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A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth
Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821896/ https://www.ncbi.nlm.nih.gov/pubmed/34274535 http://dx.doi.org/10.1016/j.ymthe.2021.07.003 |
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author | Han, Bingchen Alonso-Valenteen, Felix Wang, Zhe Deng, Nan Lee, Tian-Yu Gao, Bowen Zhang, Ying Xu, Yali Zhang, Xinfeng Billet, Sandrine Fan, Xuemo Shiao, Stephen Bhowmick, Neil Medina-Kauwe, Lali Giuliano, Armando Cui, Xiaojiang |
author_facet | Han, Bingchen Alonso-Valenteen, Felix Wang, Zhe Deng, Nan Lee, Tian-Yu Gao, Bowen Zhang, Ying Xu, Yali Zhang, Xinfeng Billet, Sandrine Fan, Xuemo Shiao, Stephen Bhowmick, Neil Medina-Kauwe, Lali Giuliano, Armando Cui, Xiaojiang |
author_sort | Han, Bingchen |
collection | PubMed |
description | Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC. |
format | Online Article Text |
id | pubmed-8821896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-88218962023-02-02 A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth Han, Bingchen Alonso-Valenteen, Felix Wang, Zhe Deng, Nan Lee, Tian-Yu Gao, Bowen Zhang, Ying Xu, Yali Zhang, Xinfeng Billet, Sandrine Fan, Xuemo Shiao, Stephen Bhowmick, Neil Medina-Kauwe, Lali Giuliano, Armando Cui, Xiaojiang Mol Ther Original Article Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC. American Society of Gene & Cell Therapy 2022-02-02 2021-07-16 /pmc/articles/PMC8821896/ /pubmed/34274535 http://dx.doi.org/10.1016/j.ymthe.2021.07.003 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Han, Bingchen Alonso-Valenteen, Felix Wang, Zhe Deng, Nan Lee, Tian-Yu Gao, Bowen Zhang, Ying Xu, Yali Zhang, Xinfeng Billet, Sandrine Fan, Xuemo Shiao, Stephen Bhowmick, Neil Medina-Kauwe, Lali Giuliano, Armando Cui, Xiaojiang A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
title | A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
title_full | A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
title_fullStr | A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
title_full_unstemmed | A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
title_short | A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
title_sort | chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821896/ https://www.ncbi.nlm.nih.gov/pubmed/34274535 http://dx.doi.org/10.1016/j.ymthe.2021.07.003 |
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