Molecular Characterization of Neuroendocrine Lung-Tumors Induced in Hamsters by Treatment With Nitrosamines and Hyperoxia

Miller, '; Baxter, J.W.; Jw, Moore; Lewis, J. S.; Hm, Schuller

doi:10.3892/ijo.4.1.5

Cited by 11 publications

(6 citation statements)

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“…These neuroendocrine lung tumors were comprised of invasively growing well differentiated cells that expressed the neuroendocrine markers serotonin, mammalian bombesin, calcitonin, and neuron-specific enolase, thus warranting a classification as neuroendocrine carcinomas in accordance with a recently established histological tumor classification for rodents (Nikitin, Alcaraz, Anver, Bronson, Cardiff, Dixon, Fraire, Gabrielson, Gunning, Haines, Kaufman, Linnoila, Maronpot, Rabson, Reddick, Rehm, Rozengurt, Schuller, Shmidt, Travis, Ward and Jacks, 2004). Similar to SCLC, the neuroendocrine lung tumors in hamsters did not harbor activating point mutations in k-ras while overexpressing c-myc (Miller, Baxter, Moore and Schuller, 1994). In analogy to our in vitro experiments (Jull, Plummer and Schuller, 2001), an inhibitor of PKC completely blocked the development of DEN-induced neuroendocrine lung carcinomas in hamsters with pulmonary fibrosis (Schuller, Correa, Orloff and Reznik, 1990).…”

Section: Nitrosamine-induced Signaling Via Nachrs and Lung Cancermentioning

confidence: 65%

Nitrosamines as nicotinic receptor ligands

Schüller

2007

Life Sciences

107

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Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (α7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the α7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the a7nAChR and caused influx of Ca 2+ , activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the α7nAChR was enhanced when cells were maintained in an environment of 10-15% CO 2 similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the α7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.

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Section: Nitrosamine-induced Signaling Via Nachrs and Lung Cancermentioning

confidence: 65%

Nitrosamines as nicotinic receptor ligands

Schüller

2007

Life Sciences

107

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“…In some instances, the lack of a detailed morphological and biochemical characterization has hindered wider applications of proposed NE lung tumor models. [185][186][187] This has prompted a search for more relevant models of lung NE carcinogenesis.…”

Section: Innervation and Chemoreception Function Of Pnecsmentioning

confidence: 99%

Functional facets of the pulmonary neuroendocrine system

Linnoila

2006

Laboratory Investigation

176

143

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Pulmonary neuroendocrine cells (PNECs) have been around for 60 years in the scientific literature, although phylogenetically they are ancient. Their traditionally ascribed functions include chemoreception and regulation of lung maturation and growth. There is recent evidence that neuroendocrine (NE) differentiation in the lung is regulated by genes and pathways that are conserved in the development of the nervous system from Drosophila to humans (such as achaete-scute homolog-1), or implicated in the carcinogenesis of the nervous or NE system (such as the retinoblastoma tumor suppressor gene). In addition, complex neural networks are in place to regulate chemosensory and other functions. Even solitary PNECs appear to be innervated. For the first time ever, we have mouse models for lung NE carcinomas, including the most common and virulent small cell lung carcinoma. Moreover, PNECs may be important for inflammatory responses, and pivotal for lung stem cell niches. These discoveries signify an exciting new era for PNECs and are likely to have therapeutic and diagnostic applications.

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“…Both agents had significant chemopreventive effects on the development of neuroendocrine lung tumors whereas they demonstrated significant tumor promoting effects on adenomas/adenocarcinomas. Our neuroendocrine hamster lung tumors resemble human small cell lung carcinoma [36][37][38] in that they express the neuroendocrine markers 5-HT, mammalian bombesin/GRP, calcitonin, overexpress c-myc, while lacking point mutations in the ras gene [32,33]. Intracellular signaling of autocrine growth factors of the neuropeptide and 5-HT families in SCLC includes activation of protein kinase C, Raf-1 and the mitogen activated protein kinase (MAPK) pathway [3,21].…”

Section: Discussionmentioning

confidence: 99%

“…When the animals were 6 weeks old, they were randomly assigned to eight groups of 20 hamsters each. Neuroendocrine lung tumors were induced in three groups as previously described [27,[30][31][32][33] by subcutaneous injections of NNK (Chemsyn Laboratories, Lennexa, KT; 1.5 g per 100 g bodyweight three times a week for 10 weeks) in hamsters with hyperoxic lung injury caused by continuous exposure of the animals in their own cages to an environment of 60% O 2 . This dose of NNK is the highest dose in hyperoxic hamsters that did not cause toxicity (weightloss, mortality) during a 4-week dose-range finding study prior to previously published experiments [33] in this animal model.…”

Section: Methodsmentioning

confidence: 99%