Multiple myeloma cancer stem cells

Abstract

Multiple myeloma (MM) remains incurable despite much progress that has been made in the treatment of the disease. MM cancer stem cell (MMSC), a rare subpopulation of MM cells with the capacity for self-renewal and drug resistance, is considered to lead to disease relapse. Several markers such as side population (SP) and ALDH1+ have been used to identify MMSCs. However, ideally and more precisely, the identification of the MMSCs should rely on MMSCs phenotype. Unfortunately the MMSC phenotype has not been properly defined yet. Drug resistance is the most important property of MMSCs and contributes to disease relapse, but the mechanisms of drug resistance have not been fully understood. The major signaling pathways involved in the regulation of self-renewal and differentiation of MMSCs include Hedgehog (Hh), Wingless (Wnt), Notch and PI3K/Akt/mTOR. However, the precise role of these signaling pathways needs to be clarified. It has been reported that the microRNA profile of MMSCs is remarkably different than that of non-MMSCs. Therefore, the search for targeting MMSCs has also been focused on microRNAs. Complex and mutual interactions between the MMSC and the surrounding bone marrow (BM) microenvironment sustain self-renewal and survival of MMSC. However, the required molecules for the interaction of the MMSC and the surrounding BM microenvironment need to be further identified. In this review, we summarize the current state of knowledge of MMSCs regarding their phenotype, mechanisms of drug resistance, signaling pathways that regulate MMSCs self-renewal and differentiation, abnormal microRNAs expression, and their interactions with the BM microenvironment.

High-dose BCNU/Melphalan conditioning regimen before autologous stem cell transplantation in newly diagnosed multiple myeloma

“…Another possibility is that BCNU could have effects on the bone marrow microenvironment, thus rendering MM cells more susceptible to chemotherapy. 31,32 Our finding that 21% of patients treated with BCNU/HDM remained without evidence of progressive disease over 10 years post transplant in the absence of any additional maintenance therapy suggests that a distinct effect is occurring with this combination, as this number is measurably higher than that experienced with HDM alone. 1,27,28 The growing evidence of clonal heterogeneity and evolution throughout the myeloma disease course has been supported by genomic studies showing that patient myeloma cell populations experience both linearly derived and branching clonal evolution.…”

Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

“…A growing body of evidence suggests that a minor, therapy-resistant, clonogenic sub-population of tumor cells is most likely the principal roadblock to curing MM [4, 8]. However, the identity of these stem-like MM cells remains only partially resolved [5, 7].…”

“…OCT4, NANOG, SOX2), drug resistance and chromosomal instability genes (i.e. NEK2, BTK, RARα2), BCRP , and/or ALDH1A1 expression has been used to identify stem-like MM cells [7, 8]. In the present study we have used two established markers of MM stem-like cells (CD138 immunophenotyping and SP staining) to characterize the oxidative metabolic properties of stem-like cells.…”

“…de-differentiated pre-plasma cells, genetically distinct clones, and stem-like tumor cells [4–6]. Although the cancer stem cell (CSC) hypothesis remains controversial in MM, several groups have demonstrated a distinct stem-like sub-population that displays increased clonogenicity, sustained self-renewal, differentiation towards CD138 + mature MM cells, and chemo-resistance [5, 7, 8]. Therefore, successful therapy requires an approach to induce cytotoxicity in the drug-resistant tumor cells with the overall objective to reduce MM recurrence.…”

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

“…However, those drugs were able to inhibit CD138+ PCs growth [234][235][236]. Nonetheless, another study demonstrated that clonotypic CD138 + PCs also have some properties of CSCs such as self-renewal, tumour-initiating potential and drug resistance [237,238]. A more recent study with gene expression profiling of putative CSCs and the main population of MM cells derived from 11 MM patients, identified CD24+ MM cells as being capable of maintaining CSC features of self-renewal and drug resistance [239].…”