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BACKGROUND: Cellular adhesion molecules (CAMs), which are normally associated with leukocyte trafficking, have also been shown to play an essential role in tumor metastasis to non-CNS sites. However, the role played by CAMs in brain metastasis is largely unexplored. It is known that leukocyte recruitment to the brain is very atypical and that mechanisms of disease in peripheral tissues cannot be extrapolated to the brain. Here, we have established the spatiotemporal expression of 12 key CAMs in the initial phases of tumor seeding in 2 different models of brain metastasis. METHODS: BALB/c or SCID mice were injected intracardially (10(5) cells/100 μL phosphate-buffered saline with either 4T1-GFP or MDA231BR-GFP cells, respectively (n = 4-6/group), and expression of the CAMs was determined by immunohistochemistry and immunofluorescence colocalisation. RESULTS: Endothelial expression of E-selectin, VCAM-1, ALCAM, ICAM-1, VLA-4, and β4 integrin was markedly increased early in tumor seeding. At the same time, the natural ligands to these adhesion molecules were highly expressed on the metastatic tumor cells both in vitro and in vivo. Two of these ligands showed particularly high tumor cell expression (ALCAM and VLA-4), and consequently their functional role in tumor seeding was determined. Antibody neutralization of either ALCAM or VLA-4 significantly reduced tumor seeding within the brain (>60% decrease in tumor number/mm(2) brain; P < .05-0.01). CONCLUSIONS: These findings suggest that ALCAM/ALCAM and VLA-4/VCAM-1 interactions play an important functional role in the early stages of metastasis seeding in the brain. Moreover, this work identifies a specific subset of ligand-receptor interactions that may yield new therapeutic and diagnostic targets for brain metastasis.

Original publication

DOI

10.1093/neuonc/not222

Type

Journal article

Journal

Neuro Oncol

Publication Date

04/2014

Volume

16

Pages

540 - 551

Keywords

brain, cellular adhesion molecules, endothelium, metastasis, mouse, neutralizing antibody, Animals, Antibodies, Neutralizing, Apoptosis, Blotting, Western, Brain Neoplasms, Breast Neoplasms, Cell Adhesion Molecules, Cell Movement, Cell Proliferation, Endothelium, Vascular, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Integrin alpha4beta1, Mice, Mice, Inbred BALB C, Mice, SCID, Tumor Cells, Cultured, Xenograft Model Antitumor Assays