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 6

IL-8/CXCR1 signaling in CSCs treated with chemotherapy alone or in combination with repertaxin.

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IL-8/CXCR1 signaling in CSCs treated with chemotherapy alone or in combi...
(A) Potential IL-8/CXCR1 cell signaling in CSCs. CXCR1 activation upon IL-8 binding induces FAK phosphorylation. Active FAK phosphorylates AKT and activates the WNT pathway, which regulates stem cell self-renewal and FOXO3A that regulates cell survival. Activation of FAK protects CSCs from a FASL/FAS-mediated bystander effect by inhibiting FADD, a downstream effector of FAS signaling. In the presence of chemotherapy, only the bulk tumor cells are sensitive to the treatment and release a high level of IL-8 and FASL proteins during the apoptotic process. Breast CSCs are stimulated via an IL-8–mediated bystander effect and are resistant to the bystander killing effect mediated by FASL. TCF, T cell factor. (B) Repertaxin treatment blocks IL-8/CXCR1 signaling and inhibits breast CSC self-renewal and survival. When repertaxin treatment is combined with chemotherapy, the CSCs are sensitized to the bystander killing effect mediated by FASL.