文章：

吸烟相关的肺和胰腺腺癌发展机制

Mechanisms of smoking-related lung and pancreatic adenocarcinoma development

原文发布日期：2002-06-01

DOI: 10.1038/nrc824

类型: Review Article

开放获取: 否

要点：

1. Adenocarcinomas of the lung and pancreas are among the most common and most deadly cancers. They share two risk factors — smoking and high-fat diet — with cardiovascular disease.
2. The arachidonic acid (AA) cascade is important in cardiovascular disease, and the overexpression of the gene that encodes cyclooxygenase-2 (COX2) in pulmonary and pancreatic adenocarcinoma indicates that the AA-cascade is also involved in the development of these cancers.
3. A nicotine-derived nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), causes adenocarcinomas of the lung and pancreas in laboratory animals, and is thought to be largely responsible for the development of these cancers in smokers.
4. NNK has genotoxic effects on cells, such as the formation of DNA adducts and mutations in the RAS gene. These effects of NNK probably cause the development of cancers that express such gene mutations (∼30% of pulmonary and 50–90% of pancreatic adenocarcinomas).
5. NNK also has epigenetic effects on pulmonary and pancreatic cells by functioning as an agonist for β-adrenergic receptors. This reaction activates various signal-transduction pathways, and causes the release of AA followed by the formation of mitogenic AA metabolites. These β-adrenergic-receptor-mediated events activate transcription and cell proliferation, and are thought to cause pulmonary and pancreatic adenocarcinomas that do not express RAS mutations, as well as synergizing with the cancer-causing effects of mutated RAS.
6. β-Blockers, inhibitors of AA-metabolizing enzymes and a low-fat diet are already widely used for the treatment and prevention of cardiovascular disease. The data compiled in this review indicate that they will also be effective for the treatment and prevention of pulmonary and pancreatic adenocarcinomas.
7. Overexpression of COX2 in adenocarcinomas of the colon, prostate and breast, as well as recent reports that β-adrenergic signalling regulates growth of these cancers, indicate that adenocarcinomas at these organ sites might also be treated or prevented with β-blockers. They might also be treated with pharmacological or dietary inhibitors of the AA cascade.

要点翻译：

1. 肺腺癌和胰腺癌是最常见且致死率最高的癌症类型。它们与心血管疾病共享两大风险因素——吸烟和高脂饮食。
2. 花生四烯酸（AA）级联反应在心血管疾病中起重要作用，而环氧化酶-2（COX2）编码基因在肺腺癌和胰腺癌中的过度表达表明，AA级联反应也参与了这些癌症的发生发展。
3. 尼古丁衍生的亚硝胺——4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮（NNK）在实验动物中可诱发肺腺癌和胰腺癌，被认为与吸烟者罹患这些癌症密切相关。
4. NNK对细胞具有遗传毒性效应，例如形成DNA加合物及引发RAS基因突变。这些效应可能导致携带此类基因突变的癌症发生（约30%的肺腺癌和50-90%的胰腺腺癌存在该突变）。
5. NNK还通过作为β-肾上腺素能受体激动剂对肺和胰腺细胞产生表观遗传效应。该反应激活多种信号转导通路，引起AA释放并随后形成促有丝分裂的AA代谢物。这些β-肾上腺素能受体介导的事件可激活转录和细胞增殖，被认为会导致不表达RAS突变的肺腺癌和胰腺癌发生，并与突变RAS的致癌效应产生协同作用。
6. β受体阻滞剂、AA代谢酶抑制剂及低脂饮食已广泛用于心血管疾病的治疗和预防。本综述汇总的数据表明，这些干预措施对肺腺癌和胰腺癌的防治同样有效。
7. 结肠癌、前列腺癌和乳腺癌中COX2的过度表达，以及近期关于β-肾上腺素能信号通路调控这些癌症生长的报道表明，这些器官的腺癌也可能通过β受体阻滞剂进行防治。药物性或膳食性AA级联反应抑制剂也可能对其产生治疗效果。

英文摘要：

Adenocarcinoma of the lungs and pancreas are among the most common and most deadly smoking-associated cancers. Cigarette smoke contains various toxic chemicals, including a carcinogenic nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). One of the most well-known features of NNK is the ability of its metabolites to bind to DNA and induce activating point mutations in the RAS gene. But NNK is also a β-adrenergic-receptor agonist that stimulates arachidonic acid release, leading to the formation of mitogenic metabolites that stimulate DNA synthesis and cell proliferation. NNK therefore contributes to tobacco-induced carcinogenesis by several mechanisms.

摘要翻译： 

肺腺癌和胰腺癌是最常见且最致命的吸烟相关癌症之一。香烟烟雾中含有多种有毒化学物质，其中包括一种致癌性亚硝胺——4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）。NNK 最众所周知的特征之一是其代谢产物能与 DNA 结合，诱导 RAS 基因发生激活型点突变。但 NNK 同时也是一种 β-肾上腺素受体激动剂，可刺激花生四烯酸释放，进而形成具有促有丝分裂活性的代谢产物，促进 DNA 合成和细胞增殖。因此，NNK 通过多种机制参与烟草诱导的致癌过程。

原文链接：

Mechanisms of smoking-related lung and pancreatic adenocarcinoma development