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Carcinogenesis. 2019 Mar 4. pii: bgz047. doi: 10.1093/carcin/bgz047. [Epub ahead of print]

Tobacco chemical-induced mouse lung adenocarcinoma cell lines pin the prolactin orthologue proliferin as a lung tumour promoter.

Author information

1
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine; University of Patras; Rio, Achaia, Greece.
2
Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD); Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL); Munich, Bavaria, Germany.
3
Stem Cell Biology Laboratory, Department of Physiology, Faculty of Medicine; University of Patras; Rio, Achaia, Greece.
4
Department of Anatomy, Faculty of Medicine; University of Patras; Rio, Achaia, Greece.

Abstract

Lung adenocarcinoma (LADC) is the leading cause of cancer death worldwide. Nevertheless, syngeneic mouse models of the disease are sparse, and cell lines suitable for transplantable and immunocompetent mouse models of LADC remain unmet needs. We established multiple mouse LADC cell lines by repeatedly exposing two mouse strains (FVB, Balb/c) to the tobacco carcinogens urethane or diethylnitrosamine and by culturing out the resulting lung tumors for prolonged periods of time. Characterization of the resulting cell lines (n=7) showed that they were immortal and phenotypically stable in vitro, and oncogenic, metastatic, and lethal in vivo. The primary tumors that gave rise to the cell lines, as well as secondary tumors generated by transplantation of the cell lines, displayed typical LADC features, such as glandular architecture and mucin and thyroid transcription factor 1 expression. Moreover, these cells exhibited marked molecular similarity with human smokers' LADC, including carcinogen-specific Kras point mutations (KrasQ61R in urethane- and KrasQ61H in diethylnitrosamine-triggered cell lines) and Trp53 deletions and displayed stemness features. Interestingly, all cell lines overexpressed proliferin, a murine prolactin orthologue, which functioned as a lung tumour promoter. Furthermore, prolactin was overexpressed and portended poor prognosis in human lung adenocarcinoma. In conclusion, we report the first LADC cell lines derived from mice exposed to tobacco carcinogens. These cells closely resemble human LADC and provide a valuable tool for the functional investigation of the pathobiology of the disease.

KEYWORDS:

KRAS; Lung adenocarcinoma; TRP53; carcinogen; tobacco chemical

PMID:
30828726
DOI:
10.1093/carcin/bgz047

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