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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Research Article Oncology

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 2

Repertaxin treatment induces a bystander effect mediated by FASL/FAS signaling.

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Repertaxin treatment induces a bystander effect mediated by FASL/FAS sig...
(A) To determine whether the bystander killing effect induced by repertaxin treatment was mediated by FASL, we measured the level of soluble FASL in the medium using an ELISA assay. After 4 days of treatment, a greater than 4-fold increase of soluble FASL was detected in the medium of cells treated with repertaxin compared with untreated controls. (B) We measured the level of FASL mRNA by RT-PCR and confirmed the increase of FASL production after treatment with repertaxin. Similar results were observed after 4 days of treatment with a FAS agonist that activates FAS signaling, with a 5-fold increase of the FASL mRNA compared with control. (C) SUM159 cells were cultured in adherent conditions and treated with repertaxin alone or in combination with anti-FASL. Interestingly, cell growth inhibition induced by repertaxin treatment was partially rescued by addition of anti-FASL. Moreover, cells treated with a FAS agonist displayed cell growth inhibition similar to that of cells treated with repertaxin alone. (D and E) The effect of repertaxin treatment, alone or in combination with anti-FASL, and FAS agonist treatment on the CXCR1+ and ALDEFLUOR+ population was analyzed. The massive decrease in the CXCR1+ and ALDEFLUOR+ population induced by repertaxin treatment was not rescued by the anti-FASL, and treatment with FAS agonist produced 10- and 3-fold increases in the percent of the CXCR1+ and ALDEFLUOR+ populations, respectively. BAAA, BODIPY aminoacetaldehyde; DEAB, diethylaminobenzaldehyde. Error bars represent mean ± SD.