文章：

慢性阻塞性肺病和肺癌之间的机制联系

Mechanistic links between COPD and lung cancer

原文发布日期：2013-03-07

DOI: 10.1038/nrc3477

类型: Review Article

开放获取: 否

要点：

1. Numerous epidemiological studies have consistently demonstrated an increased incidence of lung cancer in patients who have chronic obstructive pulmonary disease (COPD).
2. The emphysema component of COPD, which is characterized by excessive inflammation and matrix destruction, is sufficient to confer an increased risk for lung cancer. Taken together, the epidemiological literature suggests that entities involved in the airways and airspace components of COPD are both operative in increasing lung cancer risk.
3. Both COPD and lung cancer involve a substantial role for genetic susceptibility to disease, as only a minority of chronic cigarette smokers will develop one, or both, of the diseases. Several single nucleotide polymorphisms (SNPs) in candidate gene families (for example, detoxifying enzymes, proteinases, anti-proteinases and cytokines) have been implicated in disease pathogenesis for both COPD and lung cancer, and may confer a proportion of the risk.
4. The oxidant and noxious stress encountered in the lungs of cigarette smokers is overwhelming. These species cause sufficient damage to some epithelial cells such that they undergo apoptosis, resulting in emphysema. They additionally represent genotoxic stress capable of DNA adduct formation, thereby promoting the earliest stages of carcinogenesis.
5. Inflammatory cell infiltrates are common to both COPD and lung cancer. Their quantity and quality must be taken in context. Inflammation encountered in emphysema is typically cytotoxic and destructive to matrix structures. Such cells would not be expect to promote the growth of an existing tumour, but would provide the necessary genotoxic stress for tumour initiation. Once formed, small tumours polarize immune cells to alternatively activated phenotypes, which promote tumour growth and angiogenesis.
6. Matrix-degrading enzymes, especially those capable of degrading elastin (elastases) are essential for the development of emphysema. Many of these enzymes have been shown to promote lung tumour growth by a variety of mechanisms, including enhanced cellular proliferation and increased angiogenesis, which permits endovascular invasion. Therefore, these enzymes are likely to represent a proportion of the link between emphysema and lung cancer.
7. As operative mechanisms linking COPD to lung cancer are discovered, the opportunity for chemoprevention will arise. Ideally, new therapies will be developed that have the ability to retard COPD progression while reducing lung cancer risk.

要点翻译：

1. 大量流行病学研究一致表明，慢性阻塞性肺疾病（COPD）患者的肺癌发病率显著升高。
2. COPD中的肺气肿病变以过度炎症和基质破坏为特征，其本身足以增加肺癌风险。综合流行病学文献表明，与COPD气道及肺泡腔相关的病理改变共同推动了肺癌风险的提升。
3. COPD与肺癌的发病均受遗传易感性的显著影响——仅有少数长期吸烟者会发展为其中一种或两种疾病。多个候选基因家族（如解毒酶、蛋白酶、抗蛋白酶和细胞因子）中的单核苷酸多态性（SNPs）被证实与这两种疾病的发病机制相关，可能承担部分风险。
4. 吸烟者肺部承受的氧化和有害应激极为严重。这些物质会对部分上皮细胞造成足够损伤，导致细胞凋亡进而形成肺气肿。同时它们作为基因毒性应激源可引发DNA加合物形成，从而推动癌变的最初阶段。
5. 炎症细胞浸润是COPD与肺癌的共同特征。其数量与性质需结合具体背景分析：肺气肿中的炎症通常具有细胞毒性并破坏基质结构，此类细胞虽不直接促进现有肿瘤生长，但能为肿瘤起始提供必要的基因毒性应激。而已形成的小肿瘤会使免疫细胞极化为替代激活表型，从而促进肿瘤生长和血管生成。
6. 基质降解酶（尤其是能降解弹性蛋白的弹性蛋白酶）对肺气肿的发展至关重要。研究显示多种此类酶能通过增强细胞增殖、促进血管生成及血管内侵袭等机制加速肺肿瘤生长。因此，这些酶很可能构成肺气肿与肺癌关联的重要桥梁。
7. 随着连接COPD与肺癌的作用机制被逐步揭示，化学预防的机遇将应运而生。理想的新疗法应当既能延缓COPD进展，又能降低肺癌风险。

英文摘要：

Numerous epidemiological studies have consistently linked the presence of chronic obstructive pulmonary disease (COPD) to the development of lung cancer, independently of cigarette smoking dosage. The mechanistic explanation for this remains poorly understood. Progress towards uncovering this link has been hampered by the heterogeneous nature of the two disorders: each is characterized by multiple sub-phenotypes of disease. In this Review, I discuss the nature of the link between the two diseases and consider specific mechanisms that operate in both COPD and lung cancer, some of which might represent either chemopreventive or chemotherapeutic targets.

摘要翻译： 

大量流行病学研究一致表明，慢性阻塞性肺疾病（COPD）的存在与肺癌的发生密切相关，且这种关联独立于吸烟剂量。然而，其背后的机制仍不清楚。由于这两种疾病均具有高度异质性，每种疾病都包含多种亚表型，这在一定程度上阻碍了对两者关联的深入揭示。在本综述中，我将探讨这两种疾病之间的关联本质，并重点分析在COPD与肺癌中均起作用的特定机制，其中部分机制可能成为化学预防或化学治疗的潜在靶点。

原文链接：

Mechanistic links between COPD and lung cancer