Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-oste...

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Autores principales:	Ke-Xin Li, Xun Sun, Bai-Yan Li, Hiroki Yokota
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	osteoclasts breast cancer bone metastasis iTS cells Wnt signaling Hsp90ab1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6fe5fef72a444a3ab14d265d934101da
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spelling	oai:doaj.org-article:6fe5fef72a444a3ab14d265d934101da2021-11-25T17:00:57ZConversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells10.3390/cancers132255932072-6694https://doaj.org/article/6fe5fef72a444a3ab14d265d934101da2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5593https://doaj.org/toc/2072-6694Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.Ke-Xin LiXun SunBai-Yan LiHiroki YokotaMDPI AGarticleosteoclastsbreast cancerbone metastasisiTS cellsWnt signalingHsp90ab1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5593, p 5593 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	osteoclasts breast cancer bone metastasis iTS cells Wnt signaling Hsp90ab1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	osteoclasts breast cancer bone metastasis iTS cells Wnt signaling Hsp90ab1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ke-Xin Li Xun Sun Bai-Yan Li Hiroki Yokota Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
description	Osteoclasts are a driver of a vicious bone-destructive cycle with breast cancer cells. Here, we examined whether this vicious cycle can be altered into a beneficial one by activating Wnt signaling with its activating agent, BML284. The conditioned medium, derived from Wnt-activated RAW264.7 pre-osteoclast cells (BM CM), reduced the proliferation, migration, and invasion of EO771 mammary tumor cells. The same inhibitory effect was obtained with BML284-treated primary human macrophages. In a mouse model, BM CM reduced the progression of mammary tumors and tumor-induced osteolysis and suppressed the tumor invasion to the lung. It also inhibited the differentiation of RANKL-stimulated osteoclasts and enhanced osteoblast differentiation. BM CM was enriched with atypical tumor-suppressing proteins such as Hsp90ab1 and enolase 1 (Eno1). Immunoprecipitation revealed that extracellular Hsp90ab1 interacted with latent TGFβ (LAP-TGFβ) as an inhibitor of TGFβ activation, while Hsp90ab1 and Eno1 interacted and suppressed tumor progression via CD44, a cell-adhesion receptor and a cancer stem cell marker. This study demonstrated that osteoclast-derived CM can be converted into a bone-protective, tumor-suppressing agent by activating Wnt signaling. The results shed a novel insight on the unexplored function of osteoclasts as a potential bone protector that may develop an unconventional strategy to combat bone metastasis.
format	article
author	Ke-Xin Li Xun Sun Bai-Yan Li Hiroki Yokota
author_facet	Ke-Xin Li Xun Sun Bai-Yan Li Hiroki Yokota
author_sort	Ke-Xin Li
title	Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
title_short	Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
title_full	Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
title_fullStr	Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
title_full_unstemmed	Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells
title_sort	conversion of osteoclasts into bone-protective, tumor-suppressing cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/6fe5fef72a444a3ab14d265d934101da
work_keys_str_mv	AT kexinli conversionofosteoclastsintoboneprotectivetumorsuppressingcells AT xunsun conversionofosteoclastsintoboneprotectivetumorsuppressingcells AT baiyanli conversionofosteoclastsintoboneprotectivetumorsuppressingcells AT hirokiyokota conversionofosteoclastsintoboneprotectivetumorsuppressingcells
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Conversion of Osteoclasts into Bone-Protective, Tumor-Suppressing Cells

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