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

Publication ,  Journal Article
Price, TT; Burness, ML; Sivan, A; Warner, MJ; Cheng, R; Lee, CH; Olivere, L; Comatas, K; Magnani, J; Kim Lyerly, H; Cheng, Q; McCall, CM; Sipkins, DA
Published in: Sci Transl Med
May 25, 2016

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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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

May 25, 2016

Volume

8

Issue

340

Start / End Page

340ra73

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptors, CXCR4
  • Protein Binding
  • Neoplasm Recurrence, Local
  • Neoplasm Micrometastasis
  • Microscopy, Confocal
  • Mice, SCID
  • Mice
  • MCF-7 Cells
  • Immunohistochemistry
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Price, T. T., Burness, M. L., Sivan, A., Warner, M. J., Cheng, R., Lee, C. H., … Sipkins, D. A. (2016). Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med, 8(340), 340ra73. https://doi.org/10.1126/scitranslmed.aad4059
Price, Trevor T., Monika L. Burness, Ayelet Sivan, Matthew J. Warner, Renee Cheng, Clara H. Lee, Lindsey Olivere, et al. “Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.Sci Transl Med 8, no. 340 (May 25, 2016): 340ra73. https://doi.org/10.1126/scitranslmed.aad4059.
Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med. 2016 May 25;8(340):340ra73.
Price, Trevor T., et al. “Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.Sci Transl Med, vol. 8, no. 340, May 2016, p. 340ra73. Pubmed, doi:10.1126/scitranslmed.aad4059.
Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, Olivere L, Comatas K, Magnani J, Kim Lyerly H, Cheng Q, McCall CM, Sipkins DA. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med. 2016 May 25;8(340):340ra73.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

May 25, 2016

Volume

8

Issue

340

Start / End Page

340ra73

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Receptors, CXCR4
  • Protein Binding
  • Neoplasm Recurrence, Local
  • Neoplasm Micrometastasis
  • Microscopy, Confocal
  • Mice, SCID
  • Mice
  • MCF-7 Cells
  • Immunohistochemistry