Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Abstract

Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

Anti-tumor activity of nanomicelles encapsulating CXCR4 peptide antagonist E5

“…On the other hand, epithelial-to-mesenchymal transition (EMT) plays an important role in primary tumor progression and metastasis, and this process is characterized by loss of epithelial and acquisition of mesenchymal characteristics of tumor cells [31–33]. During EMT progression, the expression levels of mesenchymal markers and matrix metalloproteinases (MMPs) are increased, in contrast, epithelial adhesion of molecules are decreased, as previously reported [24,34].…”

Bone marrow blood vessels: normal and neoplastic niche

“…86 This process is observed during embryonic development, wound healing and cancer metastasis. 87 Since the tumor cells are transported by bloodstream and their diffusion is dependent upon vessels, increased angiogenesis in tumor results in augmentation of metastasis and spread of cancer cells. 88 It has been suggested that tumor endothelial cells (TECs) are involved in the survival, proliferation and metastasis of cancer cells.…”

NEK4 kinase regulates EMT to promote lung cancer metastasis

“…8 Studies have suggested that EMT is a complexed and well-coordinated process, in which the extracellular signal molecules, transcription factors, miRNAs, epigenetic and posttranslational regulation all play critical roles. 9,10 The transforming growth factor-β (TGF-β) as an EMT-induction factor induces EMT through a variety of signal pathways as well as the classical TGFβ-Smad pathway. Activated Smads combine with Smad4 to regulate the transcription of many TGF-β/Smad target genes such as E-cadherin.…”