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Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms.

Abdi J, Chen G, Chang H - Oncotarget (2013)

Bottom Line: This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment.The present review will discuss the latest findings and concepts in this regard.It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Ontario, Canada.

ABSTRACT
In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma.

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Related in: MedlinePlus

SFM-DR and CAM-DR work usually together within the bone marrow environmentAdhesion of MM cells to BMSCs and FN through integrin molecules triggers a variety of signaling pathways (including Ras/MAPK, PI3K/Akt, NFκB, Notch, Wnt, HSPs) involved in cell proliferation, anti-apoptosis, DR and cytokine secretion (IL-6), and also upregulation of anti-apoptotic BCL-2 family members BCL-2, MCL-1 or BCL-XL. The above adhesion induces secretion of several cytokines (IL-6, VEGF, HGF, IGF-1, SDF-1α, TNF-α, MCP-1) by BMSCs leading to triggering most of above pathways and induction of resistance to apoptosis and drugs in MM cells (paracrine). IL-6 can also stimulate MM cells in an autocrine manner, although this system has been shown for some other cytokines as well. Furthermore, most above cytokines may also be secreted by osteoclasts, endothelial cells and macrophages during their direct or indirect interactions with MM cells leading to triggering of above functional responses in latter cells.
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Figure 1: SFM-DR and CAM-DR work usually together within the bone marrow environmentAdhesion of MM cells to BMSCs and FN through integrin molecules triggers a variety of signaling pathways (including Ras/MAPK, PI3K/Akt, NFκB, Notch, Wnt, HSPs) involved in cell proliferation, anti-apoptosis, DR and cytokine secretion (IL-6), and also upregulation of anti-apoptotic BCL-2 family members BCL-2, MCL-1 or BCL-XL. The above adhesion induces secretion of several cytokines (IL-6, VEGF, HGF, IGF-1, SDF-1α, TNF-α, MCP-1) by BMSCs leading to triggering most of above pathways and induction of resistance to apoptosis and drugs in MM cells (paracrine). IL-6 can also stimulate MM cells in an autocrine manner, although this system has been shown for some other cytokines as well. Furthermore, most above cytokines may also be secreted by osteoclasts, endothelial cells and macrophages during their direct or indirect interactions with MM cells leading to triggering of above functional responses in latter cells.

Mentions: As a matter of fact in vitro analysis of CAM-DR and SFM-DR as two separate systems is oversimplification, because it is not unexpected to think that two processes work hand in hand inside the bone marrow (figure 1). In line with this, one study demonstrated the synergistic anti-apoptosis resistance effect of adhesion to FN (β1 integrin signaling) and IL-6 (gp130 signaling) in MM cells associated with activated STAT3 signaling pathway [199]. Moreover, treating MM cells with HGF increased their adhesion to FN which was mediated by VLA4 integrin and PI3K and NFκB pathways implying a synergistic effect of FN-adhesion and HGF in promoting CAM-DR of MM cells [193]. More interestingly, it is suggested that SFM-DR and CAM-DR confer resistance to drug-induced apoptosis in MM cells through distinct mechanisms [215].


Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms.

Abdi J, Chen G, Chang H - Oncotarget (2013)

SFM-DR and CAM-DR work usually together within the bone marrow environmentAdhesion of MM cells to BMSCs and FN through integrin molecules triggers a variety of signaling pathways (including Ras/MAPK, PI3K/Akt, NFκB, Notch, Wnt, HSPs) involved in cell proliferation, anti-apoptosis, DR and cytokine secretion (IL-6), and also upregulation of anti-apoptotic BCL-2 family members BCL-2, MCL-1 or BCL-XL. The above adhesion induces secretion of several cytokines (IL-6, VEGF, HGF, IGF-1, SDF-1α, TNF-α, MCP-1) by BMSCs leading to triggering most of above pathways and induction of resistance to apoptosis and drugs in MM cells (paracrine). IL-6 can also stimulate MM cells in an autocrine manner, although this system has been shown for some other cytokines as well. Furthermore, most above cytokines may also be secreted by osteoclasts, endothelial cells and macrophages during their direct or indirect interactions with MM cells leading to triggering of above functional responses in latter cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926819&req=5

Figure 1: SFM-DR and CAM-DR work usually together within the bone marrow environmentAdhesion of MM cells to BMSCs and FN through integrin molecules triggers a variety of signaling pathways (including Ras/MAPK, PI3K/Akt, NFκB, Notch, Wnt, HSPs) involved in cell proliferation, anti-apoptosis, DR and cytokine secretion (IL-6), and also upregulation of anti-apoptotic BCL-2 family members BCL-2, MCL-1 or BCL-XL. The above adhesion induces secretion of several cytokines (IL-6, VEGF, HGF, IGF-1, SDF-1α, TNF-α, MCP-1) by BMSCs leading to triggering most of above pathways and induction of resistance to apoptosis and drugs in MM cells (paracrine). IL-6 can also stimulate MM cells in an autocrine manner, although this system has been shown for some other cytokines as well. Furthermore, most above cytokines may also be secreted by osteoclasts, endothelial cells and macrophages during their direct or indirect interactions with MM cells leading to triggering of above functional responses in latter cells.
Mentions: As a matter of fact in vitro analysis of CAM-DR and SFM-DR as two separate systems is oversimplification, because it is not unexpected to think that two processes work hand in hand inside the bone marrow (figure 1). In line with this, one study demonstrated the synergistic anti-apoptosis resistance effect of adhesion to FN (β1 integrin signaling) and IL-6 (gp130 signaling) in MM cells associated with activated STAT3 signaling pathway [199]. Moreover, treating MM cells with HGF increased their adhesion to FN which was mediated by VLA4 integrin and PI3K and NFκB pathways implying a synergistic effect of FN-adhesion and HGF in promoting CAM-DR of MM cells [193]. More interestingly, it is suggested that SFM-DR and CAM-DR confer resistance to drug-induced apoptosis in MM cells through distinct mechanisms [215].

Bottom Line: This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment.The present review will discuss the latest findings and concepts in this regard.It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Ontario, Canada.

ABSTRACT
In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma.

Show MeSH
Related in: MedlinePlus