Hematology and Transplant Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", 84131 Salerno, Italy.
Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy.
Int J Mol Sci. 2023 Jun 23;24(13):10519. doi: 10.3390/ijms241310519.
The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies.
微环境在多发性骨髓瘤（MM）的发展、进展、细胞增殖、存活、免疫逃逸和耐药性中起着至关重要的作用。间充质基质细胞和巨噬细胞释放耐受性细胞因子，并有利于抗凋亡信号通路的激活，而尿激酶纤溶酶原激活受体（uPAR）系统有助于通过细胞外基质迁移。在这里，我们首先总结了巨噬细胞和 uPAR 系统在 MM 发病机制中的作用，然后报告了 uPAR 抑制剂在原发性 MM 衍生的贴壁细胞的一系列病例中的潜在治疗效果。我们的初步结果表明，在 uPAR 抑制剂治疗后，培养物中白细胞介素-6（平均值 ± 标准差，8734.95 ± 4169.2 pg/mL 比 359.26 ± 393.8 pg/mL，预处理与后处理；= 0.0012）和 DKK-1 水平（平均值 ± 标准差，7005.41 ± 6393.4 pg/mL 比 61.74 ± 55.2 pg/mL，预处理与后处理；= 0.0043）几乎完全被抑制，支持进一步研究 uPAR 阻断作为 MM 治疗的治疗策略。因此，uPAR 抑制剂可以发挥抗炎和促免疫监视作用。然而，我们的初步结果需要在额外的体外和体内研究中进一步验证。
