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Latest Findings on the Mechanism of the Interaction Between Multiple Myeloma Cells and Bone Marrow Microenvironment
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摘要: 多发性骨髓瘤（multiple myeloma, MM）是浆细胞来源的血液系统恶性肿瘤，其发生发展机制主要包括肿瘤细胞遗传学异常和细胞与骨髓微环境（bone marrow microenvironment, BMME）互作。MM细胞在BMME内恶性增殖，通过细胞与细胞外基质的直接或间接互作，促进MM的发生发展。探讨MM细胞与微环境的互作机制，对阐明MM发生发展机制及早诊和治疗有着重要意义。肿瘤的代谢重编程是肿瘤学研究的重点之一。本文总结出微环境中MM的代谢重编程改变和MM代谢与微生物互作的特征，以便于深入了解MM的发生发展及耐药性机制，最终达到挖掘MM治疗的新策略之目的。Abstract: Multiple myeloma (MM) is a hematologic malignancy of terminally differentiated plasma cells. The mechanisms of the pathogenesis and progression of MM include genetic abnormalities of the MM cells and the interaction between MM cells and bone marrow microenvironment (BMME). MM cells start malignant proliferation in BMME and contribute to the pathogenesis and progression of MM through direct or indirect interactions between cells and the extracellular matrix. Exploring the mechanism of interaction between MM cells and the microenvironment is crucial to improving our understanding of the pathogenesis and progression of MM and early diagnosis and treatment. In addition, the metabolic reprogramming of tumors is one of the key issues of oncology research. Herein, we summarized published findings on the the altered metabolic reprogramming of MM and the characteristics of MM metabolic-microbial interactions in order to gain an in-depth understanding of MM pathogenesis and progression and drug resistance mechanisms, and ultimately to explore for new strategies for MM treatment.
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图 1 MM肿瘤细胞与微环境的相互作用
Figure 1. The interaction between MM cells andthe microenvironment
VEGR: vascular endothelial growth factor; IFN: interferon; MMP13: matrix metalloproteinase 13; RANKL: receptor activator of nuclear factor-kappa B ligand; PD1: programmed cell death protein 1; PDL1: programmed death ligand 1; IL: interleukin; IL6R: interleukin 6 receptor; IFN: interferon; CCL3: C-C motif chemokine ligand 3; SLC6A9: solute carrier family 6 member 9; CXCR4: C-X-C motif chemokine receptor 4; CXCL12: C-X-C motif chemokine ligand 12; VCAM1: vascular cell adhesion molecule 1; BMSC: bone marrow stromal cells; Gly: glycine.
表 1 MM骨髓微环境互作细胞及功能
Table 1. The functions of interacting cells in bone marrow microenvironment in MM
Cell Cytokines Functions Ref. BMSC IL-6 Stimulating MM cell growth, survival and drug resistance (DR) [19] Growth factor, TNF-α MM cell growth, survival, DR, and migration [20] VEGF Upregulation of IL-6 secretion [21] CD40 & CD40L Increasing MM cell adhesion [21] IL-8 Enabling MM cells to recruit new blood vessels in the bone marrow [22] BMEC Angiopoietin 1 Up-regulation of angiogenically active factors after MM cell growth promotion by mutual adhesion [23] IL-6 , IGF1 MM cell growth [24] TGFβ, PDGF, IL-1 Pro-angiogenic molecules [25] Osteoclast RANKL Promotion of osteolytic lesions [26] MIP-1α Osteoclast formation inducer [27] Osteoblast DKK1, IL-3 Inhibition of osteoblast differentiation [28] BMSC: bone marrow stromal cells; IL: interleukin; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor; CD40: CD40 antigen; CD40L: CD40 antigen ligand; IGF1: insulin like growth factor 1; TGFβ: transforming growth factor beta; PDGF: platelet derived growth factor subunit B; RANKL : receptor activator of nuclear factor-kappa B ligand; MIP-1α: macrophage inflammatory protein-1 alpha; DKK1: Dickkopf WNT signaling pathway inhibitor 1. 
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