Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 496, Issue 2, Pages 490-496Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2018.01.034
Keywords
Multiple myeloma; Bone marrow microenvironment; Hypoxia; Myeloma stem cells; TGF-beta; Smad2
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) [23591404, 26461436, 16K08722, 23112507, 25112706]
- MEXT-Supported Program for the Strategic Research Foundation at Private Universities [S1511024L]
- Grants-in-Aid for Scientific Research [17K16197, 16K08722, 25112706, 16K07171, 23591404] Funding Source: KAKEN
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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% O-2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O-2). 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)-beta/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-beta/Smad pathway activation. (C) 2018 Elsevier Inc. All rights reserved.
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