Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk
Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk
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DOI：
10.1126/scitranslmed.aai9048
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发表时间：
2017-11-15
影响因子：
17.1
通讯作者：
Savai, Rajkumar
中科院分区：
文献类型：
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作者：
Pullamsetti, Soni Savai;Kojonazarov, Baktybek;Savai, Rajkumar
呼吸困难是晚期肺癌的一种常见、毁灭性且知之甚少的症状。在我们的队列中，在519例接受计算机断层扫描诊断肺癌的患者中，250例平均肺动脉直径>28 mm，表明肺动脉高压（PH）。在人肺癌组织中，我们始终观察到血管重塑和血管周围炎性细胞积聚（巨噬细胞/淋巴细胞）增加。在三种肺癌小鼠模型（LLC 1、KRas（LA 2）和cRaf-BxB）中模拟血管重塑、PH和血管周围炎性细胞积聚。相反，NOD。Cg-Prkdc（scid）Il 2 rgtm 1 Wjl/SzJ免疫缺陷异种移植物和显性阴性IKK 2突变体三重转基因（Sftpc-rtTA/Tet-O-Ikk 2DN）小鼠没有发展PH。将人肺癌细胞与巨噬细胞和淋巴细胞共培养强烈上调细胞因子释放，引起增强的迁移、凋亡抗性和磷酸二酯酶5（PDE 5）介导的人肺血管细胞的上调，这是PH的典型特征。PDE 5抑制剂西地那非在LLC 1模型中极大地抑制了PH。我们得出结论，肺癌相关PH代表了一种独特的PH类别;靶向微环境中的炎症和PDE 5提供了一种潜在的治疗选择。
Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/ lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRas(LA2), and cRaf-BxB). In contrast, NOD. Cg-Prkdc(scid) Il2rgtm1Wjl/SzJ immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing human lung cancer cells with macrophages and lymphocytes strongly up-regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)-mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1 model. We conclude that lung cancer-associated PH represents a distinct PH category; targeting inflammation in the micro-environment and PDE5 offers a potential therapeutic option.