Xavier Leleu, MD, PhD
Dr. Leleu indicated no relevant conflicts of interest.
Jakubikova J, Adamia S, Kost-Alimova M, et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood. 2011;117:4409-4419.
Despite recent advances in drug development, multiple myeloma (MM) remains incurable for the majority of patients due to relapse and disease progression. Moreover, progression-free survival rates decrease progressively as relapses occur. A question that remains unanswered is why it has been impossible to cure myeloma. One potential mechanism is based on the concept of tumor dormancy, defined as persistence of non-dividing residual tumor cells for long periods of time. Evidence has emerged from experimental myeloma models suggesting that a balance exists between dormant tumor cells, which seem to persist in very small numbers, and the host microenvironment.1 Cross-talk between tumor cells and their microenvironment, angiogenesis, and anti-tumor immune responses play a role in the control of dormant tumor cells. Various mechanisms help maintain this equilibrium,2 including expression of immunoregulatory molecules, epigenetic modifications, and activation of autocrine loops.
Experimental models indicate that the dormant tumor cell population may be constituted of so-called cancer stem cells (CSCs) that enter a quiescent state but are capable of clonogenic growth, self-renewal, and differentiation into myeloma plasma cells. This model suggests that the long-term proliferative potential responsible for disease initiation, maintenance, and relapse is contained within specific subpopulations of biologically distinct tumor cells. Matsui et al. had first described the myeloma CSC, a rare cell population phenotypically resembling normal memory B cells (CD20 and CD27 positive) but lacking CD138. They found that cells expressing CD138+, an antigen present at high levels on MM plasma cells in virtually all patients, could not form tumor colonies in semi-solid media, in contrast to CD138-negative cells. The myeloma CSCs also appeared to be relatively resistant to a wide variety of anti-myeloma therapeutic agents, suggesting that they may persist following treatment and mediate tumor re-growth and relapse. However, controversy surrounds the exact phenotype and biology of myeloma CSCs.
Jakubikova and colleagues from the Dana-Farber Cancer Center in Boston have attempted to characterize these tumor-initiating subpopulations, also called side population (SP) cells, which are characterized by their “stem-like” features. They observed evidence for the clonogenic potential of SP cells in myeloma, as well as the ability of SP cells to regenerate original population cells. Moreover, SP cells revealed higher tumorigenicity compared to myeloma plasma cells. SP cells exhibited substantial heterogeneity in MM cell lines and primary MM cells but expressed CD138 antigen and had a higher proliferation index compared to non-SP cells.
This study provides more insight into the behavior of myeloma SP/CSC cells, providing further evidence for the role of the bone marrow microenvironment and the bi-directional interactions between the SP/CSC and microenvironment to sustain equilibrium between quiescence and self renewal. The stem cell niche provides protection and nourishment to SP/CSC cells, and myeloma cell adherence to the bone marrow stromal cells increases the percentage, viability, and proliferation potential of the SP/CSC cells. Interestingly, immunomodulatory drugs lenalidomide and thalidomide attenuated this stimulatory effect of stromal cells, thereby significantly decreasing SP/CSC cell percentages. Defining the biological features and molecular characteristics of the MM stem-like/tumor-initiating cells that are responsible for tumor re-growth will facilitate the development of new strategies to prevent relapse and halt myeloma progression.
- Matsui W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells. Blood. 2004;103:2332-2336.
- Kuranda K, Berthon C, Dupont C, et al. A subpopulation of malignant CD34+CD138+B7–H1+ plasma cells is present in multiple myeloma patients. Exp Hematol. 2010;38:124-131.
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