Characterization of the melanoma brain metastatic niche in mice and humans

Authors

  • Moran Amit,

    1. The Laboratory for Applied Cancer Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Leonor Laider-Trejo,

    1. The Pathology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Vardit Shalom,

    1. The Laboratory for Applied Cancer Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Ayelet Shabtay-Orbach,

    1. The Laboratory for Applied Cancer Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Yakov Krelin,

    1. The Laboratory for Applied Cancer Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Ziv Gil

    Corresponding author
    1. Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Rappaport School of Medicine, the Technion Israel Institute of Technology, Haifa, Israel
    • The Laboratory for Applied Cancer Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author

Correspondence

Ziv Gil, Department of Otolaryngology Rambam Medical Center, Rappaport School of Medicine, the Technion, Israel institute of technology, 6 Ha'Aliya Street, POB 9602, Haifa 31096, Israel. Tel/Fax: 972-4-8542480; E-mail: ziv@baseofskull.org

Abstract

Brain metastases occur in 15% of patients with melanoma and are associated with a dismal prognosis. Here, we investigate the architectural phenotype and stromal reaction of melanoma brain metastasis in mice and humans. A syngeneic, green fluorescence protein (GFP)-expressing murine B16-F1 melanoma clone was introduced via intracardiac injection, and was examined in vivo in comparison with human specimens. Immunofluorescence analyses of the brain metastases revealed that F4/80+ macrophages/microglia were most abundant at the tumor front, but rare in its core, where they were found only around blood vessels (P = 0.01). Similar pattern of infiltration was found in CD3+ T cells (P < 0.01). Infiltrating T cells were prominently CD4+ compared with CD8+ T cells (< 0.001). Blood vessels (CD31+) were less abundant at the tumor front than in its center (12 ± 1 vs. 4 ± 0.6 vessels per high-power field [HPF], < 0.001). In contrast, there were few vessels at the tumor front, but their diameter was significantly larger at the front (8236 μm2 vs. 4617 μm2 average cross-sectional area, < 0.005). This is the first comparative analysis of melanoma brain metastases showing similar stromal reaction in murine models and human specimens. Our results validate the utility of this murine model of melanoma brain metastases for investigating the mechanism of the human disease.

Ancillary