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
    • "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.
    EMBO Molecular Medicine 11/2014; 7(1). DOI:10.15252/emmm.201303698 · 8.67 Impact Factor
  • 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.
    FEBS letters 06/2014; DOI:10.1016/j.febslet.2014.06.019 · 3.17 Impact Factor
  • Source
    • "However, Celia-Terrassa et al. have reported that PC3-derived clonal populations enriched for epithelial phenotype exhibit a stronger expression of self-renewal/pluripotency gene networks and more aggressive attributes [55]. Furthermore, the suppression of epithelial program inhibited the self-renewal/pluripotency gene network of tumor cells, their capacity to grow under attachment-independent conditions, and their tumorigenic and metastatic potentials [55]. This study also suggested the coexistence of heterogeneous populations with epithelial or mesenchymal phenotype interacting and co-operating to impact on the tumor’s potency for local invasiveness and distant metastasis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A better molecular understanding of prostate carcinogenesis is warranted to devise novel targeted preventive and therapeutic strategies against prostate cancer (PCA), a major cause of mortality among men. Here, we examined the role of two epithelial-to-mesenchymal transition (EMT) regulators, the adherens junction protein E-cadherin and its transcriptional repressor SNAI1, in regulating the aggressiveness of PCA cells. The growth rate of human prostate carcinoma PC3 cells with stable knock-down of E-cadherin (ShEC-PC3) and respective control cells (Sh-PC3) was compared in MTT and clonogenic assays in cell culture and in nude mouse xenograft model in vivo. Stemness of ShEC-PC3 and Sh-PC3 cells was analyzed in prostasphere assay. Western blotting and immunohistochemistry (IHC) were used to study protein expression changes following E-cadherin and SNAI1 knock-down. Small interfering RNA (siRNA) technique was employed to knock- down SNAI1 protein expression in ShEC-PC3 cells. ShEC-PC3 cells exerted higher proliferation rate both in cell culture and in athymic nude mice compared to Sh-PC3 cells. ShEC-PC3 cells also formed larger and a significantly higher number of prostaspheres suggesting an increase in the stem cell-like population with E-cadherin knock-down. Also, ShEC-PC3 prostaspheres disintegration, in the presence of serum and attachment, generated a bigger mass of proliferating cells as compared to Sh-PC3 prostaspheres. Immunoblotting/IHC analyses showed that E-cadherin knock-down increases the expression of regulators/biomarkers for stemness (CD44, cleaved Notch1 and Egr-1) and EMT (Vimentin, pSrc-tyr416, Integrin beta3, beta-catenin, and NF-kappaB) in cell culture and xenograft tissues. The expression of several bone metastasis related molecules namely CXCR4, uPA, RANKL and RunX2 was also increased in ShEC-PC3 cells. Importantly, we observed a remarkable increase in SNAI1 expression in cytoplasmic and nuclear fractions, prostaspheres and xenograft tissues of ShEC-PC3 cells. Furthermore, SNAI1 knock-down by specific siRNA strongly inhibited the prostasphere formation, clonogenicity and invasiveness, and decreased the level of pSrc-tyr416, total Src and CD44 in ShEC-PC3 cells. Characterization of RWPE-1, WPE1-NA22, WPE1-NB14 and DU-145 cells further confirmed that low E-cadherin is associated with higher SNAI1 expression and prostasphere formation. Together, these results suggest that E-cadherin loss promotes SNAI1 expression that controls the aggressiveness of PCA cells.
    Molecular Cancer 02/2014; 13(1):37. DOI:10.1186/1476-4598-13-37 · 4.26 Impact Factor
Show more