Establishment and characterization of a human adrenocortical carcinoma xenograft model

Adrenocortical carcinomas are rare malignant tumors. They have a poor progn osis, as they are often diagnosed late and are usually resistant to chemoth erapy. The lack of a suitable animal model for these tumors has been a majo r obstacle to the evaluation of new therapeutic agents. The aim of this stu dy was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for f uture therapeutic trials. This cell line was sc injected (6 x 10(6) cells) into nude mice (n = 20). Solid tumors were locally measurable after 45 days at 90% of the inoculation sites. The xenografts were similar histologicall y to the original adrenocortical carcinoma from which the cell line was der ived. The xenografts precisely reproduced the dysregulation of the insulin- like growth factor (IGF) system [overexpression of the IGF-II and IGF-bindi ng protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarl y to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregn enolone, 17-hydroxyprogesterone, dehydroepiandrosterone, Delta(4)-androsten edione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts pro duced all three class of steroids, with the preferential production of andr ogens of the Delta(4) pathway. The H295R xenograft model is a good model of human adrenocortical carcinoma , as it mimics dysregulation of the IGF system usually found in these tumor s. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.