Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Bari, Italy.
Department of Biomedical Sciences and Human Oncology, Unit of General Pathology, University of Bari Aldo Moro, Bari, Italy.
Am J Pathol. 2021 Apr;191(4):748-758. doi: 10.1016/j.ajpath.2020.12.016. Epub 2021 Jan 29.
Multiple myeloma (MM) progression closely depends on bone marrow (BM) angiogenesis. Several factors sustain angiogenesis, including cytokines, growth factors, and cell-to-cell interactions. Herein, BM thrombopoietin (TPO) was shown to support angiogenesis and disease progression in MM. Patients with MM at different progression phases had higher levels of BM and circulating TPO than monoclonal gammopathy of undetermined significance/smoldering MM patients, suggesting that TPO correlates with disease progression and prognosis. Endothelial cells from patients with monoclonal gammopathy of undetermined significance (MGECs) and endothelial cells from MM (MMECs) expressed TPO receptor, and the TPO treatment triggered their angiogenic capabilities in vitro. Indeed, TPO-treated MGECs and MMECs showed enhanced angiogenesis on Matrigel and spontaneous cell migration and chemotaxis by acting as a chemotactic agent. TPO also had an angiogenic activity in vivo in the chorioallantoic membrane assay system. Finally, TPO treatment increased the release of active matrix metalloproteinase (MMP)-9 and MMP-2 in MGECs and of MMP-2 in MMECs and affected the balance between angiogenic/antiangiogenic factors in the MM BM. Our results support the angiogenic activity of TPO, and suggest that it may have a critical role in promoting the angiogenic switch during MM progression. Accordingly, TPO may be envisaged as a new angiogenic and prognostic factor in patients with MM.
多发性骨髓瘤（MM）的进展与骨髓（BM）血管生成密切相关。有几种因素维持着血管生成，包括细胞因子、生长因子和细胞间相互作用。在此，BM 血小板生成素（TPO）被证明可支持 MM 中的血管生成和疾病进展。处于不同进展阶段的 MM 患者的 BM 和循环 TPO 水平高于单克隆丙种球蛋白病/冒烟型 MM 患者，表明 TPO 与疾病进展和预后相关。意义不明的单克隆丙种球蛋白病（MGECs）和 MM 患者的内皮细胞（MMECs）表达 TPO 受体，TPO 处理在体外触发了它们的血管生成能力。事实上，TPO 处理的 MGECs 和 MMECs 在 Matrigel 上显示出增强的血管生成，以及自发的细胞迁移和趋化性，充当趋化剂。TPO 在鸡胚尿囊膜分析系统中也具有血管生成活性。最后，TPO 处理增加了 MGECs 中活性基质金属蛋白酶（MMP）-9 和 MMP-2 的释放，以及 MMECs 中 MMP-2 的释放，并影响 MM BM 中血管生成/抗血管生成因子的平衡。我们的结果支持 TPO 的血管生成活性，并表明它可能在促进 MM 进展中的血管生成开关中发挥关键作用。因此，TPO 可被视为 MM 患者的一种新的血管生成和预后因子。
