Cargando…

A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment

Production of metastasis capable precursors begins within the primary tumor. Here, we define the bidirectional interactions with stromal cells involved in promoting these precursors within BRCA1-IRIS (hereafter IRIS) overexpressing (IRISOE) TNBC tumors. We define an aggressiveness niche, functionall...

Descripción completa

Detalles Bibliográficos
Autores principales: Ryan, Daniel, Bogan, Danielle, Davies, Joanna, Koziol, Jim, ElShamy, Wael M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732721/
https://www.ncbi.nlm.nih.gov/pubmed/29262555
http://dx.doi.org/10.18632/oncotarget.20892
_version_ 1783286764398444544
author Ryan, Daniel
Bogan, Danielle
Davies, Joanna
Koziol, Jim
ElShamy, Wael M.
author_facet Ryan, Daniel
Bogan, Danielle
Davies, Joanna
Koziol, Jim
ElShamy, Wael M.
author_sort Ryan, Daniel
collection PubMed
description Production of metastasis capable precursors begins within the primary tumor. Here, we define the bidirectional interactions with stromal cells involved in promoting these precursors within BRCA1-IRIS (hereafter IRIS) overexpressing (IRISOE) TNBC tumors. We define an aggressiveness niche, functionally defined as the necrotic/hypoxic core of the tumor, in which metabolically stressed, hypoxic, and inflamed IRISOE TNBC cells secrete higher levels of cytokines, chemokines and growth factors. One cytokine; IL-1β attracts mesenchymal stem cells (MSCs) to the niche and activates them to secrete CXCL1 that entrains IRISOE cells to secrete higher levels of CCL2 and VEGF. CCL2 attracts macrophages (TAMs) to the niche and activates them to secrete S100A8, and VEGF attracts endothelial cells (ECs) and activates them to secrete IL-8. In concert, CXCL1, S100A8 and IL-8 entrain aggressiveness in IRISOE TNBC cells within the niche. Indeed, compared to IRISOE cells alone, tumors developed by co-injecting IRISOE cells admixed with MSCs (10:1) in athymic mice were bigger and more aggressive. They contained more TAMs and ECs, expressed higher-levels of basal, epithelial to mesenchymal transition, and stemness biomarkers, quickly progressed to lymph-node or visceral metastases, and were highly sensitive to the IL-1β inhibitor “Anakinra”. Our findings supported by human data show that breast cancer patients with high-levels of IL-1β, CXCL1, CCL2, S100A8, VEGF, and IL-8 would show worse clinical outcomes. Our findings argue that this cytokine set is a diagnostic biomarker for patients who may benefit from an IRIS inhibitor-based therapy, and is a blue print for translation of approaches to combining that therapy with inhibitors of these bidirectional interactions to overcome TNBC metastasis.
format Online
Article
Text
id pubmed-5732721
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-57327212017-12-19 A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment Ryan, Daniel Bogan, Danielle Davies, Joanna Koziol, Jim ElShamy, Wael M. Oncotarget Research Paper Production of metastasis capable precursors begins within the primary tumor. Here, we define the bidirectional interactions with stromal cells involved in promoting these precursors within BRCA1-IRIS (hereafter IRIS) overexpressing (IRISOE) TNBC tumors. We define an aggressiveness niche, functionally defined as the necrotic/hypoxic core of the tumor, in which metabolically stressed, hypoxic, and inflamed IRISOE TNBC cells secrete higher levels of cytokines, chemokines and growth factors. One cytokine; IL-1β attracts mesenchymal stem cells (MSCs) to the niche and activates them to secrete CXCL1 that entrains IRISOE cells to secrete higher levels of CCL2 and VEGF. CCL2 attracts macrophages (TAMs) to the niche and activates them to secrete S100A8, and VEGF attracts endothelial cells (ECs) and activates them to secrete IL-8. In concert, CXCL1, S100A8 and IL-8 entrain aggressiveness in IRISOE TNBC cells within the niche. Indeed, compared to IRISOE cells alone, tumors developed by co-injecting IRISOE cells admixed with MSCs (10:1) in athymic mice were bigger and more aggressive. They contained more TAMs and ECs, expressed higher-levels of basal, epithelial to mesenchymal transition, and stemness biomarkers, quickly progressed to lymph-node or visceral metastases, and were highly sensitive to the IL-1β inhibitor “Anakinra”. Our findings supported by human data show that breast cancer patients with high-levels of IL-1β, CXCL1, CCL2, S100A8, VEGF, and IL-8 would show worse clinical outcomes. Our findings argue that this cytokine set is a diagnostic biomarker for patients who may benefit from an IRIS inhibitor-based therapy, and is a blue print for translation of approaches to combining that therapy with inhibitors of these bidirectional interactions to overcome TNBC metastasis. Impact Journals LLC 2017-09-14 /pmc/articles/PMC5732721/ /pubmed/29262555 http://dx.doi.org/10.18632/oncotarget.20892 Text en Copyright: © 2017 Ryan et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Ryan, Daniel
Bogan, Danielle
Davies, Joanna
Koziol, Jim
ElShamy, Wael M.
A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
title A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
title_full A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
title_fullStr A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
title_full_unstemmed A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
title_short A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
title_sort niche that triggers aggressiveness within brca1-iris overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732721/
https://www.ncbi.nlm.nih.gov/pubmed/29262555
http://dx.doi.org/10.18632/oncotarget.20892
work_keys_str_mv AT ryandaniel anichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT bogandanielle anichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT daviesjoanna anichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT kozioljim anichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT elshamywaelm anichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT ryandaniel nichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT bogandanielle nichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT daviesjoanna nichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT kozioljim nichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment
AT elshamywaelm nichethattriggersaggressivenesswithinbrca1irisoverexpressingtriplenegativetumorsissupportedbyreciprocalinteractionswiththemicroenvironment