Cancer Initiating Cell of Lung Squamous Cell Carcinoma in Mice Might Be Derived from the Bronchiolar Alveolar Stem Cell

Abstract

ABSTRACT Aim: The cell of origin of lung squamous cell carcinoma (SCC) has not been clearly identified. Recently, carcinogenic studies for identifying the cell of origin of cancer have been focused on the relationship between the adult tissue stem cells and the cancer-initiating cells (CICs) in various organs. It is proposed that the CICs for lung adenocarcinoma are putative bronchiolar alveolar stem cell (BASC) that is known as adult tissue stem cells for peripheral portion of the mice lung in KrasLSL-G12D mice. However, little is known about the CICs for lung SCC. The aim of the present study is to identify the involvement of BASC in the early stage of development of SCC using a N-nitroso-tris-chloroethylurea (NTCU)-induced mouse lung SCC model. Methods: Forty female A/J mice were treated topically with NTCU in acetone twice a week for 4 weeks and 16 control mice were treated topically with acetone. All mice were sacrificed 8 weeks after the start of the experiment. Lung tissues were used for histopathological analysis, flow cytometry, microarray analysis and proteome analysis. Results: Histopathologically, numbers of BASC (SPCpos CC10pos cell) were significantly increased in the terminal bronchiole of NTCU-treated group compared with control group. Ki-67pos and p63pos BASCs were only identified in NTCU-treated group. We sorted Sca-1pos BASC from lungs of NTCU-treated mice and control mice by flow cytomtry. We found that cancer stem cell markers CD133, CD44, c-kit, c-myc and klf4 were overexpressed in the BASCs of NTCU-treated mice compared the control mice. Furthermore, microarray analysis revealed that p38/ERK/MAPK pathway was activated in the BASCs of NTCU-treated mice. Moreover, we identified 11 proteins overexpressed in NTCU-treated BASC by proteome analysis, including the Rev1 that is known as a TLS polymerase. Conclusions: The present study suggested that expansion of BASC induced by NTCU treatment might be involved in the development of NTCU-induced SCC at early stage of carcinogenesis and BASC with multiple genetic alterations might be the origin of lung SCC. Disclosure: All authors have declared no conflicts of interest.