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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Veröffentlicht in:	The Journal of clinical investigation Jg. 122; H. 5; S. 1849 - 1868
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.05.2012
Schlagworte:	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-Zugang:	Volltext
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI59218