Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation.
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. ©2016 AACR.
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Hila
H
Schwartz
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Eran
E
Blacher
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Malak
M
Amer
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Nir
N
Livneh
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Lilach
L
Abramovitz
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.
Anat
A
Klein
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dikla
D
Ben-Shushan
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Shelly
S
Soffer
Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany.
Raquel
R
Blazquez
Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
Alonso
A
Barrantes-Freer
Tumor Models Unit, German Cancer Research Center, Heidelberg, Germany.
Meike
M
Müller
Tumor Models Unit, German Cancer Research Center, Heidelberg, Germany.
Karin
K
Müller-Decker
Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Reuven
R
Stein
Department of Diagnostic Imaging, Chaim Sheba Medical Center, Ramat Gan, Israel.
Galia
G
Tsarfaty
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ronit
R
Satchi-Fainaro
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.
Viktor
V
Umansky
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.
Tobias
T
Pukrop
Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. netaerez@post.tau.ac.il.
Neta
N
Erez
D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D008545:Melanoma / Q000150:complications* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000473:pathology; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma