Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma

Abstract

Background Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant. Methods Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group. Results CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo. Conclusion Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.

Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents

“…Currently, SP analysis is increasingly applied in CSCs research as an indication of stemness [86][87][88] and therapy resistance. 89,90 Noncoding RNAs In recent years, research on noncoding RNAs has become increasingly prominent. Many studies have indicated noncoding RNA can be a CSC marker.…”

Novel insights into the function of CD24: A driving force in cancer

“…The CD24+ phenotype of CSCs has also been demonstrated in other tumors including cervical cancer, 148,149 cholangiocarcinoma, 150 colorectal cancer, 151 and gastric cancer 152 . A recent study described that TICs in multiple myeloma (MM) were positive for CD24 153 . CD24+ MM cells exhibited increased clonogenicity, drug resistance and tumorigenicity.…”

“…Different formats were used for therapy. These included unconjugated mAbs, where the effector mechanism mainly relies on antibody‐dependent cell‐mediated cytotoxicity of SWA11, 153,159 ALB9, 160 antibody‐drug conjugates, 161‐163 bispecific antibodies, 164 chimeric antigen receptor T cells 166 or chimeric antigen receptor‐natural killer cells 165 . In all these experiments more or less efficient killing of tumor target cells was observed in vitro or in vivo in human tumors grafted into immunodeficient mice.…”

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

“…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].…”