMT and MET in gastric and colorectal carcinomas, pancreatic cancer, hepatocellular and cholangiocarcinomas, and lung, breast and prostate cancers, respectively in sarcomas and gastrointestinal stromal tumors are presented in detail.

Mechanism and regulation of epithelial–mesenchymal transition in cancer

“…8,32 E-cadherin loss can be due to inactivating gene mutations, 33 however, most often downregulation is due to epigenetic or transcriptional silencing. 3,34,35 A study by Onder et al suggests that even though loss of E-cadherin protein expression is sufficient for metastasis, active β-catenin is necessary for invasion of cells in culture and an experimental metastasis model. 36 Together, these findings suggest that even though E-cadherin is an integral player in maintaining the epithelial phenotype, it is likely that additional factors act in concert with the loss of this protein to induce a full EMT.…”

Interleukin-6 induces epithelial-mesenchymal transition in breast cancer cells

“…Several markers implied in EMT have been described, and one of the most widely studied is E-cadherin expression decrease, which is a protein involved in cell-cell adhesion that lowered its levels to the minimum with an exchange for N-cadherin. There are other markers that are positively regulated in EMT, such as: vimentin, fibronectin, smooth muscle actin; transcription factors such as Snail, Twist, Slug and ZEB; in addition to growth factors such as platelet-derived growth factor (PDGF) [12][13][14][15] . Other cell-cell adhesion molecules such as claudin 3, 4, 7, α-catenin, γ-catenin and occludins are negatively regulated in cells with the mesenchymal phenotype 13,15 .…”

“…There are other markers that are positively regulated in EMT, such as: vimentin, fibronectin, smooth muscle actin; transcription factors such as Snail, Twist, Slug and ZEB; in addition to growth factors such as platelet-derived growth factor (PDGF) [12][13][14][15] . Other cell-cell adhesion molecules such as claudin 3, 4, 7, α-catenin, γ-catenin and occludins are negatively regulated in cells with the mesenchymal phenotype 13,15 . EMT is a dynamic process and is activated by different stimuli of the tumor microenvironment, which include growth factors, tumor cell-stroma interactions and hypoxia 16 .…”

La interleucina 6 induce transición epitelio-mesénquima en células de cáncer de mama

“…Uno de los más estudiados es la disminución de la expresión de E-cadherina, proteína involucrada en las uniones célula-célula, la cual baja sus valores al mínimo, con un intercambio por N-cadherina. Existen otros marcadores que son regulados positivamente en la TEM, como son la vimentina, la fibronectina y la actina de músculo liso, y factores de transcripción como Snail, Twist, Slug y ZEB, además de factores de crecimiento como el factor derivado de plaquetas [12][13][14][15] . Otras moléculas de adhesión célula-célula, como las claudinas 3, 4 y 7, la α-catenina, la γ-catenina y las ocludinas, son reguladas negativamente en células con fenotipo mesenquimatoso 13,15 .…”

“…Existen otros marcadores que son regulados positivamente en la TEM, como son la vimentina, la fibronectina y la actina de músculo liso, y factores de transcripción como Snail, Twist, Slug y ZEB, además de factores de crecimiento como el factor derivado de plaquetas [12][13][14][15] . Otras moléculas de adhesión célula-célula, como las claudinas 3, 4 y 7, la α-catenina, la γ-catenina y las ocludinas, son reguladas negativamente en células con fenotipo mesenquimatoso 13,15 . La TEM es un proceso dinámico y es activado por diversos estímulos del microambiente tumoral, que incluyen factores de crecimiento, interacciones célula tumoral-estroma e hipoxia 16 .…”