Schuller H M, McGavin M D, Orloff M, Riechert A, Porter B
Carcinogenesis and Developmental Therapeutics Program, College of Veterinary Medicine, University of Tennessee, Knoxville, USA.
Lab Invest. 1995 Sep;73(3):448-56.
We have shown that the nicotine-derived nitrosamine 4-(methyl-nitrosamino)-3-(pyridyl)-1-butanone (NNK) causes a high incidence of neuroendocrine lung tumors in male Syrian golden hamsters when administered to animals maintained in an atmosphere of 60% hyperoxia. In vitro studies with fetal hamster pulmonary neuroendocrine cells (PNE cells) and human neuroendocrine lung cancer cell lines revealed that nicotine and NNK are both potent mitogens for normal and neoplastic PNE cells when the cells were maintained in an atmosphere of high CO2. These effects were completely inhibited by antagonists of nicotinic acetylcholine receptors (nAChR). NNK displaced 3H-(-)L-nicotine from the nAchR in radioreceptor assays with cell membrane fractions from hamster lungs enriched in PNE cells. We therefore hypothesized that NNK acts as an agonist of the nAchR in PNE cells and that stimulation of this receptor in an environment of impaired pulmonary oxygenation is an important molecular event leading to the development of lung tumors with a neuroendocrine phenotype.
To test this hypothesis, we exposed male Syrian golden hamsters maintained in 60% hyperoxia to s.c. injections of nicotine for the duration of their life. To allow for a survival time long enough to assess a potential carcinogenic effect of this treatment, animals demonstrating symptoms of respiratory distress were returned to ambient air for 24 hours throughout the experiment.
A low but significant number of the animals exposed to hyperoxia and nicotine developed tumors of the nasal cavity, lungs, and adrenal glands. All of the tumor-bearing animals had survived 40 weeks or longer. The lung tumors demonstrated focal areas of positive immunoreactivity to neuron-specific enolase (NSE) and 5-hydroxy-tryptamine (5-HT, serotonin), both of which are markers of neuroendocrine differentiation. Hamsters maintained in ambient air and receiving identical injections with nicotine as well as animals maintained in hyperoxia and injected with saline did not develop tumors in any organs. All hamsters exposed to hyperoxia and surviving more than 12 weeks had thickened alveolar walls and emphysema.
Our data support the hypothesis that chronic stimulation of the nAChR in an environment of impaired pulmonary oxygenation contributes to the carcinogenic burden associated with exposure to cigarette smoke and provides selective growth advantage for lung tumors with a neuroendocrine phenotype.
我们已经表明，当将尼古丁衍生的亚硝胺4-(甲基亚硝氨基)-3-(吡啶基)-1-丁酮（NNK）给予饲养在60%高氧环境中的雄性叙利亚金仓鼠时，会导致神经内分泌性肺肿瘤的高发病率。对胎仓鼠肺神经内分泌细胞（PNE细胞）和人神经内分泌肺癌细胞系的体外研究表明，当细胞饲养在高二氧化碳环境中时，尼古丁和NNK对正常和肿瘤性PNE细胞都是有效的促有丝分裂原。这些作用被烟碱型乙酰胆碱受体（nAChR）拮抗剂完全抑制。在使用富含PNE细胞的仓鼠肺细胞膜组分进行的放射受体分析中，NNK从nAchR上取代了3H-(-)L-尼古丁。因此，我们推测NNK在PNE细胞中作为nAchR的激动剂起作用，并且在肺氧合受损的环境中对该受体的刺激是导致具有神经内分泌表型的肺肿瘤发生的重要分子事件。
为了验证这一假设，我们在雄性叙利亚金仓鼠的整个生命过程中，将其饲养在60%高氧环境中，并皮下注射尼古丁。为了有足够长的存活时间来评估这种治疗的潜在致癌作用，在整个实验过程中，对出现呼吸窘迫症状的动物放回常氧环境24小时。
暴露于高氧和尼古丁的动物中，有少量但显著数量的动物发生了鼻腔、肺和肾上腺肿瘤。所有患肿瘤的动物都存活了40周或更长时间。肺肿瘤显示出对神经元特异性烯醇化酶（NSE）和5-羟色胺（5-HT，血清素）呈阳性免疫反应的局灶区域，这两者都是神经内分泌分化的标志物。饲养在常氧环境中并接受与尼古丁相同注射的仓鼠，以及饲养在高氧环境中并注射生理盐水的动物，任何器官都未发生肿瘤。所有暴露于高氧且存活超过12周的仓鼠都有肺泡壁增厚和肺气肿。
我们的数据支持这样的假设，即在肺氧合受损的环境中对nAChR的慢性刺激会增加与接触香烟烟雾相关的致癌负担，并为具有神经内分泌表型的肺肿瘤提供选择性生长优势。
