Journal
ONCOGENE
Volume 32, Issue 5, Pages 631-640Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.77
Keywords
immunity; sphingolipids; cancer; nerve growth factor; trafficking
Funding
- DFG [Br999, FOG 784, GRK 757]
- Sander Foundation [2007.070.2]
- Deutsche Krebshilfe [109599]
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Tumor-associated macrophages (TAMs) are a major supportive component within neoplasms. Mechanisms of macrophage (M(1)) attraction and differentiation to a tumor-promoting phenotype, which is characterized by pronounced interleukin (IL)-10 production, are under investigation. We report that supernatants of dying cancer cells induced substantial IL-10 release from primary human MOs, dependent on signaling through tyrosine kinase receptor A (TRKA or neurotrophic tyrosine kinase receptor type 1 (NTRK1)). Mechanistically, sphingosine-1-phosphate (SIP) release from apoptotic cancer cells triggered src-dependent shuttling of cytosolic TRKA to the plasma membrane via S1P receptor signaling. Plasma membrane-associated TRKA, which was activated by constitutively autocrine secreted nerve growth factor, used phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase (MAPK) signaling to induce IL-10. Interestingly, TRKA-dependent signaling was required for cytokine production by TAMs isolated from primary murine breast cancer tissue. Besides IL-10, this pathway initiated secretion of IL-6, tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein-1 (MCP-1), indicating relevance in cancer-associated inflammation. Our findings highlight a fine-tuned regulatory system including S1P-dependent TRKA trafficking for executing TAM-like cell function in vitro as well as in vivo. Oncogene (2013) 32, 631-640; doi:10.1038/onc.2012.77; published online 12 March 2012
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