Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells
Toni Celià-Terrassa, … , Pedro L. Fernández, Timothy M. Thomson
Toni Celià-Terrassa, … , Pedro L. Fernández, Timothy M. Thomson
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1849-1868. https://doi.org/10.1172/JCI59218.
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Research Article Oncology

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

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.

Authors

Toni Celià-Terrassa, Óscar Meca-Cortés, Francesca Mateo, Alexia Martínez de Paz, Nuria Rubio, Anna Arnal-Estapé, Brian J. Ell, Raquel Bermudo, Alba Díaz, Marta Guerra-Rebollo, Juan José Lozano, Conchi Estarás, Catalina Ulloa, Daniel ρlvarez-Simón, Jordi Milà, Ramón Vilella, Rosanna Paciucci, Marian Martínez-Balbás, Antonio García de Herreros, Roger R. Gomis, Yibin Kang, Jerónimo Blanco, Pedro L. Fernández, Timothy M. Thomson

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Figure 1

Divergent growth and metastatic potentials of 2 clonal populations derived from PC-3 prostate cancer cells.

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Divergent growth and metastatic potentials of 2 clonal populations ...
(A) PC-3/Mc, but not PC-3/S, cells rapidly formed tumors upon orthotopic implantation in NOD-SCID mice, developing lymph node and distant metastases as early as 14 days after implantation. Parental PC-3 cells grew and metastasized with efficiencies intermediate between the 2 clonal populations. Cells (1.0 × 105) were implanted in the ventral lobes of 6-week-old male mice. Anterior (a) or posterior (p) halves were imaged independently for enhanced resolution. Upper right panel: growth curves of orthotopic tumors, with photon counts normalized to values on day 0. Lower right panel: Kaplan-Meier plots for metastasis-free (met free) mice. (B) PC-3/Mc cells grew rapidly after i.m. grafting (2.0 × 105 cells), with detection in lymph nodes after 19 days (arrow). PC-3/S cells formed tumors after 75 days, without detectable distant spread. Bottom panel: growth curves at the i.m. implantation sites. (C) Grafting of limited numbers of PC-3/Mc cells readily produced tumors. 105, 104, or 103 cells were injected i.m. in each hind limb. Right panel: growth curves at the i.m. implantation site. (D) PC-3/Mc, but not PC-3/S, cells readily colonized lungs upon i.v. injection (2.5 × 105 cells). Bottom panel: Kaplan-Meier plots for lung colonization–free mice at each time point. (E) PC-3/Mc, but not PC-3/S, cells readily colonized bones upon i.c. injection (2.0 × 105 cells). Bottom panel: Kaplan-Meier plots for bone metastasis–free mice. Results are expressed as mean ± SEM.