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.
Highlights
Multiple myeloma (MM) is the second most prevalent hematological malignancy in the United States, with a survival rate of 47% within the first five years post diagnosis [1,2]
MIF-1 regulates interconversion of cancer stem cells characterized by the proliferation of clonal plasma cells within the bone marrow, which can interfere with normal blood cell production and secrete non-functioning monoclonal antibodies called M proteins [3,4,5]
We identified MIF-1 as a secreted cytokine that controls this interconversion in MM cell lines, and show that by MIF-1 regulates interconversion of cancer stem cells manipulating the activity or levels of MIF-1 present in the culture media we can shift the set point towards more differentiation or more dedifferentiation
Summary
Multiple myeloma (MM) is the second most prevalent hematological malignancy in the United States, with a survival rate of 47% within the first five years post diagnosis [1,2]. Relapse is usually occurs, suggesting that there exists a subset of MM tumor cells that are able to evade cytotoxic insult and eventually recapitulate tumor burden [8,9,10]. This has lead to the hypothesis that a population of chemoresistant cancer stem cells (CSC) persists and remains dormant until a time posttreatment when they reinitiate growth and re-establish tumor burden [10,11,12]
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