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Review
. 2010 Feb 1;16(3):784-9.
doi: 10.1158/1078-0432.CCR-09-1015. Epub 2010 Jan 26.

Nuclear factor-kappaB and tumor-associated macrophages

Alessandra Mancino  1 , Toby Lawrence
Affiliations
Review

Nuclear factor-kappaB and tumor-associated macrophages

Alessandra Mancino et al. Clin Cancer Res. .

Abstract

Tumor-associated macrophages (TAM) have been linked with the progression of cancer by favoring tumor angiogenesis, growth, and metastasis. The precise mechanisms that maintain the protumor phenotype of TAM are poorly understood, but recent research has highlighted a number of signaling pathways that are important in TAM phenotype and function. Nuclear factor-kappaB (NF-kappaB) is considered the master regulator of inflammatory and immune responses. Recently several genetic studies have indicated NF-kappaB is an important pathway in TAM for the integration of signals from the tumor microenvironment that promote carcinogenesis. This review will focus on the role of NF-kappaB in TAM and the potential of targeting this pathway as a novel therapeutic strategy against cancer.

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Figures

Figure 1
Figure 1. Signaling pathways regulating TAM phenotype and function
Various factors have been suggested to activate the pro-tumor phenotype of TAM; extracellular matrix (ECM) components, such as hyaluronan (HA) and versican, pro-inflammatory cytokines IL-1 and TNFα, and tumor hypoxia activates both HIF-1 and NF-κB. Collectively these signaling pathways favor the transcription of genes promoting angiogenesis, malignant cell survival, invasion and metastasis. Engagement of TLRs or the IL-1 receptor (IL-1R) triggers expression of pro-inflammatory cytokines and anti-apoptotic genes through the adaptor protein MyD88 and classical NF-κB activation. TLR/IL-1R signaling also triggers MAPK and AP-1 activation, co-regulating the expression of pro-inflammatory and anti-inflammatory genes. TLR4 also triggers a MyD88-independent pathway, through the adaptor molecule TRIF, to induce the phosphorylation of TBK and the downstream activation of IRF3, which regulates the transcription of type I interferons (IFN). M1 macrophages are characterized by IFN-mediated expression of STAT1/2-dependent genes including NOS2, IL-12 and MHC II. Whereas, the M2 phenotype is associated with IL-10, IL-4 and IL-13 signaling through STAT3 and STAT6. There are several levels of cross-talk between these pathways that regulate macrophage activation; over-expression of p50 negatively regulates NF-κB dependent pro-inflammatory gene transcription, STAT3/6 antagonize STAT1 activation, and NF-κB was also recently shown to inhibit STAT1 activity.
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References

    1. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44. - PubMed
    1. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8. - PubMed
    1. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12. - PubMed
    1. Murdoch C, Tazzyman S, Webster S, Lewis CE. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol. 2007;178:7405–11. - PubMed
    1. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55. - PubMed