Metastasis to the F344 Rat Pancreas from Lung Cancer Induced by 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)- 1-butanol, Constituents of Tobacco Products

Abstract

Lung cancer is the most common cause of cancer-related deaths in humans worldwide. There is strong evidence that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) play an important role in carcinogenesis caused by tobacco products. NNK and racemic NNAL are reported to induce lung and pancreatic tumors in rats. The carcinogenicity in Fischer 344 rats of NNK, NNAL, and its enantiomers ( R)-NNAL and ( S)-NNAL has been studied recently, and all test compounds induced significant numbers of lung tumors. We report here the detailed histopathological and immunohistochemical characterization of these tumors and their aggressive nature as shown by their metastasis locally and to the pancreas. The spectrum of treatment-related histopathological findings comprised pulmonary alveolar/bronchiolar (A/B) epithelial hyperplasia, A/B adenomas, and A/B carcinomas. A/B carcinomas frequently exhibited local invasion/metastasis within the mediastinum and thoracic cavity and distant metastasis to the pancreas that was confirmed by immunohistochemistry using the lung-specific markers prosurfactant protein-C and club (Clara) cell-10. Our observation regarding metastasis to the pancreas was an important, and unexpected, finding in this study both for the experimental animal model and potential human relevance.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone provokes progression from chronic pancreatitis to pancreatic intraepithelial neoplasia

“…However, six rats showed PanINs pathology when they were treated with NNK and DBTC ( Figures 4 E and 4F). To testify whether these lesions on pancreas were metastasis from NNK-induced lung malignancy ( Kovi et al., 2018 ), we performed immunohistochemical staining for type II pneumocytes marker SP-C and bronchioles marker CC-10. No reactive staining was found in the pancreatic lesions ( Figure S5 ).…”

“…found that these compounds induced exocrine pancreatic cancer as well as lung cancer ( Rivenson et al., 1988 ). Recently, cigarette smoking was found to not only accelerate pancreatic cancer progression but also induce pancreatic cancer stemness ( Kovi et al., 2018 ; Nimmakayala et al., 2018 ).…”

The Role of Nitric Oxide in Cancer: Master Regulator or NOt?

“…RR’NNO can act as carcinogens. In particular, tobacco associated RR’NNO such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are key players in the development of lung cancer [ 51 ] and also promote the development of metastasis [ 52 ].…”

Chimeric RNA RRM2-C2orf48 plays an oncogenic role in the development of NNK-induced lung cancer

“… 8 It promotes lung tumorigenesis 9 and increases the invasive ability of lung cancer cells. 10 , 11 NNK also affects biodegradation and metabolism, and it binds with DNA and hemoglobin in animals, resulting in a high level of carcinogenicity. 12 Although NNK has been found to induce lung cancer through various mechanisms, its oncogenic mechanisms have not been thoroughly elucidated.…”