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NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model

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 (N...

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Autores principales: Connelly, Linda, Barham, Whitney, Onishko, Halina M, Chen, Lianyi, Sherrill, Taylor P, Zabuawala, Tahera, Ostrowski, Michael C, Blackwell, Timothy S, Yull, Fiona E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236346/
https://www.ncbi.nlm.nih.gov/pubmed/21884585
http://dx.doi.org/10.1186/bcr2935
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author Connelly, Linda
Barham, Whitney
Onishko, Halina M
Chen, Lianyi
Sherrill, Taylor P
Zabuawala, Tahera
Ostrowski, Michael C
Blackwell, Timothy S
Yull, Fiona E
author_facet Connelly, Linda
Barham, Whitney
Onishko, Halina M
Chen, Lianyi
Sherrill, Taylor P
Zabuawala, Tahera
Ostrowski, Michael C
Blackwell, Timothy S
Yull, Fiona E
author_sort Connelly, Linda
collection PubMed
description 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. 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. 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. 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.
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spelling pubmed-32363462011-12-14 NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model Connelly, Linda Barham, Whitney Onishko, Halina M Chen, Lianyi Sherrill, Taylor P Zabuawala, Tahera Ostrowski, Michael C Blackwell, Timothy S Yull, Fiona E Breast Cancer Res Research Article 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. 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. 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. 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. BioMed Central 2011 2011-08-31 /pmc/articles/PMC3236346/ /pubmed/21884585 http://dx.doi.org/10.1186/bcr2935 Text en Copyright ©2011 Connelly et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Connelly, Linda
Barham, Whitney
Onishko, Halina M
Chen, Lianyi
Sherrill, Taylor P
Zabuawala, Tahera
Ostrowski, Michael C
Blackwell, Timothy S
Yull, Fiona E
NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
title NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
title_full NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
title_fullStr NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
title_full_unstemmed NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
title_short NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
title_sort nf-kappab activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236346/
https://www.ncbi.nlm.nih.gov/pubmed/21884585
http://dx.doi.org/10.1186/bcr2935
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