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  • stat 3 inhibitor Adhesive interactions Adhesive interactions

    2019-04-15

    Adhesive interactions: Adhesive interactions between myeloma stat 3 inhibitor and stromal cells play a significant role in both the homing of MM cells to the bone marrow and augmentation of the bone destructive process. These adhesive interactions result in activation of NF-κB and p38 MAP-kinase signaling, which is involved in the induction of RANKL expression by OBL. Blocking p38 MAP-kinase results in inhibition of IL-6 and VEGF production, as well as decreased adhesion of MM cells to marrow stromal cells [84]. Vanderkerken and coworkers reported that inhibition of p38 MAP kinase in the 5T2MM murine model of MM decreased tumor cell burden, prevented development of bone disease and increased overall survival of mice having 5T2 cells [85]. Therefore, this pathway may be a potential therapeutic target for novel therapies for MM disease. Additionally, adhesive interaction between MM cells and cells in the BM microenvironment increase production of cytokines and chemokines that enhance angiogenesis and contribute to the chemotherapy resistance of tumor cells resistant [86,87]. Angiogenesis is markedly enhanced in MM, parallels disease progression, and correlates inversely with patient survival [88]. OCL and endothelial cells are closely apposed in MM, and increased OCL activity appears to contribute to both the increased angiogenesis in MM as well as to tumor growth. OCL can support the growth of MM cells through cell-to-cell contact, which results in production of IL-6 and osteopontin [40,53]. Further, Tanaka and coworkers have shown that OCL enhance angiogenesis in MM through constitutive secretion of pro-angiogenic factors such as osteopontin, which together with vascular endothelial growth factor (VEGF) produced by MM cells, increase angiogenesis [88]. We have reported that OCL are angiogenic cells [27], and that suppression of OCL formation with OPG dose-dependently inhibited angiogenesis and osteoclastogenesis in established bone angiogenesis assays.
    Osteoblast suppression in myeloma OBL activity is suppressed in MM, with decreased bone formation and calcification despite increased bone resorption [17,89]. As a result, serum alkaline phosphatase and osteocalcin are normal or decreased in patients with myeloma bone involvement. Co-culture experiments have demonstrated reduced myeloma cell proliferation in the presence of OBLs as compared with OCL or marrow stromal cells [90], a finding that has been confirmed in murine models of myeloma bone disease [91]. A number of inhibitors of OBL differentiation have been identified in myeloma that are produced by myeloma cells or cells in the myeloma marrow microenvironment. Interestingly, myeloma patient marrow stromal cells retain their aberrant properties, such as increased production of OCL activating factors such as RANKL, IL-6, XBP1, and activin A and suppressed OBL differentiation in long-term tissue culture, suggesting that myeloma cells induce permanent changes in marrow stromal cells. The formation and differentiation of OBLs from marrow stromal cells requires the activity and function of systemic and local factors, such as parathyroid hormone (PTH), fibroblast growth factor (FGF), and bone morphogenic proteins (BMP). The activity and function of the transcription factor Runx2/Cbfal (Runx2) play a critical role in OBL development and activity. Runx2-deficient mice, which are embryonic lethal, lack OBL and bone formation [92]. Inhibition of Runx2 in OBL precursors has been demonstrated in MMBD [93], and direct cell–cell contact between myeloma cells and OBL progenitor cells as well as soluble factors produced by MM cells downregulate RUNX2 activity [93], however the mechanisms underlying this inhibition are unclear. Myeloma cells also induce marrow stromal cells to produce factors that support myeloma cell growth, survival, and chemoresistance, such as IL-6, annexin II, VCAM1, VEGF, and IGF-1; and mature osteoblasts suppress myeloma cell growth via production of decorin [90,94]. Thus, suppression of OBL differentiation in myeloma enhances tumor growth due to toxic effects of mature osteoblasts on myeloma cells.