Quantification of mouse pulmonary cancer models by microcomputed tomography imaging

Abstract

The advances in preclinical cancer models, including orthotopic implantation models or genetically engineered mouse models of cancer, enable pursuing the molecular mechanism of cancer disease that might mimic genetic and biological processes in humans. Lung cancer is the major cause of cancer deaths; therefore, the treatment and prevention of lung cancer are expected to be improved by a better understanding of the complex mechanism of disease. In this study, we have examined the quantification of two distinct mouse lung cancer models by utilizing imaging modalities for monitoring tumor progression and drug efficacy evaluation. The utility of microcomputed tomography (micro-CT) for real-time/non-invasive monitoring of lung cancer progression has been confirmed by combining bioluminescent imaging and histopathological analyses. (1) therefore, the treatment and prevention of lung cancer are major unmet needs that could be improved by a better understanding of the molecular process and progression of the disease. Advances in preclinical cancer models including orthotopic implantation models or genetically engineered mouse models (GEMMs) of cancer enable investigation of the molecular mechanism of cancer disease that might better mimic genetic and biological processes in humans than the conventional subcutaneous transplant model. (2,3) It has been recently appreciated that the tumor microenvironment plays an important role for cancer cell survival, progression, and acquiring malignant metastatic ability.(2,3) Orthotopic tumor implantation models have been considered to reflect the tumor microenvironment; therefore, tumor cells often resemble clinical cancer disease processes.(4) Amongst various cancer GEMMs that have developed to resemble human cancer disease, transgenic expression of an oncogenic mutant K-ras G12D gene in mouse lung tissues has been known to result in the development of lung adenocarcinoma, (5) and further additional expression of p53 R270H dominant-negative mutant gene using the Cre-lox recombinase has been shown to promote K-ras G12D -initiated lung cancer development.(6) Despite these advances in preclinical cancer model development, their application to the drug discovery process has often been challenging because of the difficulties in assessing quantitative information for efficacy evaluations of new drug candidates. (2,3,7,8) Imaging technology has been playing a larger role for in vivo real-time/non-invasive monitoring of disease progression as well as evaluation of the efficacy of therapeutic approaches in preclinical animal models.(9) Bioluminescence imaging (BLI) takes advantage of the detection of photons emitted by luciferaseexpressing cells in the living animal and has been used for quantitative monitoring of tumor growth or disseminated matastatic disease in deeper tissue with high sensitivity.(10-14) Amongst clinical imaging modalities, X-ray computed tomography (CT) has been demonstrated as a quantitative tool for detecting lung cancer in clinical settings and also in preclinical an...

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