Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition

University of Helsinki, Finland
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(8):e2888. DOI: 10.1371/journal.pone.0002888
Source: PubMed


Recently, two novel concepts have emerged in cancer biology: the role of so-called "cancer stem cells" in tumor initiation, and the involvement of an epithelial-mesenchymal transition (EMT) in the metastatic dissemination of epithelial cancer cells. Using a mammary tumor progression model, we show that cells possessing both stem and tumorigenic characteristics of "cancer stem cells" can be derived from human mammary epithelial cells following the activation of the Ras-MAPK pathway. The acquisition of these stem and tumorigenic characters is driven by EMT induction.

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Available from: Clémence Thomas
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    • "Stemness and EMT have often been observed in the same context, and there are a number of reports which have shown that these two processes are intertwined. Robert Weinberg's lab demonstrated that it was possible to induce stem cell features in somatic immortalized human mammary epithelial cells (HMLEs) by overexpressing either TWIST or SNAI1[178], with similar results being obtained by Morel and colleagues[179]. Conversely, the EMT-activator ZEB1 has been shown to promote tumorigenicity by repressing stemness-inhibiting miRNAs, miR-200c, miR-203 and miR-183 inclusive[180]. "
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    ABSTRACT: Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors.
    Full-text · Article · Jan 2016 · Journal of Clinical Medicine
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    • "Upon EMT, epithelial cells lose their adherence junctions and epithelial polarity, and acquire a mesenchymal phenotype with invasive properties. In addition to morphological changes, a subset of carcinoma cells acquires stem cell properties (CSCs) during EMT, which promote long-term tumor propagation, drug resistance, and metastasis [2] [3]. "
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    ABSTRACT: Changes in the tumor microenvironment (TME) can trigger the activation of otherwise non-malignant cells to become highly aggressive and motile. This is evident during initial tumor growth when the poor vascularization in tumors generates hypoxic regions that trigger the latent embryonic program, epithelial-to-mesenchymal transition (EMT), in epithelial carcinoma cells (e-cars) leading to highly motile mesenchymal-like carcinoma cells (m-cars), which also acquire cancer stem cell properties. After that, specific bidirectional interactions take place between m-cars and the cellular components of TME at different stages of metastasis. These interactions include several vicious positive feedback loops in which m-cars trigger a phenotypic switch, causing normal stromal cells to become pro-tumorigenic, which then further promote the survival, motility, and proliferation of m-cars. Accordingly, there is not a single culprit accounting for metastasis. Instead both m-cars and the TME dynamically interact, evolve and promote metastasis. In this review, we discuss the current status of the known interactions between m-cars and the TME during different stages of metastasis and how these interactions promote the metastatic activity of highly malignant m-cars by promoting their invasive mesenchymal phenotype and CSC properties.
    Full-text · Article · Jan 2016 · Cancer letters
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    • "The PI3K pathway can also be activated independently of Ras activation and substantial crosstalk between the Raf and PI3K pathways has been established (Aksamitiene et al., 2012). Despite evidence that overexpression of oncogenic Ras can repress CD24 surface expression (Morel et al., 2008) the mechanism for this regulation of CD24 is not known. Here, we examined the regulation of CD24 mRNA, protein, and promoter levels in a model of oncogenic Ras activation. "
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    ABSTRACT: CD24 is a dynamically regulated cell surface protein. High expression of CD24 leads to progression of lung, prostrate, colon, and pancreatic cancers, among others. In contrast, low expression of CD24 leads to cell proliferation and metastasis of breast cancer stem cells (BCSCs). Activating mutations in Ras are found in 30% of all human cancers. Oncogenic Ras constitutively stimulates the Raf, PI3K, and Ral GDS signaling pathways, leading to cellular transformation. Previous studies have shown that expression of oncogenic Ras in breast cancer cells generates CD24(-) cells from CD24(+) cells. However, the molecular mechanisms involved in the generation of CD24(-) cells were not determined. Here, we demonstrate that oncogenic Ras (RasV12) expression suppresses CD24 mRNA, protein, and promoter levels when expressed in NIH/3T3 cells. Furthermore, activation of only the Raf pathway was sufficient to downregulate CD24 mRNA and protein expression to levels similar to those seen in with RasV12 expression. In contrast, activation of the PI3K pathway downregulated mRNA expression with a partial effect on protein expression whereas activation of the RalGDS pathway only partially affected protein expression. Surprisingly, inhibition of MEK with U0126 only partially restored CD24 mRNA expression but not surface protein expression. In contrast, inhibition of Raf with sorafenib did not restore CD24 mRNA expression but significantly increased the proportion of RasV12 cells expressing CD24. Therefore, the Raf pathway is the major repressor of CD24 mRNA and protein expression, with PI3K also able to substantially inhibit CD24 expression. Moreover, these data indicate that the levels of CD24 mRNA and surface protein are independently regulated. Although inhibition of Raf by sorafenib only partially restored CD24 expression, sorafenib should still be considered as a potential therapeutic strategy to alter CD24 expression in CD24(-) cells, such as BCSCs.
    Full-text · Article · Aug 2015 · Frontiers in Cell and Developmental Biology
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