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Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4

Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive...

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Autores principales: Furusaka, Yuma, Inoue, Shinya, Mizoguchi, Izuru, Hasegawa, Hideaki, Katahira, Yasuhiro, Watanabe, Aruma, Sakamoto, Eri, Sekine, Ami, Miyakawa, Satomi, Umezu, Tomohiro, Owaki, Toshiyuki, Yoneto, Toshihiko, Yoshimoto, Takayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486206/
https://www.ncbi.nlm.nih.gov/pubmed/36942841
http://dx.doi.org/10.1111/cas.15789
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author Furusaka, Yuma
Inoue, Shinya
Mizoguchi, Izuru
Hasegawa, Hideaki
Katahira, Yasuhiro
Watanabe, Aruma
Sakamoto, Eri
Sekine, Ami
Miyakawa, Satomi
Umezu, Tomohiro
Owaki, Toshiyuki
Yoneto, Toshihiko
Yoshimoto, Takayuki
author_facet Furusaka, Yuma
Inoue, Shinya
Mizoguchi, Izuru
Hasegawa, Hideaki
Katahira, Yasuhiro
Watanabe, Aruma
Sakamoto, Eri
Sekine, Ami
Miyakawa, Satomi
Umezu, Tomohiro
Owaki, Toshiyuki
Yoneto, Toshihiko
Yoshimoto, Takayuki
author_sort Furusaka, Yuma
collection PubMed
description Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell‐free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC‐CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC‐CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin‐like growth factor binding proteins (IGFBPs). Among them, IGFBP‐4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP‐4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF‐1 receptor beta, and p38 MAPK in a partly IGFBP4‐dependent manner, possibly through its binding to IGF‐1/2 and blocking the signaling. The CM depleted of IGFBP‐4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC‐CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4‐dependent manner, suggesting that cell‐free therapy using MSC‐CM could be a safer promising alternative for even cancer patients.
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spelling pubmed-104862062023-09-09 Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4 Furusaka, Yuma Inoue, Shinya Mizoguchi, Izuru Hasegawa, Hideaki Katahira, Yasuhiro Watanabe, Aruma Sakamoto, Eri Sekine, Ami Miyakawa, Satomi Umezu, Tomohiro Owaki, Toshiyuki Yoneto, Toshihiko Yoshimoto, Takayuki Cancer Sci ORIGINAL ARTICLES Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell‐free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC‐CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC‐CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin‐like growth factor binding proteins (IGFBPs). Among them, IGFBP‐4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP‐4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF‐1 receptor beta, and p38 MAPK in a partly IGFBP4‐dependent manner, possibly through its binding to IGF‐1/2 and blocking the signaling. The CM depleted of IGFBP‐4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC‐CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4‐dependent manner, suggesting that cell‐free therapy using MSC‐CM could be a safer promising alternative for even cancer patients. John Wiley and Sons Inc. 2023-04-11 /pmc/articles/PMC10486206/ /pubmed/36942841 http://dx.doi.org/10.1111/cas.15789 Text en © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle ORIGINAL ARTICLES
Furusaka, Yuma
Inoue, Shinya
Mizoguchi, Izuru
Hasegawa, Hideaki
Katahira, Yasuhiro
Watanabe, Aruma
Sakamoto, Eri
Sekine, Ami
Miyakawa, Satomi
Umezu, Tomohiro
Owaki, Toshiyuki
Yoneto, Toshihiko
Yoshimoto, Takayuki
Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4
title Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4
title_full Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4
title_fullStr Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4
title_full_unstemmed Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4
title_short Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4
title_sort potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via igfbp‐4
topic ORIGINAL ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486206/
https://www.ncbi.nlm.nih.gov/pubmed/36942841
http://dx.doi.org/10.1111/cas.15789
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