Research ArticleCancer

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone

Science Translational Medicine  25 May 2016:
Vol. 8, Issue 340, pp. 340ra73
DOI: 10.1126/scitranslmed.aad4059

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Taking away cancer’s hideouts

Breast cancer is notorious for its ability to relapse after many years, long after a patient had completed treatment. Price et al. demonstrate that the culprits responsible for such late metastasis may be dormant cancer cells hiding in perivascular niches. The authors showed that proteins called E-selectin and CXCR4 exert different forces on these cancer cells, with CXCR4 anchoring breast cancer cells to their niches and E-selectin allowing entry of cancer cells into the bone marrow. These findings suggest that combining a CXCR4 inhibitor to force the cells out of their niches and an E-selectin inhibitor to prevent metastasis to the bone marrow could help trap the cells in the vasculature, where they could be killed with chemotherapy.

Abstract

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin– and stromal cell–derived factor 1 (SDF-1)–rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1+ vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.

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