Tobacco carcinogen induced mouse lung adenocarcinoma cell lines as tools to identify novel lung cancer genes

• Κύριος συγγραφέας: Κανελλάκης, Νικόλαος
• Άλλοι συγγραφείς: Σταθόπουλος, Γεώργιος
• Μορφή: Thesis
• Γλώσσα: English
• Έκδοση: 2020
• Θέματα: Lung; Adenocarcinoma; Tobacco; KRAS; TRP53; Carcinogen; Smoking; Πνεύμονας; Αδενοκαρκίνωμα; Καπνός; Καρκινογόνο; Κάπνισμα; 616.994 240 6

Cancer bears a heavy socio-economic burden to both economically developed and developing societies. The incidence of cancer has been increasing over the years due to the aging of the population and the augmenting occurrence of established cancer risk factors such as tobacco smoking. Lung cancer is the leading cause of cancer death worldwide. Carcinogen inflicted malignancies, including tobacco smoking derived lung adenocarcinoma, harbor thousands of mutations per genome. Over the last decades many new lung adenocarcinoma oncogenes have been identified and thus new anticancer agents have been introduced in the clinical practice. These agents have changed the prognosis and the quality of life of patients. However, due to limitations the underlying driver oncogenes remain unknown in approximately half of the cases. Although elaborate lung cancer genetic models exist they do not really recapitulate the human disease. The development of a faithful mouse model suitable for the identification of the missing lung cancer driving oncogenes and mutations remains an unmet and urgent research call. We managed to develop a methodology to obtain mouse lung adenocarcinoma cell lines from various strains (FVB and Balb/c) following repetitive exposure to the tobacco carcinogens: urethane and diethylnitrosamine. Importantly the resulting cell lines (n = 7) were immortal and phenotypically stable in vitro, oncogenic, metastatic and lethal in vivo. Moreover, these cells exhibited marked similarity with the human lung adenocarcinoma, including stemness features, Kras and Trp53 mutations. All cell lines overexpressed proliferin, a murine prolactin orthologue, functioning as a lung tumor promoter. Interestingly prolactin was found overexpressed and portended poor prognosis in human lung adenocarcinoma. In conclusion these cells closely resemble the human disease, providing invaluable vehicles for the discovery and functional investigation of the missing lung cancer genes, driving mutations, and promoting lung carcinogenesis molecular pathways and mechanisms.