Pacheco-Rodriguez Gustavo, Kumaki Fumiyuki, Steagall Wendy K, Zhang Yi, Ikeda Yoshihiko, Lin Jing-Ping, Billings Eric M, Moss Joel
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2009 Feb 1;182(3):1270-7. doi: 10.4049/jimmunol.182.3.1270.
Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction caused by LAM cells (smooth-muscle-like cells) that have mutations in the tumor suppressor genes tuberous sclerosis complex (TSC) 1 or 2 and have the capacity to metastasize. Since chemokines and their receptors function in chemotaxis of metastatic cells, we hypothesized that LAM cells may be recruited by chemokine(s) in the lung. Quantification of 25 chemokines in bronchoalveolar lavage fluid from LAM patients and healthy volunteers revealed that concentrations of CCL2, CXCL1, and CXCL5 were significantly higher in samples from LAM patients than those from healthy volunteers. In vitro, CCL2 or MCP-1 induced selective migration of cells, showing loss of heterozygosity of TSC2 from a heterogeneous population of cells grown from explanted LAM lungs. Additionally, the frequencies of single-nucleotide polymorphisms in the CCL2 gene promoter region differed significantly in LAM patients and healthy volunteers (p = 0.018), and one polymorphism was associated significantly more frequently with the decline of lung function. The presence (i.e., potential functionality) of chemokine receptors was evaluated using immunohistochemistry in lung sections from 30 LAM patients. Expression of chemokines and these receptors varied among LAM patients and differed from that seen in some cancers (e.g., breast cancer and melanoma cells). These observations are consistent with the notion that chemokines such as CCL2 may serve to determine mobility and specify the site of metastasis of the LAM cell.
淋巴管平滑肌瘤病（LAM）的特征是由淋巴管平滑肌瘤细胞（平滑肌样细胞）导致的肺囊性破坏，这些细胞在肿瘤抑制基因结节性硬化复合物（TSC）1或2中发生突变，并具有转移能力。由于趋化因子及其受体在转移细胞的趋化作用中发挥功能，我们推测LAM细胞可能被肺中的趋化因子募集。对LAM患者和健康志愿者支气管肺泡灌洗液中25种趋化因子的定量分析显示，LAM患者样本中CCL2、CXCL1和CXCL5的浓度显著高于健康志愿者样本。在体外，CCL2或单核细胞趋化蛋白-1（MCP-1）诱导细胞选择性迁移，显示出从移植的LAM肺生长的异质细胞群体中TSC2杂合性缺失。此外，CCL2基因启动子区域单核苷酸多态性的频率在LAM患者和健康志愿者中存在显著差异（p = 0.018），并且一种多态性与肺功能下降的关联更为频繁。使用免疫组织化学对30例LAM患者的肺切片进行趋化因子受体存在情况（即潜在功能）评估。趋化因子及其受体的表达在LAM患者中各不相同，且与某些癌症（如乳腺癌和黑色素瘤细胞）中的情况不同。这些观察结果与CCL2等趋化因子可能决定LAM细胞迁移能力并确定转移部位的观点一致。
