Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells. Despite the development of a diverse array of targeted drug therapies over the last decade, patients often relapse and develop refractory disease due to multidrug resistance. Obesity is a growing public health threat and a risk factor for multiple myeloma, although the mechanisms by which obesity contributes to MM growth and progression have not been fully elucidated. In the present study, we evaluated whether crosstalk between adipocytes and MM cells promoted drug resistance and whether this was amplified by obesity. Human adipose-derived stem cells (ASCs) from nineteen normal (BMI = 20–25 kg/m2), overweight (25–30 kg/m2), or obese (30–35 kg/m2) patients undergoing elective liposuction were utilized. Cells were differentiated into adipocytes, co-cultured with RPMI 8226 or U266B1 multiple myeloma cell lines, and treated with standard MM therapies, including bortezomib or a triple combination of bortezomib, dexamethasone, and lenalidomide. We found that adipocytes from overweight and obese individuals increased cell adhesion-mediated drug resistance (CAM-DR) survival signals in MM cells, and P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) drug transporter expression. Further, co-culture enhanced in vitro angiogenesis, MMP-2 activity, and protected MM cells from drug-induced decreases in viability. In summary, we provide an underlying mechanism by which obesity can impair the drug response to MM and allow for recurrence and/or disease progression.
多发性骨髓瘤（MM）是一种无法治愈的血液系统恶性肿瘤，其特征为恶性浆细胞的克隆性增殖。尽管过去十年间已开发出多种靶向药物治疗方案，但患者常因多药耐药性而复发并发展为难治性疾病。肥胖作为日益严重的公共卫生威胁，是多发性骨髓瘤的风险因素，但其促进骨髓瘤生长与进展的具体机制尚未完全阐明。本研究旨在探讨脂肪细胞与骨髓瘤细胞间的相互作用是否会促进耐药性，以及肥胖是否会放大这种效应。研究采用19例接受择期吸脂手术患者（包括体重正常者BMI=20–25 kg/m²、超重者25–30 kg/m²及肥胖者30–35 kg/m²）的人源脂肪干细胞（ASCs），将其分化为脂肪细胞后与RPMI 8226或U266B1多发性骨髓瘤细胞系共培养，并采用标准骨髓瘤治疗方案（包括硼替佐米单药或硼替佐米、地塞米松、来那度胺三联疗法）进行处理。研究发现，超重和肥胖个体的脂肪细胞能增强骨髓瘤细胞中由细胞黏附介导的耐药性（CAM-DR）生存信号，并上调P-糖蛋白（P-gp）及多药耐药相关蛋白（MRP）等药物转运蛋白的表达。此外，共培养体系还增强了体外血管生成能力与基质金属蛋白酶-2（MMP-2）活性，并保护骨髓瘤细胞免受药物诱导的活性降低。综上所述，本研究揭示了肥胖损害多发性骨髓瘤药物反应、导致疾病复发和/或进展的内在机制。
Unlocking Drug Resistance in Multiple Myeloma: Adipocytes as Modulators of Treatment Response
肿瘤(癌症)患者之家