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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.

Authors :
Connelly L
Barham W
Onishko HM
Chen L
Sherrill TP
Zabuawala T
Ostrowski MC
Blackwell TS
Yull FE
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

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.

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