title: Functional role of endothelial adhesion molecules in the early stages of brain metastasis.
abstract: 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.
authors: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, UK (M.S.S., S. S., N.R.S.; Department of Pharmacology, University of Oxford, Oxford UK (D.C.A.).
authors: Manuel Sarmiento
authors: MS
authors: Soto
authors: Sébastien
authors: S
authors: Serres
authors: Daniel C
authors: DC
authors: Anthony
authors: Nicola R
authors: NR
authors: Sibson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D039041:Integrin alpha4beta1; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1
keywords: brain; cellular adhesion molecules; endothelium; metastasis; mouse; neutralizing antibody