Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation
Yoko Nakagawa, Eishi Ashihara, Hisayuki Yao, Asumi Yokota, Yuki Toda, Yasuo Miura, Susumu Nakata, Hideyo Hirai, Taira Maekawa
The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation.
Published - 05-02-2018
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Cell Marker Chemical Compounds 100%
Transforming Growth Factors Medicine & Life Sciences 64%
Multiple Myeloma Medicine & Life Sciences 60%
Hypoxia Medicine & Life Sciences 48%
Stem Cells Medicine & Life Sciences 45%
Transplantation Medicine & Life Sciences 5%
Bone Marrow Medicine & Life Sciences 5%
Messenger RNA Medicine & Life Sciences 4%
Nakagawa, Y., Ashihara, E., Yao, H., Yokota, A., Toda, Y., Miura, Y., Nakata, S., Hirai, H., & Maekawa, T. (2018). Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation. Biochemical and Biophysical Research Communications, 496(2), 490-496. https://doi.org/10.1016/j.bbrc.2018.01.034
Nakagawa, Yoko ; Ashihara, Eishi ; Yao, Hisayuki et al. / Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation. In: Biochemical and Biophysical Research Communications. 2018 ; Vol. 496, No. 2. pp. 490-496.
@article{4411b27fc645415eb65eedbdf3427e55,
title = "Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation",
abstract = "The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation.",
author = "Yoko Nakagawa and Eishi Ashihara and Hisayuki Yao and Asumi Yokota and Yuki Toda and Yasuo Miura and Susumu Nakata and Hideyo Hirai and Taira Maekawa",
note = "Funding Information: Y. Nakagawa, E. Ashihara, H. Yao, A. Yokota, Yuki Toda, Y. Miura, and S. Nakata have no financial conflict of interest to disclose. H. Hirai received research funding from Kyowa Hakko Kirin and Novartis Pharma . T. Maekawa received research funding from Bristol-Meyers K.K. Funding Information: This work was partly supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT, 23591404 and 26461436 to EA, 16K08722 to SN, and 23112507 and 25112706 to TM) and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities , 2015–2019 ( S1511024L to EA). Appendix A ",
Nakagawa, Y, Ashihara, E, Yao, H, Yokota, A, Toda, Y, Miura, Y, Nakata, S, Hirai, H & Maekawa, T 2018, 'Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation', Biochemical and Biophysical Research Communications, vol. 496, no. 2, pp. 490-496. https://doi.org/10.1016/j.bbrc.2018.01.034
Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation. / Nakagawa, Yoko; Ashihara, Eishi; Yao, Hisayuki et al.
In: Biochemical and Biophysical Research Communications, Vol. 496, No. 2, 05.02.2018, p. 490-496.
T1 - Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation
AU - Nakagawa, Yoko
AU - Ashihara, Eishi
AU - Yao, Hisayuki
AU - Yokota, Asumi
AU - Toda, Yuki
AU - Miura, Yasuo
AU - Nakata, Susumu
AU - Hirai, Hideyo
AU - Maekawa, Taira
N1 - Funding Information: Y. Nakagawa, E. Ashihara, H. Yao, A. Yokota, Yuki Toda, Y. Miura, and S. Nakata have no financial conflict of interest to disclose. H. Hirai received research funding from Kyowa Hakko Kirin and Novartis Pharma . T. Maekawa received research funding from Bristol-Meyers K.K. Funding Information: This work was partly supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT, 23591404 and 26461436 to EA, 16K08722 to SN, and 23112507 and 25112706 to TM) and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities , 2015–2019 ( S1511024L to EA). Appendix A
N2 - The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation.
AB - The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation.
Nakagawa Y, Ashihara E, Yao H, Yokota A, Toda Y, Miura Y et al. Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation. Biochemical and Biophysical Research Communications. 2018 Feb 5;496(2):490-496. doi: 10.1016/j.bbrc.2018.01.034