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dc.contributor.authorFultang, L
dc.contributor.authorGamble, LD
dc.contributor.authorGneo, L
dc.contributor.authorBerry, AM
dc.contributor.authorEgan, SA
dc.contributor.authorDe Bie, F
dc.contributor.authorYogev, O
dc.contributor.authorEden, GL
dc.contributor.authorBooth, S
dc.contributor.authorBrownhill, S
dc.contributor.authorVardon, A
dc.contributor.authorMcConville, CM
dc.contributor.authorCheng, PN
dc.contributor.authorNorris, MD
dc.contributor.authorEtchevers, HC
dc.contributor.authorMurray, J
dc.contributor.authorZiegler, DS
dc.contributor.authorChesler, L
dc.contributor.authorSchmidt, R
dc.contributor.authorBurchill, SA
dc.contributor.authorHaber, M
dc.contributor.authorDe Santo, C
dc.contributor.authorMussai, F
dc.date.accessioned2019-04-10T11:24:19Z
dc.date.issued2019-02
dc.identifier.citationCancer research, 2019, 79 (3), pp. 611 - 624
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3178
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-18-2139
dc.description.abstractNeuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1β and TNFα in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1β and TNFα established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest-derived cells. Proteomic analysis revealed that enrichment of IL1β and TNFα in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited. SIGNIFICANCE: These findings illustrate that cross-talk between myeloid cells and tumor cells creates a metabolic regulatory loop that promotes neuroblastoma progression.
dc.formatPrint-Electronic
dc.format.extent611 - 624
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectMacrophages
dc.subjectMyeloid Cells
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectHumans
dc.subjectMice
dc.subjectNeuroblastoma
dc.subjectArginase
dc.subjectArginine
dc.subjectTumor Necrosis Factor-alpha
dc.subjectMAP Kinase Signaling System
dc.subjectInterleukin-1beta
dc.subjectTumor Microenvironment
dc.subjectSarcoma, Ewing
dc.titleMacrophage-Derived IL1β and TNFα Regulate Arginine Metabolism in Neuroblastoma.
dc.typeJournal Article
dcterms.dateAccepted2018-12-05
rioxxterms.versionofrecord10.1158/0008-5472.can-18-2139
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2019-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue3
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.publication-statusPublished
pubs.volume79
pubs.embargo.termsNot known
icr.researchteamPaediatric Solid Tumour Biology and Therapeuticsen_US
dc.contributor.icrauthorChesler, Louisen


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