Monitoring serum levels ELR+ CXC chemokines and the relationship between microvessel density and angiogenic growth factors in multiple myeloma
Monitoring serum levels ELR+ CXC chemokines and the relationship between microvessel density and angiogenic growth factors in multiple myeloma
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DOI：
10.1016/j.cyto.2011.08.034
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发表时间：
2011-12-01
期刊：
影响因子：
3.8
通讯作者：
Alexandrakis, M. G.
中科院分区：
文献类型：
--
作者：
Pappa, C. A.;Tsirakis, G.;Alexandrakis, M. G.
背景：ELR + CXC趋化因子是肿瘤发生的重要介质，与其血管生成特性相关。血管生成似乎是多发性骨髓瘤（MM）进展的一个突出特征。CXC趋化因子具有四个高度保守的半胱氨酸氨基酸残基，前两个半胱氨酸分子被单个氨基酸分开。该组的血管生成潜力由三个氨基酸残基的存在决定（Glu-Leu-Arg：ELR基序），位于NH 2末端第一个半胱氨酸氨基酸之前。本研究的目的是测定血管生成相关趋化因子ELR+基序，如白细胞介素-8（IL-8），上皮中性粒细胞活化蛋白-78（ENA-78）和生长相关基因α（GRO-α），以及MM患者诊断时和治疗后平台期的骨髓微血管密度（MVD）。方法：ELR + CXC趋化因子：IL-8，ENA-78和GRO-α以及血管生成因子的血清水平：肝细胞生长因子（HGF）、血管内皮生长因子（VEGF）和肿瘤坏死因子-α对63例初诊MM患者、30例平台期患者和20例健康对照者进行血清肿瘤坏死因子-α（TNF-α）水平测定。用市售ELISA试剂盒进行血清测定。在治疗前和治疗后的平台期进行骨髓活检，以抗CD31染色血管来确定MVD。MM患者组血清IL-8、ENA-78、GRO-α和TNF-α浓度显著高于对照组，与对照组相比（分别为44.5 +/-25.3、765 +/-572.1、186.5 +/-129.1和4.2 +/-2.8 pg/ml）（27.3 +/-6.4，335.1 +/-268.6，112.5 +/-76.1和1.3 +/-0.8 pg/ml）（对于GRO-α，p <0.02，对于其他病例，p <0.001）。我们还发现，未治疗的患者比治疗后的患者具有更高的IL-8、ENA-78、GRO-α水平，但仅发现IL-8的统计学显著差异（48.36 +/-30.93 pg/ml vs.35.05 +/-19.77 pg/ml，p <0.001）。此外，IL-8、GRO-α、TNF-α、HGF和VEGF随着疾病分期的增加而显著升高（在所有情况下p <0.001）。ENA-78血清水平在III期高于I期和II期，但无统计学意义。此外，我们将每种促炎细胞因子与众所周知的血管生成因子如HGF、VEGF和TNF-α相关联。血清HGF与IL-8和GRO-α之间呈正相关（分别为r = 0.316 p <0.01，r = 0.297 p <0.02）。类似地，血清VEGF与ENA-78和GRO-α相关（分别为r = 0.323 p <0.01，r = 0.469 p <0.001）。治疗前骨髓MVD与血清GRO-α水平呈正相关（r = 0.304，P <0.01）。IL-8、ENA-78和GRO-α水平高于中位数与低水平患者之间的生存时间存在差异，但差异在任何情况下都无法达到统计学显著性。这些发现支持ELR+基序CXC趋化因子，如IL-8，ENA-78和GRO-α与血管生成生长因子相关，可能在MM的进展中发挥作用。需要进一步研究以确定其预后和预测意义。(C)2011爱思唯尔有限公司版权所有。
Background: The ELR+ CXC chemokines are important mediators of tumorigenesis, related to their angiogenic properties. Angiogenesis appears to be a prominent feature in the progression of multiple myeloma (MM). CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine molecules separated by a single amino acid. The angiogenic potential of this group is determined by the presence of three amino acid residues (Glu-Leu-Arg: the ELR motif) preceding the first cysteine amino acid, in the NH2 terminus.Aims: The purpose of this study was to determine serum concentrations of angiogenesis-related chemokines ELR+ motif, such as interleukin-8 (IL-8), epithelial neutrophil activating protein-78 (ENA-78) and growth-related gene alpha (GRO-alpha), as well the bone marrow microvascular density (MVD) in patients with MM at diagnosis and after treatment, in plateau phase. We also evaluated the relationship among them with other known growth factors involved in angiogenesis.Methods: Serum levels of the ELR+ CXC chemokines: IL-8, ENA-78 and GRO-alpha as well as of the angiogenic factors: hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) were determined in 63 newly diagnosed MM patients, in 30 in plateau phase and in 20 healthy controls. Serum measurements of them were performed with commercially available kits for ELISA. Bone marrow biopsies were performed before and after treatment, in plateau phase, in order to determine MVD by staining vessels with anti-CD31.Results: Serum concentrations of IL-8, ENA-78, GRO-alpha and TNF-alpha were significantly higher in the group of MM patients (44.5 +/- 25.3, 765 +/- 572.1, 186.5 +/- 129.1 and 4.2 +/- 2.8 pg/ml, respectively) in comparison to control group (27.3 +/- 6.4, 335.1 +/- 268.6, 112.5 +/- 76.1 and 1.3 +/- 0.8 pg/ml) (p < 0.02 for GRO-alpha, p < 0.001 for other cases). We also found that untreated patients had higher levels of IL-8, ENA-78, GRO-alpha than post treatment patients, but statistical significant difference was found only for IL-8 (48.36 +/- 30.93 pg/ml vs. 35.05 +/- 19.77 pg/ml, p < 0.001). Furthermore IL-8, GRO-alpha, TNF-alpha, HGF and VEGF were significantly higher with increasing disease stage (p < 0.001 in all cases). ENA-78 serum levels were higher in stage III than in stage I and II, but without statistical significance. Additionally we correlated each proinflammatory cytokine with well known angiogenic factors such as HGF, VEGF and TNF-alpha. A positive correlation was found between serum HGF and IL-8 and GRO-alpha (r = 0.316 p < 0.01, r = 0.297 p < 0.02, respectively). Similarly serum VEGF correlated with ENA-78 and GRO-alpha (r = 0.323 p < 0.01, r = 0.469 p < 0.001, respectively). In the pretreatment group of patients a positive correlation between bone marrow MVD and serum levels of GRO-alpha was found (r = 0.304 p < 0.01). There was a difference in survival times between patients with higher than median versus low IL-8, ENA-78 and GRO-alpha levels, but the differences could not reach statistical significance in either case.Conclusions: These findings support the hypothesis that ELR+ motif CXC chemokines, such as IL-8, ENA-78 and GRO-alpha correlate with angiogenic growth factors and may play a role in the progression of MM. Further studies are needed to determine their prognostic and predictive significance. (C) 2011 Elsevier Ltd. All rights reserved.