title: Disruption of tumour-host communication by downregulation of LFA-1 reduces COX-2 and e-NOS expression and inhibits brain metastasis growth.
abstract: Over 20% of cancer patients will suffer metastatic spread to the brain, and prognosis remains poor. Communication between tumour cells and host tissue is essential during metastasis, yet little is known of the processes underlying such interactions in the brain.Here we test the hypothesis that cross-talk between tumour cells and host brain cells, through tumour cell leukocyte function associated protein-1 (LFA-1), is critical in metastasis development. Temporal expression of LFA-1 and its major ligand intercellular adhesion molecule-1 (ICAM-1) was determined in two different mouse models of brain metastasis. Marked upregulation of both proteins was found, co-localising with astrocytes, microglia and tumour cells themselves. Silencing of LFA-1 expression in MDA231Br-GFP cells prior to intracerebral injection resulted in > 70% reduction in tumour burden compared to control MDA231Br-GFP cells (p < 0.005, n = 5). Subsequent qRT-PCR analysis of brain tissue revealed significant reductions in COX-2, VEGF and eNOS from host brain tissue, but not tumour cells, in mice injected with LFA-1 knockdown cells (p < 0.0001, n = 5). Finally, expression of both LFA-1 and ICAM-1 was demonstrated in human brain metastasis samples.The results of this study suggest LFA-1 as a new target in brain metastasis therapy and highlight the potential synergy with current anti-COX-2 and anti-NOS therapies.
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Manuel Sarmiento
authors.initials: MS
authors.lastname: Soto
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Emma R
authors.initials: ER
authors.lastname: O'Brien
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Kleopatra
authors.initials: K
authors.lastname: Andreou
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Scrace
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK.
authors.forename: Rasheed
authors.initials: R
authors.lastname: Zakaria
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK.|Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, L97LJ, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jenkinson
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: O'Neill
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D064593:Heterografts; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000502:physiology*
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; D051546:Cyclooxygenase 2
keywords: COX-2; LFA-1; brain metastasis; cellular adhesion molecules; eNOS