Establishment and characterization of a human adrenocortical carcinoma xenograft model.
Adrenocortical carcinomas are rare malignant tumors. They have a poor prognosis, as they are often diagnosed late and are usually resistant to chemotherapy. The lack of a suitable animal model for these tumors has been a major obstacle to the evaluation of new therapeutic agents. The aim of this study was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for future 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 histologically to the original adrenocortical carcinoma from which the cell line was derived. The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system [overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarly to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, delta4-androstenedione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts produced all three class of steroids, with the preferential production of androgens of the delta4 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 tumors. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.
Logié
A
A
Laboratoire d'Explorations Fonctionnelles Endocriniennes, INSERM U-515, Hôpital d'Enfants Armand Trousseau, Paris, France.
Boudou
P
P
Boccon-Gibod
L
L
Baudin
E
E
Vassal
G
G
Schlumberger
M
M
Le Bouc
Y
Y
Gicquel
C
C
D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013002:Somatomedins / Q000096:biosynthesis; D013256:Steroids / Q000096:biosynthesis / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018971:Insulin-Like Growth Factor Binding Protein 2; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D013002:Somatomedins; D013256:Steroids