Cancer Prevention Research：揭示慢性阻塞性肺疾病为何会增加患肺癌风险

除了众所周知的抽烟这个风险因素之外，慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)也会增加患上肺癌的风险。如今，来自美国科罗拉多大学癌症中心的一项最新研究详细描述了该风险的一种新的机制：长期性缺氧(long-term oxygen depletion)激活促进肿瘤生长的信号。此外，这项在动物模型上完成的研究证实这些由COPD诱导的信号引起的肿瘤可能特别敏感于关闭这些信号的用于预防或者甚至治疗的药物(也就是VEGFR-2和EGFR抑制剂)。相关研究结果于2012年6月14日在线发表在Cancer Prevention Research期刊上。

论文通信作者York Miller博士说，至少在动物模型中，来自肺部缺氧区域的肺肿瘤中被激活的一种重要的途径，并不在来自其他肺癌中以几乎相同的程度被激活。不过其他机制也可能促进COPD模式动物体内产生肺癌，比如炎症，不过这项研究表明这种低氧感知途径在这些COPD肺癌模式动物中特异性地被激活，而且这种感知途径在很大程度上促进肿瘤生长。

特别地是，他的研究利用经培养患上癌症的模式动物开展研究，并将它们放置在高海拔的房间中以便模仿因患上COPD而在肺部部分区域观察到的长期缺氧。在低氧环境下的小鼠要比处于正常氧气水平下的小鼠产生更大的肿瘤。不过，按照Miler的说法，最令人关注的是肿瘤生长的原因。

研究人员发现模拟COPD症状(包括慢性支气管炎和肺气肿)的低氧环境下的肿瘤生长是由于HIF-2a信号引起的。HIF-2a接着激活促进癌症生长的包括VEGF、EGFR配体(即TGFa)在内的机制。

类似地，正如来自低氧条件下的肿瘤确实通过激活导致VEGF和TGFa过量产生的途径来进行生长的，因此这些肿瘤对阻断这些生长因子的抗癌治疗特别敏感。毫无疑问，服用药物凡德他尼(vandetanib)---一种同时抑制VEGFR和EGFR的试剂---的模式动物在低氧条件下不容易患上肺癌。

本文编译自How chronic obstructive pulmonary disease increases risk of lung cancer

原文摘要：

Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism

Vijaya Karoor1,3, Mysan Le4, Daniel Merrick2,3,4, Karen A. Fagan5, Edward C. Dempsey1,3,4, and York E. Miller

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.