POLYOMA-INDUCED NEOPLASMS OF THE MOUSE ADRENAL-MEDULLA - CHARACTERIZATION OF THE TUMORS AND ESTABLISHMENT OF CELL-LINES

BACKGROUND: Pheochromocytomas that are usually noradrenergic arise com monly in the adult rat adrenal medulla. The widely studied PC12 cell l ine, that is representative of these rat adrenal tumors, is also norad renergic. The reasons for the absence of epinephrine production by mos t rat pheochromocytoma cells are unknown, and there are currently no a drenergic adrenal medullary cell lines. Pheochromocytomas are rare in mice. EXPERIMENTAL DESIGN: Tumors induced by polyoma virus in the adre nal medullas of postnatal mice were studied immunocytochemically for c atecholamine biosynthetic enzymes in order to determine how their prof iles of catecholamine production compared with those of rat pheochromo cytomas. Clonal cell lines were established from a representative tumo r and were evaluated for responsiveness to agents known to affect the development and function of normal and neoplastic rat chromaffin cells . RESULTS: Although adrenal medullary cells from normal rodents produc e epinephrine before birth, polyoma-induced mouse adrenal tumor cells are immature or poorly differentiated. They synthesize norepinephrine, but not epinephrine, which during normal development is produced late r than norepinephrine. They also produce relatively large quantities o f dihydroxyphenylalanine, suggesting an abnormality of catecholamine b iosynthesis such that tyrosine hydroxylase is not rate-limiting. Secre tory granules are sparse, as demonstrated by electron microscopy or by staining for chromogranin A, and catecholamine stores are low. Furthe r, the tumor cells appear to be phenotypically unstable, as judged fro m heterogeneous staining for tyrosine hydroxylase even in early passag e, twice-cloned cell lines. Tumor cell morphology and catecholamine pr ofiles appear to be unaffected or minimally affected by nerve growth f actor, forskolin or dexamethasone, which are known to affect normal or neoplastic rat chromaffin cells. However, tumors formed after subcuta neous injection of cell lines into mice show up to a 10-fold increase in catecholamine stores, suggesting that the cells are subject to some forms of regulation. The cloned cell lines do not produce detectable polyoma virus, but express all three viral T antigens, including a cha racteristic, truncated form of large T. CONCLUSIONS: The findings sugg est that the process of neoplastic transformation and/or the presence of polyoma virus T antigens results in suppression of the adrenergic p henotype in mouse adrenal chromaffin cells. T antigens might therefore be useful as tools for studying mechanisms that regulate the differen tiation and maturation of chromaffin cells in normal and neoplastic st ates. Furthermore, although polyoma virus cannot be readily used to pr oduce adrenergic cell lines from the mouse adrenal medulla, the lines that are produced might substitute for PC12 cells in some types of stu dies that require a mouse model.