Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

Department of Cell Biology, Barcelona Institute of Molecular Biology, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
The Journal of clinical investigation (Impact Factor: 13.22). 04/2012; 122(5):1849-68. DOI: 10.1172/JCI59218
Source: PubMed


Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.

Download full-text


Available from: Toni Celià-Terrassa
  • Source
    • "This is supported by the observation that inside the tumor mass, cells with mesenchymal features reside predominantly at the invasive front at the tumor-stroma interface [2]. Within a tumor, epithelial and mesenchymal cells coexist and cooperate, by direct cell-cell interactions or by diffusible factors, allowing epithelial cells to undergo EMT and increase their ability to locally invade into the surrounding tissues and intravasate into the blood vessels, initiating their spreading to distant organs [3]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The growing understanding of the molecular mechanisms underlying epithelial-to-mesenchymal transition (EMT) may represent a potential source of clinical markers. Despite EMT drivers have not yet emerged as candidate markers in the clinical setting, their association with established clinical markers may improve their specificity and sensitivity. Mass spectrometry-based platforms allow analyzing multiple samples for the expression of EMT candidate markers, and may help to diagnose diseases or monitor treatment efficiently. This review highlights proteomic approaches applied to elucidate the differences between epithelial and mesenchymal tumors and describes how these can be used for target discovery and validation.
    Full-text · Article · Jan 2016 · EuPA Open Proteomics
  • Source
    • "In squamous cell carcinoma, spatiotemporal regulation of the epithelial–mesenchymal transition is essential for the dissemination and eventual metastasis (Tsai et al, 2012). The mesenchymal phenotype of CTCs that underwent EMT promotes motility but does not favor growth (Celia-Terrassa et al, 2012). Indeed, cancer cells must undergo a reverse mesenchymal-to-epithelial transition (MET) to acquire the ability to proliferate and thus form a metastatic tumor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.
    Full-text · Article · Nov 2014 · EMBO Molecular Medicine
  • Source
    • "This is supported by the fact that generation of induced pluripotent stem cells (iPCSs) from mouse embryonic fibroblast requires the transition to the epithelial state at the initial phase of the reprogramming process and is orchestrated by BMP signaling [44]. Similarly, downregulation of potent EMT inducers is associated not only with the acquisition of an epithelial-but also-of a stem cell phenotype [24] [45]. Irrespectively of the question if it is the epithelial or mesenchymal state that is associated with the stem cell phenotype it is very likely that cancer cells can readily switch between these states in response to external stimuli, which might help them to effectively adopt to various environments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cell plasticity is an event that has been observed in several malignancies. In fact, most of the solid tumors are characterized by cellular heterogeneity and undergo constant changes as the tumor develops. The increased plasticity displayed by these cells allows them to acquire additional properties, enabling epithelial-mesenchymal transitions, dedifferentiation and the acquisition of stem cell-like properties. Here we discuss the particular importance of an inflammatory microenvironment for the bidirectional control of cellular plasticity and the potential for therapeutic intervention.
    Full-text · Article · Jun 2014 · FEBS letters
Show more