Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions

Abstract

Cancer stem cells (CSCs) are key drivers of tumor progression and disease recurrence in multiple myeloma (MM). However, little is known about the regulation of MM stem cells. Here, we show that a population of MM cells, known as the side population (SP), exhibits stem-like properties. Cells that constitute the SP in primary MM isolates are negative or seldom expressed for CD138 and CD20 markers. Moreover, the SP population contains stem cells that belong to the same lineage as the mature neoplastic plasma cells (MPC). Importantly, our data indicate that the side (SP) and non-side (NSP) population percentages in heterogeneous MM cells are balanced, and that this balance can be achieved through a prolonged in vitro culture. Furthermore, we show that SP cells, with confirmed molecular characteristics of MM stem cells, can be regenerated from purified NSP cell populations. We also show that the percentage of SP cells can be enhanced by the hypoxic stress, which is frequently observed within MM tumors. Finally, hypoxic stress enhanced the expression of transforming growth factor β1 (TGF-β1) and blocking the TGF-β1 signaling pathway inhibited the NSP de-differentiation. Taken together, these findings indicate that the balance between MM SP and NSP is regulated by environmental factors and TGF-β1 pathway is involved in hypoxia-induced increase of SP population. Understanding the mechanisms that facilitate SP maintenance will accelerate the design of novel therapeutics aimed at controlling these cells in MM.

Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells

“…Given the preferential expression of SSEA-1 in normal stem cells of humans, dogs, and mice [41017], it could be surmised that this trait is shared between normal stem cells and cancer stem cells. However, recent data suggest that proliferation, self-renewal, limited lineage differentiation, and other properties that define cancer stem cells cannot be attributed to any single element, and the acquisition of these properties is dynamic in nature [716]. Our observation that after depletion of SSEA-1 + cells, a subset of SSEA-1 − cells upregulated SSEA-1 to the membrane is consistent with this notion.…”

Inhibition of Transforming Growth Factor-β Activation Diminishes Tumor Progression and Osteolytic Bone Disease in Mouse Models of Multiple Myeloma

“…4 TGF-b is also critical for hypoxia-induction of myeloma cancer stem cellelike side populations. 8 TGF-b stimulates early osteoblast proliferation while blocking late-stage osteoblast differentiation and mineralization to reduce bone formation. 9 TGF-b also increases bone lytic activity through stimulation of RANKL secretion and enhancement of osteoclast survival.…”

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

“…For both cell lines, SP cells showed higher OCT4 expression than MP cells (Table 1). Notably, SP cells have been reported to be CD138 -/low in clinical MM samples [65]. Furthermore, CD138 low cells were detected in MM patients [56, 66] and a retrospective study correlated poor prognosis with increased CD138 low cells at diagnosis and relapse [67].…”

“…Wen et al . [65] reported a 5-fold increase in SP cells (8226 and U266 cells) when cultured under hypoxia for 5 days that was suggested to arise from MP cells without any additional stimuli. To assess hypoxia-mediated alterations in the number CD138 low cells, we cultured HMCLs in 1% O 2 for 3 days.…”