Metastatic spread is the leading cause of death from cancer. Early detection of cancer at primary and metastatic sites by noninvasive imaging modalities would be beneficial for both therapeutic intervention and disease management. Noninvasive imaging modalities such as bioluminescence (optical), positron emission tomography (PET)/X-ray computed tomography (CT), and magnetic resonance imaging (MRI) can provide complementary information and accurately measure tumor growth as confirmed by histopathology. Methods. We validated two metastatic tumor models, MDA-MD-231-Luc and B16-F10-Luc intravenously injected, and 4T1-Luc cells orthotopically implanted into the mammary fat pad. Longitudinal whole body bioluminescence imaging (BLI) evaluated metastasis, and tumor burden of the melanoma cell line (B16-F10-Luc) was correlated with (PET)/CT and MRI. In addition, ex vivo imaging evaluated metastasis in relevant organs and histopathological analysis was used to confirm imaging. Results. BLI revealed successful colonization of cancer cells in both metastatic tumor models over a 4-week period. Furthermore, lung metastasis of B16-F10-Luc cells imaged by PET/CT at week four showed a strong correlation ( ) with histopathology. The presence and degree of metastasis as determined by imaging correlated ( ) well with histopathology findings. Conclusions. We validated two metastatic tumor models by longitudinal noninvasive imaging with good histopathology correlation. 1. Introduction Metastasis of cancer cells from primary tumors is one of the leading causes of poor prognosis and death from the disease. Metastatic spread is the root of approximately 90% of cancer-related deaths [1]. Early detection of cancer cell metastasis would be incredibly beneficial for timely therapeutic intervention and management of the disease. In most preclinical animal studies, gross examination and histopathological analysis are commonly used to evaluate dissemination of cancer cells to secondary sites. These techniques are limited, however, as they cannot be used to adequately monitor tumor development. Furthermore, optical microscopy may have an inadequate field of view (3D morphometric) for thorough tumor evaluation. Noninvasive imaging provides the ability to perform real-time serial imaging to enhance the observation of disease progression and/or evaluate therapeutic treatment response. In addition, noninvasive imaging allows researchers to use fewer animals with greater statistical power. Orthotopic and metastatic tumor models provide an appropriate tumor microenvironment (seed and soil
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