Format

Send to

Choose Destination
PLoS One. 2018 Nov 1;13(11):e0206368. doi: 10.1371/journal.pone.0206368. eCollection 2018.

Macrophage Inhibitory Factor-1 (MIF-1) controls the plasticity of multiple myeloma tumor cells.

Author information

1
School of Graduate Studies, SUNY Downstate Medical Center, Brooklyn, N.Y., United States of America.
2
Department of Medicine, Division of Hematology and Oncology, Kings County Hospital Center and SUNY Downstate Medical Center, Brooklyn, N.Y., United States of America.
3
Depts. of Pediatrics and Cell Biology, SUNY Downstate Medical Center, Brooklyn, N.Y., United States of America.

Abstract

Multiple Myeloma (MM) is the second most common hematological malignancy with a median survival of 5-10 years. While current treatments initially cause remission, relapse almost always occurs, leading to the hypothesis that a chemotherapy-resistant cancer stem cell (CSC) remains dormant, and undergoes self-renewal and differentiation to reestablish disease. Our finding is that the mature cancer cell (CD138+, rapidly proliferating and chemosensitive) has developmental plasticity; namely, the ability to dedifferentiate back into its own chemoresistant CSC progenitor, the CD138-, quiescent pre-plasma cell. We observe multiple cycles of differentiation and dedifferentiation in the absence of niche or supportive accessory cells, suggesting that soluble cytokines secreted by the MM cells themselves are responsible for this bidirectional interconversion and that stemness and chemoresistance are dynamic characteristics that can be acquired or lost and thus may be targetable. By examining cytokine secretion of CD138- and CD138+ RPMI-8226 cells, we identified that concomitant with interconversion, Macrophage Migration Inhibitory Factor (MIF-1) is secreted. The addition of a small molecule MIF-1 inhibitor (4-IPP) or MIF-1 neutralizing antibodies to CD138+ cells accelerated dedifferentiation back into the CD138- progenitor, while addition of recombinant MIF-1 drove cells towards CD138+ differentiation. A similar increase in the CD138- population is seen when MM tumor cells isolated from primary bone marrow aspirates are cultured in the presence of 4-IPP. As the CD138+ MM cell is chemosensitive, targeting MIF-1 and/or the pathways that it regulates could be a viable way to modulate stemness and chemosensitivity, which could in turn transform the treatment of MM.

PMID:
30383785
PMCID:
PMC6211687
DOI:
10.1371/journal.pone.0206368
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center