Cancer stem cells (CSCs) have been identified in a variety of tumour types, including breast tumours, and have been proposed to be responsible for recurrence, resistance to chemotherapy and, perhaps, metastasis of cancers. Targeting of these CSCs in the treatment of cancer is therefore of great interest. The ability of the ionophore antibiotic, salinomycin, to kill breast tumour CSCs was recently reported and now collaborators from the University of Michigan Comprehensive Cancer Center and the Centre de Recherche en Cancérologie de Marseille have identified a new potential drug target.
In this latest study the team identified overexpression of CXCR1, the receptor for interleukin-8 (IL-8), by the CSC subpopulation in a breast cancer cell line. Furthermore, addition of recombinant IL-8 increased the CSC population and enhanced the propensity for invasion. Conversely, use of CXCR1-blocking antibodies or repertaxin, a small-molecule CXCR1 antagonist, selectively depleted the breast CSCs both in vitro and in murine xenograft models.
CXCR1 blockade also induced massive apoptosis in bulk tumour cells, mediated by FASL/FAS signalling. The effects on CSC viability as well as FASL production were mediated by the focal adhesion kinase/AKT/forkhead transcription factor FKHRL1 (FAK/AKT/FOXO3A) pathway. Importantly, administration of repertaxin reduced tumour growth and the development of systemic breast cancer metastasis in NOD/SCID mice.
The authors of the study, published in the Journal of Clinical Investigation, suggest blockade of CXCR1 as a novel target for depletion of CSCs, potentially enhancing the efficacy of chemotherapeutic regimes.