Original articleMultimodal imaging for the detection and characterization of liver lesions in a mouse model of neuroendocrine tumorImagerie multimodale pour la détection et la caractérisation de lésions hépatiques dans un modèle de tumeur neuroendocrine chez la souris
Introduction
Neuroendocrine tumors are rare [1], with autopsy series reporting a prevalence of 1/1000 for pancreatic tumors and intestinal carcinoid tumors [2], but they are also a serious therapeutic challenge in terms of controlling secretion and reducing tumor volume. Except for curative surgery, a straightforward method for localized tumors [3], the various possible treatments are complex, requiring highly specialized management. As underlined by several authors [4], [5], [6], [7], prolonged patient survival will require the development of new compounds, specifically designed for each type of tumor. Certain simple histoprognostic factors, such as tumor size, proliferation index or signs of local invasion, allow a statistically significant, but often unsatisfactory, prediction of malignancy risk. The only relevant criterion of malignancy is the presence of metastatic dissemination, generally to the lymph nodes or liver. Hepatic metastases arising from an endocrine tumor are relatively common and have a considerable effect on therapeutic and surveillance strategies. Despite the clinical importance of this problem, little is known of the natural history of hepatic metastases from gastrointestinal neuroendocrine tumors and of the factors that determine tumor growth and progression.
Clinical studies have generally used morphological and molecular imaging to better understand the diversity and evolution of these tumors [8], [9], [10], [11], [12], [13], [14]. For detecting metastases, particularly from endocrine tumors, the best sensitivity is probably provided by thin-slice T2-weighted fat-saturation magnetic resonance imaging (MRI) [15]. Experimental work with small animals has enabled the development of oncological models closely mimicking human pathology that can be helpful in better targeting new compounds or therapeutic indications. Starting with an experimental model of hepatic dissemination of human enteropancreatic endocrine tumors developed in the nude mouse [1], the purpose of the present work was to develop and validate variously adapted imaging protocols. More precisely, the goal was to identify the characteristic T2-weighed MRI and nuclear-isotope-labeled imaging features of this model of neuroendocrine tumors by evaluating the appropriateness and complementary efficacy of these two imaging techniques.
Section snippets
Animal model
The animal model was based on a murine cell line, STC-1, derived from an intestinal endocrine tumor, developed in a double-transgenic mouse and expressing the rat insulin promoter-linked to the SV40-T antigen and the polyomavirus T antigen. This cell line in animals in vivo can induce tumors presenting morphological and functional properties similar to those observed in human gastrointestinal endocrine carcinomas. Tumors derived from STC-1 cells contain cells with an endocrine morphology that
In vivo MRI
Hepatic lesions were detected starting from day 12. The lesions were always seen as a high-intensity signal on the T2 images. The smallest detectable lesions, measuring about 100 μm, could only be detected when in clusters. The largest lesions, which appeared as well-delineated nodules, were noted from day 23 to day 29 and measured up to 5 mm (Fig. 1(a–d)).
The hepatic tumor fraction increased linearly with time [coefficient of correlation r2 = 0.89 from day 12 (0.9%) to day 29 (48%)] (Fig. 2), but
Discussion
Neuroendocrine tumors are slow-growing tumors, often discovered after the development of hepatic metastasis, with clinical manifestations generally related to tumor secretion [17], [18]. The primary tumor, often composed of amine precursor uptake and decarboxylation (APUD) cells that dominate the clinical expression, generally arises in the pancreas. The rate of malignancy varies from 10 to 100%, depending on the type of secretion. Proposed therapeutic strategies are highly complex and of
Conclusion
This multimodal imaging study using the nude mouse model of hepatic metastatic dissemination of neuroendocrine tumors provides encouraging results that reinforce the idea that imaging can play an important role in explorative strategies in projects involving small animals. It demonstrated that hepatic lesions from neuroendocrine tumors can be explored in the nude mouse for both the detection and surveillance required for the evaluation of new therapeutic modalities.
Acknowledgement
This research was funded by the CNRS-CEA's ‘imaging of small animals’ program. The Animage platform was used for acquisitions. FDG was furnished by Cermep.
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