A Chemically Induced Model for Squamous Cell Carcinoma of the Lung in Mice

Abstract

Lung cancer, primarily associated with tobacco use, is the leading cause of cancer morbidity and mortality in the United States. Squamous cell carcinoma (SCC) is one of the four major histological types of lung cancer. Although there are several established models for lung adenoma and adenocarcinomas, there is no well-established mouse model for lung SCC. We treated eight different inbred strains of mice with N-nitroso-trischloroethylurea by skin painting and found that this regimen induced lung SCCs in five strains of mouse (SWR/J, NIH Swiss, A/J, BALB/cJ, and FVB/J) but not in the others (AKR/J, 129/svJ, and C57BL/6J). Mouse lung SCCs have similar histopathological features and keratin staining to human SCC. Moreover, a wide spectrum of abnormal lung squamous phenotypes including hyperplasia, metaplasia, carcinoma in situ, and invasive carcinoma, were observed. There are strain-specific differences in susceptibility to Lscc induction by N-nitroso-tris-chloroethylurea with NIH Swiss, A/J, and SWR/J mice developing scores of SCCs whereas the resistant strains AKR/J, 129/svJ, and C57BL/6J failed to develop any SCCs. FVB/J and BALB/cJ mice had an intermediate response. We conducted whole-genome linkage disequilibrium analysis in seven strains of mice, divided into three phenotype categories of susceptibility, using Fisher's exact test applied to 6,128 markers in publically available databases. Three markers were found significantly associated with susceptibility to SCC with the P < 0.05. They were D1Mit169, D3Mit178, and D18Mit91. Interestingly, none of these sites overlap with the major susceptibility loci associated with lung adenoma/adenocarcinoma development in mice. The mouse SCC described here is highly significant for preclinical studies of lung cancer chemopreventive agents because most human trials have been conducted against precancerous lesions for SCC. Furthermore, this model can be used in determining genetic modifiers that contribute to susceptibility or resistance to lung SCC development.

Chemopreventive Effects of Pioglitazone on Chemically Induced Lung Carcinogenesis in Mice

“…Previously, we reported the successful induction of mouse lung SCCs using the organ specific carcinogen NTCU in different strains of mice, including A/J and NIH Swiss (12). The histopathology of the mouse lung SCC is similar to that seen in humans with well-defined pathologic development from normal to bronchiolar hyperplasia, metaplasia, SCC in situ, and SCC (12).…”

“…The lesions, including invasive SCC, SCC in situ, and the bronchial hyperplasia/ metaplasia, were scored. The criteria for histopathologic examination and scoring were described previously (12).…”

“…Transgenic mice carrying a missense p53 mutation (Ala-135-Val) develops a high incidence of lung adenocarcinomas (11), lung squamous cell carcinomas (SCC; ref. 12), head and neck SCC (13), and osteosarcomas and lymphomas (14) when compared with wild-type mice. We have systematically characterized this model for use in chemoprevention studies of lung adenocarcinoma and lung SCC (11,13,(15)(16)(17)(18)(19)(20).…”

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

“…In the laboratory mice, SCCs do not occur spontaneously. To induce SCC, Wang et al (Wang et al, 2004) treated eight inbred mouse strains with a chemical carcinogen by skin painting and found SCC in five mouse strains. Interestingly, in this model of chemical carcinogenesis the C57BL/6J mice failed to develop any SCC.…”

N-Nitroso-tris-chloroethylurea Induces Pre-malignant Squamous Dysplasia in Mice

“…The FVB/N murine strain selection was based on previous reports of susceptibility to NTCU (9). Strains such as FVB and Balb/C classically exhibit an intermediate degree of sensitivity to lung carcinogens (14)(15)(16), and display many similarities to human AC (17)(18)(19).…”