Abstract
BackgroundThe aim of the study was to develop a nude mouse xenograft model implanted with both benign and malignant xenografts as the preliminary candidate screening tool for contrast agent development in lesion malignancy indication.ResultsA malignant xenograft (either MCF-7 cell/matrigel™ or MDA-MB 231 cell/matrigel) and a benign xenograft (culture medium/matrigel) with cleft and slit-like features of intracanaliculer fibroadenoma were implanted subcutaneously into flanks of individual nu/nu nude mouse with >90 % successful inoculation rate. Both malignant and benign xenografts with volume up to 4 cm3 and (size up to 2 cm) after 5th week were characterized in vivo by sonogram (exhibiting endogenous morphological contrast features between benign and malignant xenografts), dynamic contrast enhanced multi-detector computed tomography (presenting non-targeting exogenous morphological and dynamic contrast features between benign and malignant xenografts), and then were harvested for histological and immunohistochemistry (revealing example of targeting/molecular contrast features, such as expression of cancer vascular markers of malignant xenografts). Malignant xenografts appeared morphologically taller than wide (axis parallel to skin) with angular/ill-defined margin under sonogram observations, revealed more evident rim enhancement, angular margin and washout pattern in the time-density curve from dynamic contrast enhance multi-detector computed tomography images, and had more visible cancer vascular markers (CD31 and VEGF) expression. With limited number of subjects (5–27 for each group of a specific imaging contrast feature), those imaging contrast features of the xenograft model had larger than 85 % sensitivity, specificity, accuracy, positive and negative prediction values in indicating xenograft malignancy except for results from color Doppler detections.ConclusionsThe murine xenograft model might provide an earlier efficacy evaluation of new contrast agent candidate for lesion malignancy interrogation with qualitative and quantitative indication before a human study to reduce the risk and conserve the resources (time, finance and manpower).
Highlights
The aim of the study was to develop a nude mouse xenograft model implanted with both benign and malignant xenografts as the preliminary candidate screening tool for contrast agent development in lesion malignancy indication
In the study, 100 % (17/17) of the MDA-MD 231 xenografts, 90.9 % (20/22) of the MCF-7 xenografts and 92.3 % (36/39) of the benign xenografts successfully developed in vivo for image acquisitions and were harvested for histology/IHC analysis
No evident metastasis related to the xenograft inoculations was observed with only one subject showing signs of a spleen anomaly at 26 weeks after receiving both benign and malignant implants
Summary
The aim of the study was to develop a nude mouse xenograft model implanted with both benign and malignant xenografts as the preliminary candidate screening tool for contrast agent development in lesion malignancy indication. The therapeutic value of a leading drug candidate can usually be identified through in vitro studies; the feasibility of new contrast agents in specific clinical applications always requires an in vivo model to provide adequate target quantities for verification [13]. To develop an agent for breast lesion malignancy screening, the identification is more challenging; the specificity generally cannot be accessed without human subject studies, because the present animal models do not sufficiently represent key features of clinically benign lesions for screening with contrast agents [15, 16]. The carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) was found to induce both benign and malignant mammary lesions in rats [17] This DMBA-induced animal model is extensively applied to investigate the mechanism of cancer or the efficiency of preventative agents [18, 19]. The main pitfall of this model is the low transgenic success rate (7–14 %) even with the continued use of the pig follicle stimulating hormone to assist transgene integration into the rat gene sequence [22]
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