New methods for investigating experimental human adrenal tumorigenesis.

Adenomas and nodules of the human adrenal cortex are common, whereas adrenocortical carcinomas are rare. Genes such as IGF2 have been suggested to be important in human adrenocortical tumorigenesis but their role has not been directly investigated. We describe here elements of a system in which hypotheses concerning the molecular basis for the formation of benign and malignant adrenocortical lesions can be experimentally tested. Various viral vectors have been employed in the study of adrenocortical cell biology. Because of the low proliferative rate of primary human adrenocortical (pHAC) cells, a lentiviral system is ideal for transducing these cells with genes that may alter their characteristics or cause them to acquire benign or malignant tumorigenicity. Cultures of pHAC cells were highly infectible with lentiviruses and showed a higher proliferative potential when transduced with a lentivirus encoding IGF2. For tumorigenesis studies of genetically modified adrenocortical cells, we use RAG2(-/-), gammac(-/-) mice. Using this immunodeficient mouse model, we established an orthotopic intra-adrenal cell transplantation technique for adrenocortical cells that should be of value for future studies of the experimental conversion of human adrenocortical cells to a benign or malignant tumorigenic state.