期刊
CANCER RESEARCH
卷 79, 期 3, 页码 611-624出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-2139
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类别
资金
- Cancer Research UK
- Niayah's Fund
- Neuroblastoma UK
- Children with Cancer
- Treating Children with Cancer
- Children's Cancer
- Leukaemia Group
- Association Francaise contre les Myopathies
- National Health and Medical Research Council Australia
- Cancer Institute
- AKO Foundation
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 IL1 beta and TNF alpha in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1 beta and TNF alpha 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 IL1 beta and TNF alpha 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.
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