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Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma

The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence, GSCs with highly invasive and highly migratory activities must assume a less-motile state and proliferate to regenerate tumor mass. Elucidating the mo...

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Autores principales: Nishikawa, Masahiro, Inoue, Akihiro, Ohnishi, Takanori, Yano, Hajime, Ozaki, Saya, Kanemura, Yonehiro, Suehiro, Satoshi, Ohtsuka, Yoshihiro, Kohno, Shohei, Ohue, Shiro, Shigekawa, Seiji, Watanabe, Hideaki, Kitazawa, Riko, Tanaka, Junya, Kunieda, Takeharu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175402/
https://www.ncbi.nlm.nih.gov/pubmed/34052625
http://dx.doi.org/10.1016/j.tranon.2021.101137
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author Nishikawa, Masahiro
Inoue, Akihiro
Ohnishi, Takanori
Yano, Hajime
Ozaki, Saya
Kanemura, Yonehiro
Suehiro, Satoshi
Ohtsuka, Yoshihiro
Kohno, Shohei
Ohue, Shiro
Shigekawa, Seiji
Watanabe, Hideaki
Kitazawa, Riko
Tanaka, Junya
Kunieda, Takeharu
author_facet Nishikawa, Masahiro
Inoue, Akihiro
Ohnishi, Takanori
Yano, Hajime
Ozaki, Saya
Kanemura, Yonehiro
Suehiro, Satoshi
Ohtsuka, Yoshihiro
Kohno, Shohei
Ohue, Shiro
Shigekawa, Seiji
Watanabe, Hideaki
Kitazawa, Riko
Tanaka, Junya
Kunieda, Takeharu
author_sort Nishikawa, Masahiro
collection PubMed
description The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence, GSCs with highly invasive and highly migratory activities must assume a less-motile state and proliferate to regenerate tumor mass. Elucidating the molecular mechanism underlying this transition from a highly invasive phenotype to a less-invasive, proliferative tumor could facilitate the identification of effective molecular targets for treating GBM. Here, we demonstrate that severe hypoxia (1% O(2)) upregulates CD44 expression via activation of hypoxia-inducible factor (HIF-1α), inducing GSCs to assume a highly invasive tumor. In contrast, moderate hypoxia (5% O(2)) upregulates osteopontin expression via activation of HIF-2α. The upregulated osteopontin inhibits CD44-promoted GSC migration and invasion and stimulates GSC proliferation, inducing GSCs to assume a less-invasive, highly proliferative tumor. These data indicate that the GSC phenotype is determined by interaction between CD44 and osteopontin. The expression of both CD44 and osteopontin is regulated by differential hypoxia levels. We found that CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo. Mouse brain tumors generated from CD44-knockdown GSCs exhibited diminished invasiveness, and the mice survived significantly longer than control mice. In contrast, siRNA-mediated silencing of the osteopontin gene decreased GSC proliferation. These results suggest that interaction between CD44 and osteopontin plays a key role in tumor progression in GBM; inhibition of both CD44 and osteopontin may represent an effective therapeutic approach for suppressing tumor progression, thus resulting in a better prognosis for patients with GBM.
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spelling pubmed-81754022021-06-16 Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma Nishikawa, Masahiro Inoue, Akihiro Ohnishi, Takanori Yano, Hajime Ozaki, Saya Kanemura, Yonehiro Suehiro, Satoshi Ohtsuka, Yoshihiro Kohno, Shohei Ohue, Shiro Shigekawa, Seiji Watanabe, Hideaki Kitazawa, Riko Tanaka, Junya Kunieda, Takeharu Transl Oncol Original Research The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence, GSCs with highly invasive and highly migratory activities must assume a less-motile state and proliferate to regenerate tumor mass. Elucidating the molecular mechanism underlying this transition from a highly invasive phenotype to a less-invasive, proliferative tumor could facilitate the identification of effective molecular targets for treating GBM. Here, we demonstrate that severe hypoxia (1% O(2)) upregulates CD44 expression via activation of hypoxia-inducible factor (HIF-1α), inducing GSCs to assume a highly invasive tumor. In contrast, moderate hypoxia (5% O(2)) upregulates osteopontin expression via activation of HIF-2α. The upregulated osteopontin inhibits CD44-promoted GSC migration and invasion and stimulates GSC proliferation, inducing GSCs to assume a less-invasive, highly proliferative tumor. These data indicate that the GSC phenotype is determined by interaction between CD44 and osteopontin. The expression of both CD44 and osteopontin is regulated by differential hypoxia levels. We found that CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo. Mouse brain tumors generated from CD44-knockdown GSCs exhibited diminished invasiveness, and the mice survived significantly longer than control mice. In contrast, siRNA-mediated silencing of the osteopontin gene decreased GSC proliferation. These results suggest that interaction between CD44 and osteopontin plays a key role in tumor progression in GBM; inhibition of both CD44 and osteopontin may represent an effective therapeutic approach for suppressing tumor progression, thus resulting in a better prognosis for patients with GBM. Neoplasia Press 2021-05-27 /pmc/articles/PMC8175402/ /pubmed/34052625 http://dx.doi.org/10.1016/j.tranon.2021.101137 Text en © 2021 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Nishikawa, Masahiro
Inoue, Akihiro
Ohnishi, Takanori
Yano, Hajime
Ozaki, Saya
Kanemura, Yonehiro
Suehiro, Satoshi
Ohtsuka, Yoshihiro
Kohno, Shohei
Ohue, Shiro
Shigekawa, Seiji
Watanabe, Hideaki
Kitazawa, Riko
Tanaka, Junya
Kunieda, Takeharu
Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma
title Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma
title_full Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma
title_fullStr Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma
title_full_unstemmed Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma
title_short Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma
title_sort hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: significance of cd44 and osteopontin as therapeutic targets in glioblastoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175402/
https://www.ncbi.nlm.nih.gov/pubmed/34052625
http://dx.doi.org/10.1016/j.tranon.2021.101137
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