Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, #12-01, 117599, Singapore.
Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, 14 Medical Drive, #12-01, 117599, Singapore.
Biochem Biophys Res Commun. 2019 Jan 22;508(4):1175-1181. doi: 10.1016/j.bbrc.2018.11.178. Epub 2018 Dec 13.
Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of abnormal plasma cells. MM dysregulates the homeostasis of the bone niche cells like osteoclasts and osteoblasts, responsible for the bone maintenance leading to bone loss and hypercalcemia, as well as the normal immune cells leading to immunodeficiency and anemia. Osteoblasts are part of the cell population differentiating from mesenchymal stem cells (MSC). MSC also gives rise to other cell types such as adipocytes and chondrocytes. It has been observed that adipocytes support MM growth by increasing its survival and chemo-resistance. As adipocytes originate from MSC, the understanding of early modifications in the MSC population during the disease progression is of paramount importance and may help for early diagnosis of MM. Herein, we have evaluated the modification of the MSC population in the bone niche in an in vivo model of MM. Our results showed that before an observable engraftment of MM in the bone niche, the proportion of MSC population is significantly decreased, while a significant increase in adipocyte related genes such as PPARγ and CEBPα expression appears, with no difference in osteogenic differentiation. These results suggest that the bone niche is switching to a "fatty" marrow which would create an adequate microenvironment for MM. This led us to screen for and identify modulated adipokines in the sera of this in vivo MM-mice model. Such changes could reflect early signs of MM and potentially be exploited as detection biomarkers of the disease.
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，其特征是异常浆细胞的克隆性增殖。MM 失调了破骨细胞和成骨细胞等骨龛细胞的内稳态，导致骨丢失和高钙血症，以及正常免疫细胞导致免疫缺陷和贫血，从而负责骨骼维持。成骨细胞是从间充质干细胞（MSC）分化而来的细胞群体的一部分。MSC 还产生其他细胞类型，如脂肪细胞和成软骨细胞。已经观察到脂肪细胞通过增加 MM 的存活和化疗耐药性来支持 MM 的生长。由于脂肪细胞起源于 MSC，因此了解疾病进展过程中 MSC 群体的早期变化至关重要，这可能有助于 MM 的早期诊断。在此，我们在 MM 的体内模型中评估了骨龛中 MSC 群体的修饰。我们的结果表明，在 MM 在骨龛中可观察到定植之前，MSC 群体的比例显著降低，而与脂肪细胞相关的基因如 PPARγ 和 CEBPα 的表达显著增加，而成骨分化没有差异。这些结果表明，骨龛正在向“脂肪”骨髓转变，这将为 MM 创造一个合适的微环境。这促使我们筛选和鉴定这种体内 MM 小鼠模型血清中的调节脂肪因子。这些变化可能反映了 MM 的早期迹象，并可能被用作该疾病的检测生物标志物。
