Abstract
Metastasis is the most common cause of death for patients with cancer. To fully understand the steps involved in metastatic dissemination, in vivo models are required, of which murine ones are the most common. Therefore, preclinical imaging methods such as magnetic resonance imaging (MRI) have mainly been developed for small mammals and their potential to monitor cancer growth and metastasis in nonmammalian models is not fully harnessed. We have here used MRI to measure primary neuroblastoma tumor size and metastasis in a chick embryo model. We compared its sensitivity and accuracy to end-point fluorescence detection upon dissection. Human neuroblastoma cells labeled with green fluorescent protein (GFP) and micron-sized iron particles were implanted on the extraembryonic chorioallantoic membrane of the chick at E7. T2 RARE, T2-weighted fast low angle shot (FLASH) as well as time-of-flight MR angiography imaging were applied at E14. Micron-sized iron particle labeling of neuroblastoma cells allowed in ovo observation of the primary tumor and tumor volume measurement noninvasively. Moreover, T2 weighted and FLASH imaging permitted the detection of small metastatic deposits in the chick embryo, thereby reinforcing the potential of this convenient, 3R compliant, in vivo model for cancer research.
Highlights
Metastasis accounts for 90% of cancer deaths,[1] yet it is one of the most poorly understood aspects of tumor progression
The labeling of cancer cells with MPIOs did not alter tumor formation on the chorioallantoic membrane (CAM). While it did not offer significant advantages for primary tumor detection compared to unlabeled cells, it was necessary for small metastasis detection in the chick embryo organs
This suggests that cancer lesions of about 2 mm are detectable in the chick embryo, a size that is smaller than the magnetic resonance imaging (MRI) detection limit of metastasis reported being 10 to 20 mm in rodents.[27]
Summary
Metastasis accounts for 90% of cancer deaths,[1] yet it is one of the most poorly understood aspects of tumor progression. Small size, heterogeneity, and large dispersal of disseminated cancer cells, combined with the limited sensitivity and spatial resolution of current clinical imaging methods, make their early and reliable detection challenging. Metastatic dissemination is a complex process involving several steps from the initial detachment of cells from the primary tumor, diffusion within the surrounding stromal tissue, degradation of the extracellular matrix, and intravasation into the blood stream. Once in the circulatory system, tumor cells have to survive the hostile environment, and attach to the endothelial cells of the vessel wall, extravasate in the extravascular tissue, and proliferate in the metastatic site to form secondary tumors.[2] many of these steps have been studied at a molecular level in vitro, visualization of the dynamic events in vivo remain elusive
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