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Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization

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Abstract

Interactions between tumor cells and the microenvironment are crucial to tumor formation and metastasis. The central nervous system serves as a “sanctuary” site for metastasis, resulting in poor prognosis in diagnosed patients. The incidence of brain metastasis is increasing; however, little is known about interactions between the brain and metastatic cells. Brain pathology was examined in an experimental model system of brain metastasis, using a subline of MDA-MB-231 human breast cancer cells. The results were compared with an analysis of sixteen resected human brain metastases of breast cancer. Experimental metastases formed preferentially in specific brain regions, with a distribution similar to clinical cases. In both the 231-BR model, and in human specimens, Ki67 expression indicated that metastases were highly proliferative (~50%). Little apoptosis was observed in either set of tumors. In the model system, metastases elicited a brain inflammatory response, with extensive reactive gliosis surrounding metastases. Similarly, large numbers of glial cells were found within the inner tumor mass of human brain metastases. In vitro co-cultures demonstrated that glia induced a ~5-fold increase in metastatic cell proliferation (P < 0.001), suggesting that brain tissue secretes factors conducive to tumor cell growth. Molecules used to signal between tumor cells and the surrounding glia could provide a new avenue of therapeutic targets for brain metastases.

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Abbreviations

DAPI 4′6:

Diamidino-2-phenylindole

EGFP:

Enhanced Green Fluorescent Protein

GFAP:

Glial Fibrillary Acidic Protein

H&E:

Hematoxylin and eosin

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Acknowledgements

We would like to thank Hong Wang (Developmental Neurobiology Section of the NHLBI Division of Intramural Research, NIH) for providing mixed glial cultures used in the soft agar experiments. This research was supported by the US Department of Defense Breast Cancer Research Program, grant number: W81 XWH-062-0033; and the Intramural Research Program of the National Cancer Institute, CCR, NIH.

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Authors and Affiliations

  1. Women’s Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, Building 37, Room 1126, National Institutes of Health, Bethesda, MD, 20892, USA

    Daniel P. Fitzgerald, Diane Palmieri, Emily Hua, Elizabeth Hargrave & Patricia S. Steeg

  2. Laboratory Animal Sciences Program, Science Applications International Corporation-Frederick, National Cancer Institute NIH, Frederick, MD, USA

    Jeanne M. Herring, Yongzhen Qian & Eleazar Vega-Valle

  3. Department of Neurosurgery and Neurological Institute, Brain Tumor & Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA

    Robert J. Weil

  4. Department of Neurosurgery, Schleswig-Holstein University Medical Center, Campus Kiel, Germany

    Andreas M. Stark

  5. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke NIH, Bethesda, MD, USA

    Alexander O. Vortmeyer

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  1. Daniel P. Fitzgerald
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  2. Diane Palmieri
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Correspondence to Daniel P. Fitzgerald.

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Fitzgerald, D.P., Palmieri, D., Hua, E. et al. Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis 25, 799–810 (2008). https://doi.org/10.1007/s10585-008-9193-z

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  • DOI: https://doi.org/10.1007/s10585-008-9193-z

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