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Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer

Breast cancer (BC) is the second-most common cause of brain metastases (BM) and BCBM patients have a reduced quality of life and a poor prognosis. Hyaluronan (HA), and in particular the hyaluronidase Hyal-1, has been already linked to the development of BCBM, and therefore presents an interesting op...

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Autores principales: Hamester, Fabienne, Stürken, Christine, Legler, Karen, Eylmann, Kathrin, Möller, Katrin, Roßberg, Maila, Gorzelanny, Christian, Bauer, Alexander T., Windhorst, Sabine, Schmalfeldt, Barbara, Laakmann, Elena, Müller, Volkmar, Witzel, Isabell, Oliveira-Ferrer, Leticia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600690/
https://www.ncbi.nlm.nih.gov/pubmed/36291142
http://dx.doi.org/10.3390/cells11203275
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author Hamester, Fabienne
Stürken, Christine
Legler, Karen
Eylmann, Kathrin
Möller, Katrin
Roßberg, Maila
Gorzelanny, Christian
Bauer, Alexander T.
Windhorst, Sabine
Schmalfeldt, Barbara
Laakmann, Elena
Müller, Volkmar
Witzel, Isabell
Oliveira-Ferrer, Leticia
author_facet Hamester, Fabienne
Stürken, Christine
Legler, Karen
Eylmann, Kathrin
Möller, Katrin
Roßberg, Maila
Gorzelanny, Christian
Bauer, Alexander T.
Windhorst, Sabine
Schmalfeldt, Barbara
Laakmann, Elena
Müller, Volkmar
Witzel, Isabell
Oliveira-Ferrer, Leticia
author_sort Hamester, Fabienne
collection PubMed
description Breast cancer (BC) is the second-most common cause of brain metastases (BM) and BCBM patients have a reduced quality of life and a poor prognosis. Hyaluronan (HA), and in particular the hyaluronidase Hyal-1, has been already linked to the development of BCBM, and therefore presents an interesting opportunity to develop new effective therapeutic options. HA metabolism was further discovered by the CRISPR/Cas9-mediated knockout of HYAL1 and the shRNA-mediated down-regulation of HA-receptor CD44 in the brain-seeking triple-negative breast cancer (TNBC) cell line MDA-MB-231-BR. Therefore, the impact of Hyal-1 on adhesion, disruption, and invasion through the brain endothelium, both in vitro and in vivo, was studied. Our analysis points out a key role of Hyal-1 and low-molecular-weight HA (LMW-HA) in the formation of a pericellular HA-coat in BC cells, which in turn promotes tumor cell adhesion, disruption, and migration through the brain endothelium in vitro as well as the extent of BM in vivo. CD44 knockdown in MDA-MB-231-BR significantly reduced the pericellular HA-coat on these cells, and, consequently, tumor cell adhesion and invasion through the brain endothelium. Thus, the interaction between Hyal-1-generated LMW-HA fragments and the HA-receptor CD44 might represent a potential target for future therapeutic options in BC patients with a high risk of cerebral metastases formation.
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spelling pubmed-96006902022-10-27 Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer Hamester, Fabienne Stürken, Christine Legler, Karen Eylmann, Kathrin Möller, Katrin Roßberg, Maila Gorzelanny, Christian Bauer, Alexander T. Windhorst, Sabine Schmalfeldt, Barbara Laakmann, Elena Müller, Volkmar Witzel, Isabell Oliveira-Ferrer, Leticia Cells Article Breast cancer (BC) is the second-most common cause of brain metastases (BM) and BCBM patients have a reduced quality of life and a poor prognosis. Hyaluronan (HA), and in particular the hyaluronidase Hyal-1, has been already linked to the development of BCBM, and therefore presents an interesting opportunity to develop new effective therapeutic options. HA metabolism was further discovered by the CRISPR/Cas9-mediated knockout of HYAL1 and the shRNA-mediated down-regulation of HA-receptor CD44 in the brain-seeking triple-negative breast cancer (TNBC) cell line MDA-MB-231-BR. Therefore, the impact of Hyal-1 on adhesion, disruption, and invasion through the brain endothelium, both in vitro and in vivo, was studied. Our analysis points out a key role of Hyal-1 and low-molecular-weight HA (LMW-HA) in the formation of a pericellular HA-coat in BC cells, which in turn promotes tumor cell adhesion, disruption, and migration through the brain endothelium in vitro as well as the extent of BM in vivo. CD44 knockdown in MDA-MB-231-BR significantly reduced the pericellular HA-coat on these cells, and, consequently, tumor cell adhesion and invasion through the brain endothelium. Thus, the interaction between Hyal-1-generated LMW-HA fragments and the HA-receptor CD44 might represent a potential target for future therapeutic options in BC patients with a high risk of cerebral metastases formation. MDPI 2022-10-18 /pmc/articles/PMC9600690/ /pubmed/36291142 http://dx.doi.org/10.3390/cells11203275 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hamester, Fabienne
Stürken, Christine
Legler, Karen
Eylmann, Kathrin
Möller, Katrin
Roßberg, Maila
Gorzelanny, Christian
Bauer, Alexander T.
Windhorst, Sabine
Schmalfeldt, Barbara
Laakmann, Elena
Müller, Volkmar
Witzel, Isabell
Oliveira-Ferrer, Leticia
Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer
title Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer
title_full Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer
title_fullStr Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer
title_full_unstemmed Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer
title_short Key Role of Hyaluronan Metabolism for the Development of Brain Metastases in Triple-Negative Breast Cancer
title_sort key role of hyaluronan metabolism for the development of brain metastases in triple-negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600690/
https://www.ncbi.nlm.nih.gov/pubmed/36291142
http://dx.doi.org/10.3390/cells11203275
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