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The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment

Background: Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. Methods: Mouse mammary...

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Autores principales: Futakuchi, Mitsuru, Lami, Kris, Tachibana, Yuri, Yamamoto, Yukari, Furukawa, Masahiro, Fukuoka, Junya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829436/
https://www.ncbi.nlm.nih.gov/pubmed/31619018
http://dx.doi.org/10.3390/ijms20205117
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author Futakuchi, Mitsuru
Lami, Kris
Tachibana, Yuri
Yamamoto, Yukari
Furukawa, Masahiro
Fukuoka, Junya
author_facet Futakuchi, Mitsuru
Lami, Kris
Tachibana, Yuri
Yamamoto, Yukari
Furukawa, Masahiro
Fukuoka, Junya
author_sort Futakuchi, Mitsuru
collection PubMed
description Background: Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. Methods: Mouse mammary tumor cells were implanted under the dorsal skin flap over the calvaria and into a subcutaneous (subQ) lesions in female mice, generating tumors in the bone and subQ micro-Es. After implantation of the tumor cells, mice were treated with a TGF-β R1 kinase inhibitor (R1-Ki). Results: Treatment with R1-Ki decreased tumor volume and cell proliferation in the bone micro-E, but not in the subQ micro-E. R1-Ki treatment did not affect the induction of necrosis or apoptosis in either bone or subQ micro-E. The number of cells positive for the CSC markers, SOX2, and CD166 in the bone micro-E, were significantly higher than those in the subQ micro-E. R1-Ki treatment significantly decreased the number of CSC marker positive cells in the bone micro-E but not in the subQ micro-E. TGF-β activation of the MAPK/ERK and AKT pathways was the underlying mechanism of cell proliferation in the bone micro-E. BMP signaling did not play a role in cell proliferation in either micro-E. Conclusion: Our results indicated that the bone micro-E is a key niche for CSC generation, and TGF-β signaling has important roles in generating CSCs and tumor cell proliferation in the bone micro-E. Therefore, it is critically important to evaluate responses to chemotherapeutic agents on both cancer stem cells and proliferating tumor cells in different tumor microenvironments in vivo.
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spelling pubmed-68294362019-11-18 The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment Futakuchi, Mitsuru Lami, Kris Tachibana, Yuri Yamamoto, Yukari Furukawa, Masahiro Fukuoka, Junya Int J Mol Sci Article Background: Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. Methods: Mouse mammary tumor cells were implanted under the dorsal skin flap over the calvaria and into a subcutaneous (subQ) lesions in female mice, generating tumors in the bone and subQ micro-Es. After implantation of the tumor cells, mice were treated with a TGF-β R1 kinase inhibitor (R1-Ki). Results: Treatment with R1-Ki decreased tumor volume and cell proliferation in the bone micro-E, but not in the subQ micro-E. R1-Ki treatment did not affect the induction of necrosis or apoptosis in either bone or subQ micro-E. The number of cells positive for the CSC markers, SOX2, and CD166 in the bone micro-E, were significantly higher than those in the subQ micro-E. R1-Ki treatment significantly decreased the number of CSC marker positive cells in the bone micro-E but not in the subQ micro-E. TGF-β activation of the MAPK/ERK and AKT pathways was the underlying mechanism of cell proliferation in the bone micro-E. BMP signaling did not play a role in cell proliferation in either micro-E. Conclusion: Our results indicated that the bone micro-E is a key niche for CSC generation, and TGF-β signaling has important roles in generating CSCs and tumor cell proliferation in the bone micro-E. Therefore, it is critically important to evaluate responses to chemotherapeutic agents on both cancer stem cells and proliferating tumor cells in different tumor microenvironments in vivo. MDPI 2019-10-15 /pmc/articles/PMC6829436/ /pubmed/31619018 http://dx.doi.org/10.3390/ijms20205117 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Futakuchi, Mitsuru
Lami, Kris
Tachibana, Yuri
Yamamoto, Yukari
Furukawa, Masahiro
Fukuoka, Junya
The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
title The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
title_full The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
title_fullStr The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
title_full_unstemmed The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
title_short The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment
title_sort effects of tgf-β signaling on cancer cells and cancer stem cells in the bone microenvironment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829436/
https://www.ncbi.nlm.nih.gov/pubmed/31619018
http://dx.doi.org/10.3390/ijms20205117
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