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Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using...

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Autores principales: Campbell, J. Preston, Karolak, Matthew R., Ma, Yun, Perrien, Daniel S., Masood-Campbell, S. Kathryn, Penner, Niki L., Munoz, Steve A., Zijlstra, Andries, Yang, Xiangli, Sterling, Julie A., Elefteriou, Florent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398959/
https://www.ncbi.nlm.nih.gov/pubmed/22815651
http://dx.doi.org/10.1371/journal.pbio.1001363
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author Campbell, J. Preston
Karolak, Matthew R.
Ma, Yun
Perrien, Daniel S.
Masood-Campbell, S. Kathryn
Penner, Niki L.
Munoz, Steve A.
Zijlstra, Andries
Yang, Xiangli
Sterling, Julie A.
Elefteriou, Florent
author_facet Campbell, J. Preston
Karolak, Matthew R.
Ma, Yun
Perrien, Daniel S.
Masood-Campbell, S. Kathryn
Penner, Niki L.
Munoz, Steve A.
Zijlstra, Andries
Yang, Xiangli
Sterling, Julie A.
Elefteriou, Florent
author_sort Campbell, J. Preston
collection PubMed
description Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the “vicious cycle” of bone destruction induced by these cells.
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spelling pubmed-33989592012-07-19 Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice Campbell, J. Preston Karolak, Matthew R. Ma, Yun Perrien, Daniel S. Masood-Campbell, S. Kathryn Penner, Niki L. Munoz, Steve A. Zijlstra, Andries Yang, Xiangli Sterling, Julie A. Elefteriou, Florent PLoS Biol Research Article Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the “vicious cycle” of bone destruction induced by these cells. Public Library of Science 2012-07-17 /pmc/articles/PMC3398959/ /pubmed/22815651 http://dx.doi.org/10.1371/journal.pbio.1001363 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Campbell, J. Preston
Karolak, Matthew R.
Ma, Yun
Perrien, Daniel S.
Masood-Campbell, S. Kathryn
Penner, Niki L.
Munoz, Steve A.
Zijlstra, Andries
Yang, Xiangli
Sterling, Julie A.
Elefteriou, Florent
Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
title Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
title_full Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
title_fullStr Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
title_full_unstemmed Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
title_short Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
title_sort stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398959/
https://www.ncbi.nlm.nih.gov/pubmed/22815651
http://dx.doi.org/10.1371/journal.pbio.1001363
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