FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells.
FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells.
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DOI：
10.18632/oncotarget.3794
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发表时间：
2015-08-14
期刊：
影响因子：
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通讯作者：
Chirgwin JM
中科院分区：
文献类型：
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作者：
Suvannasankha A;Tompkins DR;Edwards DF;Petyaykina KV;Crean CD;Fournier PG;Parker JM;Sandusky GE;Ichikawa S;Imel EA;Chirgwin JM
多发性骨髓瘤（MM）生长在骨中并破坏骨，骨细胞分泌FGF 23，一种影响磷酸盐稳态和衰老的激素。我们报道多发性骨髓瘤（MM）细胞表达FGF 23受体并对FGF 23产生应答。FGF 23增加EGFR 1及其靶向乙酰肝素酶（MM中的促溶骨性因子）的mRNA。FGF 23通过klotho和经典FGF受体（FGFR）的复合物发出信号;两者均由MM细胞系和患者样本表达。42例MM患者的骨髓浆细胞klotho染色阳性，而8例单克隆丙种球蛋白病（MGUS）患者和6例对照的浆细胞为阴性。与对照相比，MM患者血清中完整的活性FGF 23增加2.9倍。人MM细胞不表达FGF 23，但与小鼠骨共培养增加了其mRNA。FGFR抑制剂NVP-BGJ 398阻断了对FGF 23的乙酰肝素酶应答。NVP-BGJ 398在体外不抑制8226生长，但显著抑制骨生长和破骨细胞调节因子RANK配体的诱导，同时降低乙酰肝素酶mRNA。骨微环境提供对一些抗肿瘤药物的抗性，但增加NVP-BGJ 398对8226细胞的活性。FGF 23/klotho/乙酰肝素酶信号传导轴可能为治疗骨中的MM提供靶点。
Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.