Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells
Open Access
- 1 May 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (5), 1849-1868
- https://doi.org/10.1172/jci59218
Abstract
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.Keywords
This publication has 62 references indexed in Scilit:
- A Perspective on Cancer Cell MetastasisScience, 2011
- Cancer stem cells: mirage or reality?Nature Medicine, 2009
- Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor SuppressorPLoS Biology, 2008
- Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor MetastasisDevelopmental Cell, 2008
- In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like stateNature, 2007
- Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?Nature Reviews Cancer, 2007
- Identification of Pancreatic Cancer Stem CellsCancer Research, 2007
- Cancer as an evolutionary and ecological processNature Reviews Cancer, 2006
- Evolution of cooperation among tumor cellsProceedings of the National Academy of Sciences of the United States of America, 2006
- Molecular requirements for epithelial–mesenchymal transition during tumor progressionCurrent Opinion in Cell Biology, 2005