CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts
Christophe Ginestier, … , Gabriela Dontu, Max S. Wicha
Christophe Ginestier, … , Gabriela Dontu, Max S. Wicha
Published January 4, 2010
Citation Information: J Clin Invest. 2010;120(2):485-497. https://doi.org/10.1172/JCI39397.
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CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Abstract

Recent evidence suggests that breast cancer and other solid tumors possess a rare population of cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel means of targeting and eliminating breast CSCs.

Authors

Christophe Ginestier, Suling Liu, Mark E. Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Jun-Lin Guan, Gabriela Dontu, Max S. Wicha

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Figure 1

Effect of CXCR1 blockade on cell viability and on the ALDEFLUOR+ population in vitro.

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Effect of CXCR1 blockade on cell viability and on the ALDEFLUOR+ populat...
(A) Representation of the overlap between the ALDEFLUOR+ subpopulation and the CXCR1+ (top) or CXCR2+ (bottom) subpopulation of SUM159 cells. (B and C) SUM159 cells were cultured in adherent conditions and treated with repertaxin and 2 specific blocking antibodies for CXCR1 or CXCR2. After 3 days, the effect on cell viability and the CSC population was analyzed. A significant reduction of the ALDEFLUOR+ population and cell viability was observed after treatment with repertaxin or anti-CXCR1 antibody, but not with anti-CXCR2 antibody. (D) After 4 days of treatment, the number of apoptotic cells was evaluated, and 36% of apoptotic cells (green) were detected in repertaxin-treated cells compared with controls, in which mostly viable cells (blue) were present. Scale bars: 100 μm. (E) To determine whether cell death was mediated via a bystander effect, CXCR1+ and CXCR1– populations were treated with various concentrations of repertaxin. A decrease in cell viability in CXCR1+ and unsorted populations were detected, whereas no effect was observed in the CXCR1– population. (F) Serial dilutions of dialyzed conditioned medium from CXCR1+ cells treated for 3 days with repertaxin was used to treat sorted CXCR1+, CXCR1–, or unsorted populations. After 2 days of treatment, a massive decrease in cell viability was observed in both CXCR1– and unseparated populations, whereas no effect was observed in the CXCR1+ population. Error bars represent mean ± SD.