Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer

Findlay, Victoria J.; Wang, C; Watson, Dennis K.; Camp, E. Ramsay

doi:10.1038/cgt.2014.15

Cited by 108 publications

(109 citation statements)

References 101 publications

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“…S1). These proteins have been related to EMT regulation and cellular differentiation 22, 23, 24, 25. Nt2 was centered on NFkB and involved genes such as NFkB early‐response gene IER3, secreted signaling molecules bone morphogenetic protein (BMP), and TF ETS homologous factor (EHT) that belongs to an ETS TF subfamily characterized by epithelial‐specific expression and which may be involved in epithelial differentiation and carcinogenesis 26, 27, 28, 29.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

Yamamoto

Burnette

et al. 2016

Cancer Medicine

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Dysregulated epithelial to mesenchymal transition (EMT) in cancer cells endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs and therefore play a critical role in transforming early‐stage carcinomas into invasive malignancies. EMT has also been associated with tumor recurrence and drug resistance and cancer stem cell initiation. Therefore, better understanding of the mechanisms behind EMT could ultimately contribute to the development of novel prognostic approaches and individualized therapies that specifically target EMT processes. As an effort to characterize the central transcriptome changes during EMT, we have developed a Transforming growth factor (TGF)‐beta‐based in vitro EMT model and used it to profile EMT‐related gene transcriptional changes in two different cell lines, a non‐small cell lung cancer cell line H358, and a breast cell line MCF10a. After 7 days of TGF‐beta/Oncostatin M (OSM) treatment, changes in cell morphology to a mesenchymal phenotype were observed as well as concordant EMT‐associated changes in mRNA and protein expression. Further, increased motility was noted and flow cytometry confirmed enrichment in cancer stem cell‐like populations. Microarray‐based differential expression analysis identified an EMT‐associated gene expression signature which was confirmed by RT‐qPCR and which significantly overlapped with a previously published EMT core signature. Finally, two novel EMT‐regulating transcription factors, IRF5 and LMCD1, were identified and independently validated.

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Section: Discussionmentioning

confidence: 99%

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

Yamamoto

Burnette

et al. 2016

Cancer Medicine

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“…properties [145]. The acquisition of CSC properties by tumor mesenchymal-like cells in response to EMT could have major consequences, in particular by fostering tumor heterogeneity and by contributing to resistance to anticancer drugs in CCA, a tumor containing a strong contingent of CSC [55].…”

Section: Emt and Therapeutic Considerations Chemoresistancementioning

confidence: 99%

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

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

125

122

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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.

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“…[5][6][7][8][9][10][11][12] Numerous biomarkers to characterize CSCs have been reported. However, the specificity of many of these markers in terms of their ability to differentiate CSCs vs other cancer cells has not been completely demonstrated [7][8][9][10][11] (Table 1). Nonneoplastic stem cells, both embryonic and somatic, have the ability for self-renewal by continuous division and can be induced to become tissue/organ-specific cells with specialized functions.…”

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confidence: 99%

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

Hardin

Zhang

Helein

et al. 2017

Laboratory Investigation

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The cancer stem-like cell (CSC) hypothesis postulates that a small population of cells in a cancer has self-renewal and clonal tumor initiation properties. These cells are responsible for tumor initiation, growth, recurrence and for resistance to chemotherapy and radiation therapy. CSCs can be characterized using markers such as SSEA-1, SSEA-4, CD44, CD24, ALDEFLUOR and others. CSCs form spheres when they are cultured in serum-free condition in low attachment plates and can generate tumors when injected into immune-deficient mice. During epithelial to mesenchymal transition (EMT), cells lose cellular adhesion and polarity and acquire an invasive phenotype. Recent studies have established a relationship between EMT and increased numbers of CSCs in some solid malignancies. Non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs) have been shown to have important roles during EMT and some of these molecules also have regulatory roles in the proliferation of CSCs. Specific lncRNAs enhanced cell migration and invasion in breast carcinomas, which was associated with the generation of stem cell properties. The tumor microenvironment of CSCs also has an important role in tumor progression. Recent studies have shown that the interaction between tumor cells and the local microenvironment at the metastatic site leads to the development of premetastatic niche(s) and allows for the proliferation of the metastatic cells during colonization. The role of exosomes in the microenvironment during the EMT program is currently a major area of research. This review examines CSCs and the relationship between EMT and CSCs in solid tumors with emphasis on thyroid CSCs. The role of non-coding RNAs and of the microenvironment in EMT and in tumor progression are also examined. This review also highlights the growing number of studies that show the close association of EMT and CSCs and the role of exosomes and other elements of the tissue microenvironment in CSC metastasis. A better understanding of these mechanisms will lead to more effective targeting of primary and metastatic malignancies.

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Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer

Cited by 108 publications

References 101 publications

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

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

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

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