Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Sympathetic nervous system regulation of tumor associated macrophages in metastasis (#186)

Matthew A Pimentel 1 , Saul J Priceman 2 , Erica K Sloan 1
  1. Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia
  2. Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, United States

Macrophage recruitment has been associated with poor prognosis in solid cancers by promoting angiogenesis and suppressing anti-tumor immune responses. Using a mouse model of breast cancer, we have shown that chronic stress increased recruitment of macrophages to the primary tumor. Stress increased metastasis to lymph node and lung and was dependent on beta-adrenergic signaling to tumor-associated macrophages. To begin to understand the role of macrophages in neural regulation of metastasis, we carried out global gene expression profiling using Illumina mouse Ref8 beadarrays on tumor-associated macrophages to identify SNS-responsive macrophage genes. To confirm a role for adrenergic signaling we also investigated the effect of norepinephrine on bone marrow derived macrophages. Consistent with the functional changes in pro-inflammatory responses, proliferation and invasive properties, gene ontology analyses of upregulated genes found overrepresentation of neural-responsive genes with functional roles in arginine metabolism (ARG1, ARG2), cell cycle regulation (CCND1), reorganization of the actin cytoskeleton (DIAPH1, WASF1), and pro-inflammatory cytokines, chemokines, and receptors for inflammatory mediators (IL1B, IL-15, TLR2, CD14, HIF1A VEGFA, IL22RA, CXCL14). Neural regulation of macrophages resulted in down regulation of genes involved in cell cycle, DNA replication, and base excision repair (CCND2, PCNA, MCM5, MCM6, UNG) and the lysosome compartment (CTSZ, HEXB, ATP6V0A1), all p < 0.05. Current studies are elucidating the signaling pathways required for macrophages to induce primary tumor cell dissemination, and to investigate therapeutic strategies for blocking neural regulation of macrophage-tumor interactions.