TY - JOUR
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
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/2/5
Y1 - 2018/2/5
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.
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U2 - 10.1016/j.bbrc.2018.01.034
DO - 10.1016/j.bbrc.2018.01.034
M3 - Article
C2 - 29309790
AN - SCOPUS:85040523182
SN - 0006-291X
VL - 496
SP - 490
EP - 496
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -