title: Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions.
abstract: Cancer stem cells 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. In addition, the SP population contains stem cells that belong to the same lineage as the mature neoplastic plasma cells. Importantly, our data indicate that the SP and nonside population (NSP) 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 dedifferentiation. 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.
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.forename: Wenjing
authors.initials: W
authors.lastname: Tao
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Feng
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004777:Environment; D000860:Hypoxia / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1
keywords: cancer stem cells; environmental factors; multiple myeloma; side population