Development of ferret as a human lung cancer model by injecting 4-(Nmethyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
Development of ferret as a human lung cancer model by injecting 4-(Nmethyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
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DOI：
10.1016/j.lungcan.2013.09.012
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Wang XD
中科院分区：
文献类型：
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作者：
Aizawa K;Liu C;Veeramachaneni S;Hu KQ;Smith DE;Wang XD
发展与人类肺癌发生相关的新的动物肺癌模型对肺癌研究具有重要意义。以前，我们已经展示了在烟草烟雾和烟草致癌物(4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone，NNK的共同作用下，雪貂(Mustela Putorius Furo)发生肺癌的诱因。在目前的研究中，我们调查了NNK单独治疗是否会同时导致雪貂肺部的癌前病变和肿瘤病变。我们通过ip将雪貂暴露于NNK。注射NNK(50 mg/kgbw)，每月1次，连续4个月，随访24、26、32周。通过组织病理学检查评估肺组织癌前病变和肿瘤性病变的发生率。免疫组织化学和/或免疫印迹法检测肺组织中α7烟碱型乙酰胆碱受体(α7nAChR)及其相关分子生物标志物的表达。仅暴露于NNK的雪貂就会出现癌前病变(鳞状化生、不典型增生和不典型腺瘤性增生)和肿瘤(鳞状细胞癌、腺癌和腺鳞癌)，这在人类中很常见。NNK对雪貂的致瘤率呈时间依赖性(24、26和32周分别为16.7%、40.0%和66.7%)。α-7nAChR在雪貂肺泡巨噬细胞、肺泡巨噬细胞、肺泡巨噬细胞、鳞状细胞癌和腺癌均有高表达。此外，我们观察到暴露于NNK的雪貂肺组织中磷酸化ERK和细胞周期蛋白D1的蛋白水平有增加的趋势(p分别为0.081和0.080)。通过单独注射NNK在雪貂肺中形成癌前病变和肿瘤病变，为研究预防、检测和治疗人类肺癌的生物标志物/分子靶点提供了一种简单且高度相关的非啮齿动物模型。
Development of new animal lung cancer models that are relevant to human lung carcinogenesis is important for lung cancer research. Previously we have shown the induction of lung tumor in ferrets (Mustela putorius furo) exposed to both tobacco smoke and a tobacco carcinogen (4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK). In the present study, we investigated whether NNK treatment alone induces both preneoplastic and neoplastic lesions in the lungs of ferrets. We exposed ferrets to NNK by i.p. injection of NNK (50 mg/kg BW) once a month for four consecutive months and then followed up for 24, 26 and 32 weeks. The incidences of pulmonary preneoplastic and neoplastic lesions were assessed by histopathological examination. The expressions of α7 nicotinic acetylcholine receptor (α7 nAChR, which has been shown to promote lung carcinogenesis) and its related molecular biomarkers in lungs were examined by immunohistochemistry and/or Western blotting analysis. Ferrets exposed to NNK alone developed both preneoplastic lesions (squamous metaplasia, dysplasia and atypical adenomatous hyperplasia) and tumors (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma), which are commonly seen in humans. The incidence of tumor induced by NNK was time-dependent in the ferrets (16.7%, 40.0% and 66.7% for 24, 26 and 32 weeks, respectively). α7 nAChR is highly expressed in the ferret bronchial/bronchiolar epithelial cells, and alveolar macrophages in ferrets exposed to NNK, and in both squamous cell carcinoma and adenocarcinoma of the ferrets. In addition, we observed the tendency for an increase in phospho-ERK and cyclin D1 protein levels (p = 0.081 and 0.080, respectively) in the lungs of ferrets exposed to NNK. The development of both preneoplastic and neoplastic lesions in ferret lungs by injecting NNK alone provides a simple and highly relevant non-rodent model for studying biomarkers/molecular targets for the prevention, detection and treatment of lung carcinogenesis in humans.