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Mechanisms of myeloma progression related to the bone marrow microenvironment : 골수미세환경과 관련된 다발골수종 진행기전

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Authors

이찬수

Advisor
윤성수
Major
의과대학 협동과정 종양생물학전공
Issue Date
2014-08
Publisher
서울대학교 대학원
Keywords
다발 골수종체내 미세 환경골수 기질 세포사이토카인히스톤 디아세틸레이즈 억제제
Description
학위논문 (박사)-- 서울대학교 대학원 : 협동과정 종양생물학전공, 2014. 8. 윤성수.
Abstract
The dynamic interplay between multiple myeloma and bone marrow stromal cells directly affect disease progression. Various cytokines and chemokines are produced by bone marrow stromal cells, and they lead to alter the biologic behaviors of MM cells becoming a malignant type of MM cells. To understand the role of cytokines, first, I examine the expression levels of various cytokines in the serum of MM patients bone marrow at diagnosis as well as at relapse. The results indicated that the expression levels of IL-6, sIL-6R, HGF, TNF α, TGF beta, DKK1, Flt3L and OPN, such as well-known factors in MM, were detectable. According to the correlation analysis among the level of these cytokines, some cytokines might affect the expressions of other cytokines in an autocrine and/or paracrine manner. In this study, I address the biological roles and correlation of cytokines, such as TNFα, HGF, OPN, and Flt3L, releasing from BMSCs in the progression of MM.
Previous reports stated that TNFα increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in the signaling pathways by which TNFα promotes IL-6 secretion from MM cells are largely unknown. I found that TNFα treatments induce MEK, STAT3 and AKT phosphorylation in MM cells. IL-6 production stimulated by TNFα was suppressed by the inhibition of JAK2, IKK betaand small interfering RNA (siRNA) for TNF receptors (TNFR), but not by MEK, p38, and PI3K inhibitors. This implies that TNFα induced the regulation of IL-6 secretion via JAK/STAT mediated NF-kappaB activation in MM.
The levels of HGF expression were correlated with those of OPN in the BM plasma of an MM patient. The induction of OPN was regulated by HGF released from BMSCs. HGF activated both the MAPK and PI3K/AKT pathways. HGF also stimulated the increase of the RUNX2 mRNA level that contributed to the OPN expression in multiple myeloma cells. However, the expression of OPN mediated by HGF could only be suppressed by the MEK inhibitor (PD98059) and not by the PI3K inhibitor (LY294002). In addition, I observed that MMP-9 mRNA expression was increased in OPN treated BMSCs. However, its expression was suppressed by the LY294002. These results indicate that HGF induced OPN expression via the activation of the MAPK pathway and activated MMP-9 expression in BMSCs via OPN-mediated PI3/AKT pathway. It means High level of HGF in BM microenvironment could contribute to modulate the biologic behaviors of BMSCs related to MM progression.
CD44 is widely distributed in diverse biologic processes as lymphocyte homing and leukocyte activation. In particular, some reports stated that HGF-induced signaling depend on the presence of some CD44 isoforms and activation of receptor-tyrosine kinase through CD44
moreover, its CD44 variants supports cell survival and progression in MM. I found that CD44s were expressed in MM cells. As the results conveyed, CD44s were detected in the MM cell line and CD138 positive cells were obtained from the MM patients bone marrow. Further, the down-regulation of CD44s expression by CD44 shRNA controlled the HGF-mediated MAPK signaling pathway as well as the HGF-mediated induction of DKK1. It demonstrated that CD44s also can contribute to the development of bone erosion mediated by HGF stimulation.
Flt3 ligand (Flt3L) is known to be involved in hematopoietic cell differentiation and early B-cell differentiation. However, the role of Flt3L still remains unknown in MM. I found that the level of Flt3L in MM patients BM plasma was related to poor prognostic parameters. Moreover, up regulation of Flt3 phosphorylation mediated by Flt3L was related with relapse after the autologous bone marrow transplantation in MM. In addition, Flt3 activation induced DKK1 secretion mediated via JAK/STAT and AKT signaling pathways. These results implied that a high level of FLT3L is significantly related with MM progression.
To improve the clinical outcome of MM patients, many studies have been attempting to develop novel targeted drugs. Using the newly developed anti-MM drug, CKD-581, a novel HDAC inhibitor, its effect was examined in various MM cell lines. CKD-581 showed a potentially anti-myeloma effect in MM cell lines. In a combined treatment with bortezomib, CKD-581 synergistically increased bortezomib-mediated apoptosis in MM cells, and these effects were similar to the effect of co-cultured MM cells with BMSCs. This result suggested that CKD581 could overcome the interferences of BMSCs in the treatment of the anti-MM drug. In an ex vivo study using patients derived buffy coat, CD138 positive cells were decreased significantly compare to other cells when cells were treated with CKD-581. In the vivo model, mice treated with CKD-581 alone showed significantly longer survival duration compared to non-treated control mice. Mice treated with combined CKD-581 and Bortezomib also showed survival benefit
further, these mice showed a slightly longer survival compared to CKD-581 treated mice. These data indicated that CKD-581 had anti-tumor effects in MM and moreover, it has the potential to show a synergistic effect with Bortezomib.
Language
English
URI
https://hdl.handle.net/10371/121768
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