The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer.
The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer.
复制标题
巨噬细胞的积累减弱了重组人内皮抑素对肺癌的作用。
DOI：
10.2147/ott.s114389
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发表时间：
2016
影响因子：
4
通讯作者：
Cao D
中科院分区：
文献类型：
--
作者：
Liu Y;Tu L;Wang L;Long J;Wang J;Wang Y;Luo F;Cao D
虽然抗血管生成疗法在临床上应用广泛，但其疗效却不如预期。需要筛选调节因子和敏感指标来确定这些药物的有效性。通过对临床数据的回顾性研究，我们发现外周单核细胞与淋巴细胞比率（MLR）较高的患者从抗血管生成药物重组人内皮抑素（rhES, Endostar®）治疗肺癌的获益较少。由于肿瘤中MLR与巨噬细胞计数呈正相关，该结果提示巨噬细胞可能影响rhES治疗肺癌的有效性。收集了72例接受rhES治疗的肺癌患者的临床资料。对Lewis肺癌（LLC）细胞、骨髓源性巨噬细胞、巨噬细胞系RAW264.7和ANA-1细胞进行动物实验、流式细胞术、免疫荧光、酶联免疫吸附、Western blot分析和transwell迁移实验。临床资料显示，与rhES治疗前的基线MLR相比，进展性疾病患者的MLR高于部分缓解患者。实验结果显示，经rhES治疗后，LLC肿瘤中募集的巨噬细胞增多，且大部分巨噬细胞表现为m2样表型。rhES加重了肿瘤微环境中的缺氧和炎症反应。缺氧促进内皮细胞和成纤维细胞表达CCL2，诱导巨噬细胞募集，炎症因子（白细胞介素-4 [IL-4]、IL-6和IL-10）水平升高，使巨噬细胞向m2样表型极化。缺氧或炎症细胞因子处理的巨噬细胞在体外和体内均可促进LLC的进展。我们发现rhES可加重肿瘤微环境中的缺氧和炎症反应。这些变化有利于巨噬细胞的聚集，使巨噬细胞向m2样表型偏斜，有助于LLC逃避抗血管生成治疗。因此，这些数据表明，肿瘤微环境中巨噬细胞的积累可能会对rhES治疗肺癌的疗效产生不利影响。
Although anti-angiogenic therapy is widely applied clinically, its efficacy has been less than expected. Screening for regulatory factors and sensitive indicators to define the effectiveness of these drugs is required. Through a retrospective study of clinical data, we found that patients with a higher peripheral monocyte-to-lymphocyte ratio (MLR) obtained less benefit from recombinant human endostatin (rhES, Endostar®), an anti-angiogenic drug, in lung cancer. Because MLR is positively correlated with macrophage count in tumors, this result suggests that macrophages may influence the effectiveness of rhES therapy in lung cancer. Clinical data from 72 lung cancer patients treated with rhES were collected. Animal study, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, Western blot analysis, and transwell migration assays were carried on Lewis lung carcinoma (LLC) cells, bone marrow-derived macrophages, macrophage cell line RAW264.7, and ANA-1 cells. Clinical data showed that compared with the baseline MLR before rhES treatment, patients with progressive disease had higher MLRs than those of patients with partial response. Experimental results showed that more macrophages were recruited in the LLC tumors after rhES treatment and the majority of them displayed an M2-like phenotype. rhES aggravated hypoxia and the inflammatory response in the tumor microenvironment. Hypoxia promoted the expression of CCL2 by endothelial and fibroblast cells, which could induce macrophages recruitment, and increased levels of inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) skewed macrophage polarization toward the M2-like phenotype. Hypoxia or inflammation cytokine-treated macrophages enhanced the progression of LLC in vitro and in vivo. We found rhES could aggravate hypoxia and the inflammatory response in the tumor microenvironment. These changes were favorable for macrophage accumulation, and skewed their polarization toward the M2-like phenotype which could help LLC to escape from the anti-angiogenic therapy. Thus, these data indicate the accumulation of macrophages in the tumor microenvironment may adversely affect the efficacy of rhES on lung cancer.