Longitudinal microcomputed tomography-derived biomarkers for lung metastasis detection in a syngeneic mouse model: added value to bioluminescence imaging

Abstract

With more patients dying from metastasis than from primary cancers, metastasis is a very important area in cancer research. Investigators thereby heavily rely on animal models of metastasis to common organs such as the lung to improve our insight into the pathogenesis and to research novel therapeutic approaches to combat metastasis. In this experimental context, novel tools that allow longitudinal monitoring of lung metastasis in individual animals are highly needed. We have therefore evaluated for the first time microcomputed tomography (μCT) as a very efficient and crossvalidated means to noninvasively and repeatedly monitor metastasis to the lung in individual, free-breathing syngeneic mice. Two individual clones of KLN205 cancer cells were intravenously injected in syngeneic DBA/2 mice and lung metastasis was monitored weekly during 3 weeks using μCT, and was compared with the current gold standard histology and bioluminescence imaging (BLI). μCT enabled us to visualize diffuse tumor morphology and also to extract four different biomarkers that quantify not only tumor load but also aerated space in the lung as a marker of vital lung capacity and potential compensatory mechanisms. Complementary to BLI, applying this novel μCT-based approach enabled us to unravel sensitively and efficiently differences in metastatic potential between two cellular clones. In conclusion, μCT and BLI offer biomarkers that describe different and complementary aspects of lung metastasis, underlining the importance of multimodality follow-up. The added value of μCT findings is important to better assess lung metastasis and host/lung response in preclinical studies, which will be valuable for translational applications.

Longitudinal micro-computed tomography-derived biomarkers quantify non-resolving lung fibrosis in a silicosis mouse model

“…2e). We interpret the enlargement of total lung volume, observed in this and other mouse models of lung diseases, as a compensation www.nature.com/scientificreports/ mechanism for the otherwise excessive loss of airspaces 11,21,44,45 . This phenomenon is absent in human patients, but in mouse models this enlargement of the lungs affects the interpretation of µCT-and lung function-derived readouts.…”

“…µCT has already proven to have important benefits for longitudinal evaluation of disease in preclinical animal models 8,9,[11][12][13][14] . Due to its high air-tissue contrast, it is a particularly excellent technique to study and quantify lung disease burden such as pulmonary fibrosis 8,[14][15][16][17] , whereby its added non-invasive value to standard endpoint readouts such as histology and hydroxyproline assays has been established.…”

Mouse models of metastasis: progress and prospects

“…This technology is thus likely to enhance the usability of GEMMs and PDXs. Recent advances in preclinical magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are showing promise ( Fleten et al, 2017 ; Marien et al, 2017 ; Sanches et al, 2015 ; Taromi et al, 2016 ).…”

Applications of Ruthenium Complex in Tumor Diagnosis and Therapy

“…In in vivo studies of mouse MCa mammary carcinoma, this combination increased inhibition of tumor metastasis by 70%, compared to the use of doxorubicin alone. In a lung metastasis preclinical tumor model in mice, both agents demonstrated promising synergistic effects ( Marien et al, 2017 ). However, there were noticeable side effects when the maximum doses were used.…”