Cancer Letters

Cancer Letters

Volume 414, 1 February 2018, Pages 214-221
Cancer Letters

Mini-review
Targeting signaling pathways in multiple myeloma: Pathogenesis and implication for treatments

https://doi.org/10.1016/j.canlet.2017.11.020Get rights and content

Highlights

  • Summarized the most important signaling pathways that participated in the pathogenesis of multiple myeloma.

  • Summarized the evaluation methods and therapeutic strategies developed for these signaling pathways.

  • Implications for future directions with these signaling pathways.

Abstract

Multiple myeloma (MM), which is characterized by osteolytic bone lesions, anemia, hypercalcemia, and renal failure, accounts for approximately 10% of all hematologic malignancies. Although the therapeutic landscape of MM has evolved spectacularly over the past decades with 5-year median survival over 50%, most of these patients relapse eventually. The widely recognized therapeutic approaches include chemotherapy, radiation, stem cell transplant, and monoclonal antibody therapy. Former studies have implied that the proliferation, survival, migration and drug resistance of MM cells are in association with the activation of several signaling pathways. In this review, we intended to focus on the major signaling pathways such as PI3K/Akt/mTOR, Ras/Raf/MEK/MAPK, JAK/STAT, NF-κB, Wnt/β-catenin, and RANK/RANKL/OPG, that contribute to the pathogenesis of the MM and the therapeutic approaches developed to target them.

Introduction

Multiple myeloma (MM), also known as the cancer of plasma cells, is a hematologic malignancy first noticed by patients when they experience frequent infection, bone pain, and bleeding, accompanied by complications such as renal failures [1], [2]. MM remains as an incurable cancer that although the therapeutic landscape of MM has evolved spectacularly over the past decades with 5-year median survival over 50% [3], most patients relapse and become resistant to current therapies. MM is well recognized to evolve from a monoclonal gammopathy of undetermined clinical significance (MGUS) that progresses to smoldering myeloma, which will finally lead to symptomatic myeloma [4], [5]. The pathogenesis of MM is complicated, which may correlate with changes in the bone marrow microenvironment (BMM) [6], chromosome translocation [7], production of cytokines, such as osteoclast-activating factors [8], [9], and abnormality of signaling pathways [10], etc. The interactions among these pathological factors are complicated, and malfunction of one factor may lead to the corruption of the whole system, making it an incurable neoplasia due to intrinsic or acquired resistance to therapies. The genetic defects within the tumor and the interactions between MM cells and the BMM lead to the activation of signaling pathways that promote the expansion of the malignant clones, and stimulate neoangiogenesis and osteoclastogenesis, all of which play important roles in the pathogenesis of MM. In this review, we will focus on these main signaling pathways that participate in the pathogenesis of MM, and the development of the related targeting therapies (Fig. 1). These signaling pathways includes phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/Erk, JAK/STAT, nuclear factor kappa B (NF-κB), Wnt/β-catenin, and receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/osteoprotegerin (RANK/RANKL/OPG).

Section snippets

PI3K/Akt/mTOR signaling pathway

PI3K signaling pathway is a gatekeeper for tumor growth, which is activated as a result of loss of function of tumor suppressor genes, and several myeloma growth cytokines act through the PI3K/Akt/mTOR pathway, making it attractive as a therapeutic target for MM. The activation of PI3K leads to the recruitment of serine-threonine kinase Akt to the cellular membrane to catalyze their function [11], and this enables the phosphorylation of multiple downstream targets including mTOR with various

Ras/Raf/MEK/Erk signaling pathway

The Ras/Raf/MEK/extracellular signal regulated kinase (Erk) signaling pathway is an important mediator of many fundamental biological processes, including cellular survival, proliferation, angiogenesis and migration. Ras protein subfamilies play a key role in the cellular signal transduction by acting as a molecular switch, and approximately 30% of malignancies involve Ras proto oncogene mutation. The Ras mutations may be present in 23%–54% of with a new diagnosis [35], but it may increase to

JAK/STAT signaling pathway

The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway was originally discovered in the context of interferon-α (IFN-α)-, IFN-γ, and IL-6 mediated downstream signaling [54]. The JAK activation regulates cell proliferation, differentiation, migration, and apoptosis. The JAK/STAT pathway interacts with other signaling pathways and these pathways intersect at several levels, each amplifying the activation of the other [55]; thus, this pathway was considered to be

Wnt/β-catenin signaling pathway

The canonical Wnt signaling pathway relies on the stabilization of cytosolic β-catenin [71], [72]. In the absence of Wnt protein, β-catenin is phosphorylated mainly by glycogen synthase kinase3β (GSK-3β) and casein kinase 1 and targeted for ubiquitination and degradation by the proteasomal machinery. The binding of Wnt protein to its receptor inhibits the activity of GSK-3β, which will prevent β-catenin from degradation, further leading to the accumulation of β-catenin in the cytoplasm. When

NF-κB signaling pathway

NF-κB has a critical role in the pathogenesis of MM, in that 82% of MM samples expressed high levels of NF-κB activation signature molecules [81]. The activation of NF-κB signaling pathway also plays an important role in promoting one of the major clinical manifestation of MM-lytic bone disease by stimulating the development of bone-resorbing osteoclasts [82], [83]. Moreover, the NF-κB pathway is considered one of the most important signaling pathways to be activated in MM cells by external

RANK/RANKL/OPG signaling pathway

Osteolytic bone disease in MM resulted from increased osteoclastic activity, which is the consequence of overproduction of cytokines and chemokines that regulates osteoclast differentiation and activity. The increase of formation and activation of osteoclasts adjacent to myeloma cells leads to enhanced bone resorption [106]. It is widely recognized that molecular triad - RANKL, members of the TNF receptor-ligand family, its receptor RANK, and the endogenous soluble RANKL inhibitor, OPG-play

Conclusion and perspective

In this review, we summarized several main signaling pathways by describing their participation in the pathogenesis of MM and therapeutic approaches developed on them (Table 1). As described previously, targeting the signaling pathways involved in the MM can help us better understand the pathogenesis of MM and enlighten the development of future therapeutic approaches. Many therapies may act upon more than one pathway. For example, IL-6 can act through PI3K/Akt/mTOR, Ras/raf/MEK/Erk and

Authors' contributions

Dr. J.H. wrote the manuscript, Dr. W-X.H. revised the manuscript.

Conflicts of interest

The authors declare that they have no conflict of interest.

Acknowledgement

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81400819 and 81372538)

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