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

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 critica...

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Bibliographic Details
Published in:The Journal of clinical investigation Vol. 122; no. 5; pp. 1849 - 1868
Main Authors: Celià-Terrassa, Toni, Meca-Cortés, Óscar, Mateo, Francesca, Martínez de Paz, Alexia, Rubio, Nuria, Arnal-Estapé, Anna, Ell, Brian J., Bermudo, Raquel, Díaz, Alba, Guerra-Rebollo, Marta, Lozano, Juan José, Estarás, Conchi, Ulloa, Catalina, ρlvarez-Simón, Daniel, Milà, Jordi, Vilella, Ramón, Paciucci, Rosanna, Martínez-Balbás, Marian, García de Herreros, Antonio, Gomis, Roger R., Kang, Yibin, Blanco, Jerónimo, Fernández, Pedro L., Thomson, Timothy M.
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.05.2012
Subjects:
Animals
Antigens, Differentiation - genetics
Antigens, Differentiation - metabolism
Antígens
Biomedical research
Bladder cancer
Cadherins - genetics
Cadherins - metabolism
Cancer cells
Cell Line, Tumor
Cell Movement
Cell Shape
Coculture Techniques
Cooperation
Cèl·lules epitelials
Epigenetics
Epithelial Cells - pathology
Epithelial Cells - physiology
Epithelial tumors
Epithelial-Mesenchymal Transition - genetics
Factors de transcripció
Gene Expression Profiling
Gene Regulatory Networks
Genes
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Male
Metastasis
Mice
Mice, Inbred NOD
Mice, SCID
Mutation
Neoplasm Invasiveness - pathology
Neoplasm Metastasis - pathology
Neoplasm Staging
Neoplasm Transplantation
Physiological aspects
Prostate cancer
Prostatic Neoplasms
Proteïnes
Repressor Proteins - genetics
Repressor Proteins - metabolism
Snail Family Transcription Factors
Spheroids, Cellular - metabolism
Spheroids, Cellular - pathology
Stem cells
Transcription Factors - genetics
Transcription Factors - metabolism
Tumors
Twist-Related Protein 1 - genetics
Twist-Related Protein 1 - metabolism
Urinary Bladder Neoplasms
Zinc Finger E-box-Binding Homeobox 1
ISSN:0021-9738, 1558-8238, 1558-8238
Online Access:Get full text
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Summary: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.
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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI59218