Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors—monoclonal gammopathy of undetermined significance—and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor–adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured byCYP1A1andCYP1B1gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reducedCYP1B1expression and increased cellular growth. This tumor-suppressing role ofCYP1A1andCYP1B1was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression.
肥胖不仅是多发性骨髓瘤（MM）发病的危险因素，还与骨髓瘤前体疾病——意义未明的单克隆丙种球蛋白病和冒烟型骨髓瘤——进展风险增加相关。骨髓微环境中的脂肪细胞（BMAs）已被证实可通过分泌因子促进MM细胞生长，但这些分泌因子的性质及其作用机制尚未完全阐明。芳香烃受体（AhR）表达升高与包括MM在内的多种癌症相关；然而，AhR活性在肥胖相关MM细胞生长和存活中的作用尚未被探索。这尤其值得关注，因为最近研究表明骨髓脂肪细胞是内源性AhR配体的来源。通过建立多种肿瘤-脂肪细胞相互作用的体外模型模拟骨髓微环境，我们发现了脂肪细胞分泌因子在抑制MM细胞AhR活性方面的新型非毒理学作用。将六种MM细胞系分别置于（1）直接共培养、（2）Transwell共培养或（3）脂肪细胞条件培养基中与骨髓脂肪细胞共培养，以探究分泌因子对MM细胞AhR活性的影响。通过CYP1A1和CYP1B1基因诱导检测发现，AhR的核定位及转录活性均受到BMA来源因子的抑制。此外，AhR靶基因表达降低与不良临床结局相关。AhR基因敲除导致CYP1B1表达下降和细胞生长加速。患者数据支持CYP1A1和CYP1B1的肿瘤抑制作用，显示靶基因表达降低与较差的总生存期存在关联。这些数据揭示了骨髓脂肪细胞促进MM进展的新机制。
肿瘤(癌症)患者之家