Characterization of the melanoma brain metastatic niche in mice and humans

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 (P < 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], P < 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, P < 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.

Glial Activation in the Early Stages of Brain Metastasis: TSPO as a Diagnostic Biomarker

“…Moreover, coculture with astrocytes has been shown to induce reprogramming of the tumor cell transcriptome, mirroring transcriptional changes observed in vivo (25) and thus increasing both invasiveness (6) and chemoresistance (26,27). At the same time, microglial activation is also known to be a feature of the brain metastatic microenvironment (4,5,28,29) and, as with astrogliosis, studies suggest both anti-and protumorigenic roles for microglia. For example, microglial-induced tumor cytotoxicity has been demonstrated in vitro (30,31), but these cells have also been shown to facilitate metastatic colonization (29).…”

Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases

“…Furthermore, extensive research has defined the unique features of the brain as an anatomic site for metastatic seeding, encompassing: i) the blood brain barrier [18][19][20], ii) the diversity of neuronal cell types involved (e.g. astrocytes, microglia) [21][22][23][24], and other factors modulating iii) tumor cell transmigration and adhesion [18,19,25], iv) extracellular matrix degradation [23,[26][27][28][29][30], and v) angiogenesis [27,29,[31][32][33]. Improved understanding of the complex pathogenesis of MBM is needed to help improve clinical therapeutic approaches.…”

A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis

“…Microglia are important mediators of the brain response to tissue damage (82), and are similarly activated at the tumor-brain interface in brain metastasis (83,84). Immunohistochemical analysis of microglia in human brain metastases of NSCLC, breast cancer and melanoma indicated intense microglia activation with evident peritumoral accumulation and intratumoral infiltration (85). Thus, the localization of microglia is reminiscent of the gliosis response to traumatic brain injury sites, at the interface between normal and damaged brain tissue (86).…”