| First Author | Fultang L | Year | 2019 |
| Journal | Cancer Res | Volume | 79 |
| Issue | 3 | Pages | 611-624 |
| PubMed ID | 30545920 | Mgi Jnum | J:271301 |
| Mgi Id | MGI:6279705 | Doi | 10.1158/0008-5472.CAN-18-2139 |
| Citation | Fultang L, et al. (2019) Macrophage-Derived IL1beta and TNFalpha Regulate Arginine Metabolism in Neuroblastoma. Cancer Res 79(3):611-624 |
| abstractText | : 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 IL1beta and TNFalpha in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner. IL1beta and TNFalpha 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 IL1beta and TNFalpha 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. |
