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NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model.
NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model.
- Source :
-
Breast cancer research : BCR [Breast Cancer Res] 2011 Aug 31; Vol. 13 (4), pp. R83. Date of Electronic Publication: 2011 Aug 31. - Publication Year :
- 2011
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Abstract
- Introduction: Metastasis from primary tumor to the lungs is a major cause of the mortality associated with breast cancer. Both immune and inflammatory responses impact whether circulating mammary tumor cells successfully colonize the lungs leading to established metastases. Nuclear factor -kappaB (NF-κB) transcription factors regulate both immune and inflammatory responses mediated in part by the activities of macrophages. Therefore, NF-κB activity specifically within macrophages may be a critical determinant of whether circulating tumor cells successfully colonize the lungs.<br />Methods: To investigate NF-κB signaling within macrophages during metastasis, we developed novel inducible transgenic models which target expression of the reverse tetracycline transactivator (rtTA) to macrophages using the cfms promoter in combination with inducible transgenics that express either an activator (cIKK2) or an inhibitor (IκBα-DN). Doxycyline treatment led to activation or inhibition of NF-κB within macrophages. We used a tail vein metastasis model with mammary tumor cell lines established from MMTV-Polyoma Middle T-Antigen-derived tumors to investigate the effects of modulating NF-κB in macrophages during different temporal windows of the metastatic process.<br />Results: We found that activation of NF-κB in macrophages during seeding leads to a reduction in lung metastases. The mechanism involved expression of inflammatory cytokines and reactive oxygen species, leading to apoptosis of tumor cells and preventing seeding in the lung. Activation of NF-κB within macrophages after the seeding phase has no significant impact on establishment of metastases.<br />Conclusions: Our results have identified a brief, defined window in which activation of NF-κB has significant anti-metastatic effects and inhibition of NF-κB results in a worse outcome.
- Subjects :
- Animals
CD11b Antigen metabolism
Chemokine CXCL9 metabolism
Female
Floxuridine pharmacology
I-kappa B Kinase genetics
Lung metabolism
Lung pathology
Lung Neoplasms metabolism
Macrophages drug effects
Macrophages pathology
Mice
Mice, Transgenic
NF-kappa B antagonists & inhibitors
Phenotype
Polyomavirus pathogenicity
Promoter Regions, Genetic
Reactive Oxygen Species
Receptors, Colony-Stimulating Factor genetics
Signal Transduction
Veins virology
Lung Neoplasms pathology
Lung Neoplasms secondary
Macrophages metabolism
Mammary Neoplasms, Experimental pathology
NF-kappa B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1465-542X
- Volume :
- 13
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Breast cancer research : BCR
- Publication Type :
- Academic Journal
- Accession number :
- 21884585
- Full Text :
- https://doi.org/10.1186/bcr2935