Increased circulating LDL cholesterol increases myeloma tumour burden in vivo

Beatriz Gámez
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Abstract

Gámez B., Morris EV., Olechnowicz S., Sowman, A., Turner, C. and Edwards CM.   Multiple myeloma (MM) is a fatal malignancy characterized by an expansion of malignant plasma cells in the bone marrow (BM) and associated with osteolytic bone disease. MM is preceded by the benign condition, monoclonal gammopathy of undetermined significance (MGUS). Understanding MGUS progression and development of MM bone disease is key for patient management. We and others have previously demonstrated that diet-induced obesity promotes myeloma progression, but the mechanisms underlying this remain unknown. The aim of the current study was to determine the effect of dietary cholesterol on MM development. A 2% cholesterol diet was used to increase circulating LDL in mice. Mice were randomly distributed to either a) cholesterol diet 4 weeks prior to 5TGM1 MM inoculation (pretreatment) or b) cholesterol diet 4 weeks prior to MM inoculation and continued for the entire experiment (continuous). Mice on the continuous cholesterol diet had increased tumour burden, associated with an increase in lipid droplet content of MM cells. No differences in tumour burden were seen in those mice where cholesterol diet was halted at time of MM inoculation. In vitro, myeloma cells cultured with delipidated FBS had a 50% reduction in viability after 72 hours. Rich cholesterol content lipoproteins (LDL) but not VLDL could restore MM cell viability, suggesting that cholesterol is responsible for this lipid-depletion effect. Taken together, our results show that high cholesterol promotes myeloma and results in a higher lipid content in myeloma cells, ultimately increasing BM tumour burden. Pretreatment with a cholesterol diet did not alter disease progression suggesting a direct pro-tumourigenic effect of cholesterol. These results demonstrate both the detrimental effect of cholesterol on myeloma progression and the potential for dietary intervention approaches.
体内循环LDL胆固醇升高会增加骨髓瘤肿瘤负荷
Gámez B., Morris EV.。, Olechnowicz S., Sowman, A., Turner, C.和Edwards CM.。多发性骨髓瘤(MM)是一种致命的恶性肿瘤,其特征是骨髓(BM)中恶性浆细胞的扩增,并与溶骨性骨病相关。MM之前是良性状态,即未确定意义的单克隆γ病(MGUS)。了解MM骨病的MGUS进展和发展是患者管理的关键。我们和其他人之前已经证明饮食引起的肥胖促进骨髓瘤的进展,但其背后的机制尚不清楚。当前研究的目的是确定膳食胆固醇对MM发展的影响。研究人员使用2%的胆固醇饮食来增加小鼠的循环LDL。将小鼠随机分为两组:a) 5TGM1 MM接种前4周的胆固醇饮食(预处理)或b) MM接种前4周的胆固醇饮食,并持续整个实验(连续)。连续胆固醇饮食的小鼠肿瘤负荷增加,与MM细胞脂滴含量增加有关。在接种MM时停止胆固醇饮食的小鼠中,肿瘤负荷没有差异。在体外,用腐烂的FBS培养的骨髓瘤细胞在72小时后的活力降低了50%。富含胆固醇含量的脂蛋白(LDL)而非VLDL可以恢复MM细胞活力,表明胆固醇是这种脂质消耗效应的原因。综上所述,我们的研究结果表明,高胆固醇促进骨髓瘤并导致骨髓瘤细胞中更高的脂质含量,最终增加BM肿瘤负担。用胆固醇饮食进行预处理并没有改变疾病进展,这表明胆固醇具有直接的促肿瘤作用。这些结果证明了胆固醇对骨髓瘤进展的有害影响以及饮食干预方法的潜力。
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