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Cancer Res. 2016 Aug 1;76(15):4359-71. doi: 10.1158/0008-5472.CAN-16-0485. Epub 2016 Jun 3.

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation.

Author information

1
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
3
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
4
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
5
Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany.
6
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
7
Tumor Models Unit, German Cancer Research Center, Heidelberg, Germany.
8
Department of Diagnostic Imaging, Chaim Sheba Medical Center, Ramat Gan, Israel.
9
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
10
Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany. Department of Hematology/Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
11
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. netaerez@post.tau.ac.il.

Abstract

Malignant melanoma is the deadliest of skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. Nevertheless, mechanisms that govern early metastatic growth and the interactions of disseminated metastatic cells with the brain microenvironment are largely unknown. To study the hallmarks of brain metastatic niche formation, we established a transplantable model of spontaneous melanoma brain metastasis in immunocompetent mice and developed molecular tools for quantitative detection of brain micrometastases. Here we demonstrate that micrometastases are associated with instigation of astrogliosis, neuroinflammation, and hyperpermeability of the blood-brain barrier. Furthermore, we show a functional role for astrocytes in facilitating initial growth of melanoma cells. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. Studying spontaneous melanoma brain metastasis in a clinically relevant setting is the key to developing therapeutic approaches that may prevent brain metastatic relapse. Cancer Res; 76(15); 4359-71.

PMID:
27261506
DOI:
10.1158/0008-5472.CAN-16-0485
[Indexed for MEDLINE]
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