Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

Abstract

Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease.

Keywords: drug resistance; myeloma and other plasma cell dyscrasias; neoplasia; signaling therapies.

Figure 1. Putative multiple myeloma stem cell (MMSC) in the bone marrow microenvironment

The MMSC receives both tumor cell-autonomous (autocrine) signals and a plethora of para- and juxtacrine signals from a variety of bystander cells in the tumor microenvironment (TME). Collectively, these signals govern the self-renewal and survival of the MMSC, the maintenance of its cancer stem cell (CSC) state and, importantly, the acquisition of drug resistance. This is accomplished by engaging the following signaling pathways in MMSCs: (1) Notch ligands produced by bone marrow stroma cells (BMSCs) activate a Notch receptor on the MMSC. This leads to cleavage of the receptor's intra-cellular domain (ICD) by a γ-secretase, translocation of ICD to the nucleus, and ICD-dependent activation of genes involved in self-renewal, proliferation and activation of AKT. (2) Binding of Hh signals from auto- and/or paracrine sources to Hh receptors leads to de-inhibition of Smothened (Smo), which results in activation of Gli, its translocation to the nucleus, and execution of the Gli-dependent gene expression program. (3) BTK, which is not expressed in normal plasma cells, is often aberrantly expressed in myeloma including MMSCs. Activation of BTK by targeted phosphorylation in the plasma membrane leads to cross-signaling with the WNT/b-catenin (4) and AKT (5) pathways. Our research has shown that active BTK in CSC-like myeloma cells results in increased amounts of nuclear b-catenin, pAKT, ABC transporter drug efflux ability (6) and Nanog (7). Two additional stemness factors that increase the clonogenic potential of myeloma are RARα2 (8) and ALDH1 (9). Working in concert, in ways that are poorly understood, the pathways described above increase drug resistance in myeloma and cause relapse with aggressive disease. Thus, the design and testing of MMSC-targeted therapies should be a priority in myeloma.