Jöhrer Karin, Janke Katrin, Krugmann Jens, Fiegl Michael, Greil Richard
Tyrolean Cancer Research Institute at the University of Innsbruck, Innsbruck, Austria.
Clin Cancer Res. 2004 Mar 15;10(6):1901-10. doi: 10.1158/1078-0432.ccr-1053-03.
The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been shown to facilitate leukocyte transendothelial migration. In multiple myeloma, TNF-alpha is an important factor in the promotion of growth and survival of the malignant cells. Studies have shown that enhanced TNF-alpha levels in myeloma patients correlated with aggressive disease. Therefore, we investigated the effect of recombinant human TNF-alpha on the migrational behavior of myeloma cells across the physiological barrier of the major disease compartment, i.e., human bone marrow endothelial cells. In the presence of TNF-alpha, we observed significantly increased migration both in established myeloma cell lines and in plasma cells from myeloma patients. Expression of TNF-receptor 2 (TNF-R2) but not TNF-receptor 1 (TNF-R1) was detected in myeloma cell lines. Myeloma cells of patients also showed expression of TNF-R2 but not TNF-R1. The effect of TNF-alpha could not be explained by altered expression of adhesion molecules or metalloproteases. Instead, we found an up-regulation of monocyte chemoattractant protein (MCP)-1 and confirmed that myeloma cells express the relevant receptor C-C chemokine receptor 2. Preincubation of myeloma cells with recombinant human MCP-1 also enhanced cell migration, and this effect, as well as the effect of TNF-alpha, was abolished by treatment with anti-MCP-1 antibody. In contrast, migration of myeloma cells in the direction of an MCP-1 gradient, i.e., chemotaxis, could not be observed in the cell lines investigated. Additionally, the mRNA level of TNF-alpha was up-regulated by the cytokine treatment, which points to an autocrine loop augmenting and/or stabilizing the TNF-alpha-MCP-1 pathway. In summary, our data clearly support additional investigations using anti-MCP-1 antibodies in myeloma progression.
促炎细胞因子肿瘤坏死因子（TNF）-α已被证明可促进白细胞跨内皮迁移。在多发性骨髓瘤中，TNF-α是促进恶性细胞生长和存活的重要因素。研究表明，骨髓瘤患者体内TNF-α水平升高与侵袭性疾病相关。因此，我们研究了重组人TNF-α对骨髓瘤细胞跨越主要疾病隔室（即人骨髓内皮细胞）生理屏障的迁移行为的影响。在TNF-α存在的情况下，我们观察到已建立的骨髓瘤细胞系和骨髓瘤患者的浆细胞迁移均显著增加。在骨髓瘤细胞系中检测到TNF受体2（TNF-R2）的表达，但未检测到TNF受体1（TNF-R1）的表达。骨髓瘤患者的骨髓瘤细胞也显示出TNF-R2的表达，但未显示TNF-R1的表达。TNF-α的作用无法通过黏附分子或金属蛋白酶表达的改变来解释。相反，我们发现单核细胞趋化蛋白（MCP）-1上调，并证实骨髓瘤细胞表达相关受体C-C趋化因子受体2。用重组人MCP-1预孵育骨髓瘤细胞也增强了细胞迁移，并且这种作用以及TNF-α的作用被抗MCP-1抗体处理所消除。相比之下，在所研究的细胞系中未观察到骨髓瘤细胞沿MCP-1梯度的迁移，即趋化作用。此外，细胞因子处理使TNF-α的mRNA水平上调，这表明存在一个自分泌环增强和/或稳定TNF-α-MCP-1途径。总之，我们的数据明确支持在骨髓瘤进展中使用抗MCP-1抗体进行进一步研究。
