Abstract：
: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 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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Fultang L,Gamble LD,Gneo L,Berry AM,Egan SA,De Bie F,Yogev O,Eden GL,Booth S,Brownhill S,Vardon A,McConville CM,Cheng PN,Norris MD,Etchevers HC,Murray J,Ziegler DS,Chesler L,Schmidt R,Burchill SA,Haber M,De Santdoi
10.1158/0008-5472.CAN-18-2139subject
Has Abstractpub_date
2019-02-01 00:00:00pages
611-624issue
3eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-18-2139journal_volume
79pub_type
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