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Macrophage-derived IL-1? and TNF-? regulate arginine metabolism in neuroblastoma

Burchill, Susan A.; Ziegler, David S.; Etchevers, Heather C.; Norris, Murray D.; Cheng, Paul N.; McConville, Carmel M.; Berry, Andrea M.; Gamble, Laura D.; Fultang, Livingstone; Gamble, Laura D; Gneo, Luciana; Berry, Andrea M; Egan, Sharon A.; De Bie, Fenna; Yogev, Orli; Eden, Georgina L.; Booth, Sarah; Brownhill, Samantha; Vardon, Ashley; McConville, Carmel M; Cheng, Paul N; Norris, Murray D; Etchevers, Heather C; Murray, Jayne; Ziegler, David S; Chesler, Louis; Schmidt, Ronny; Burchill, Susan A; Haber, Michelle; De Santo, Carmela; Mussai, Francis

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Authors

Susan A. Burchill

David S. Ziegler

Heather C. Etchevers

Murray D. Norris

Paul N. Cheng

Carmel M. McConville

Andrea M. Berry

Laura D. Gamble

Livingstone Fultang

Laura D Gamble

Luciana Gneo

Andrea M Berry

Sharon A. Egan

Fenna De Bie

Orli Yogev

Georgina L. Eden

Sarah Booth

Samantha Brownhill

Ashley Vardon

Carmel M McConville

Paul N Cheng

Murray D Norris

Heather C Etchevers

Jayne Murray

David S Ziegler

Louis Chesler

Ronny Schmidt

Susan A Burchill

Michelle Haber

Carmela De Santo

Francis Mussai



Abstract

© 2018 American Association for Cancer Research. Neuroblastoma 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 IL1b and TNFa in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1b and TNFa 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 IL1b and TNFa 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.

Journal Article Type Article
Acceptance Date Dec 5, 2018
Online Publication Date Dec 19, 2018
Publication Date 2019-02
Deposit Date Jan 7, 2019
Publicly Available Date Jan 7, 2019
Journal Cancer Research
Print ISSN 0008-5472
Electronic ISSN 1538-7445
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 79
Issue 3
Pages 611-624
DOI https://doi.org/10.1158/0008-5472.CAN-18-2139
Keywords Cancer Research; Oncology
Public URL https://nottingham-repository.worktribe.com/output/1447746
Publisher URL http://cancerres.aacrjournals.org/content/early/2018/12/19/0008-5472.CAN-18-2139

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