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Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.
Price, Trevor T; Burness, Monika L; Sivan, Ayelet; Warner, Matthew J; Cheng, Renee; Lee, Clara H; Olivere, Lindsey; Comatas, Karrie; Magnani, John; Kim Lyerly, H; Cheng, Qing; McCall, Chad M; Sipkins, Dorothy A.
Afiliación
  • Price TT; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
  • Burness ML; Division of Hematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Sivan A; Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
  • Warner MJ; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
  • Cheng R; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
  • Lee CH; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
  • Olivere L; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
  • Comatas K; Department of Surgery, Duke University, Durham, NC 27707, USA.
  • Magnani J; GlycoMimetics Inc., Rockville, MD 20850, USA.
  • Kim Lyerly H; Department of Surgery, Duke University, Durham, NC 27707, USA.
  • Cheng Q; Department of Surgery, Duke University, Durham, NC 27707, USA.
  • McCall CM; Department of Pathology, Duke University, Durham, NC 27707, USA.
  • Sipkins DA; Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA. dorothy.sipkins@dm.duke.edu.
Sci Transl Med ; 8(340): 340ra73, 2016 05 25.
Article en En | MEDLINE | ID: mdl-27225183
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Micrometástasis de Neoplasia Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Micrometástasis de Neoplasia Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos