Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas

Basic fibroblast growth factor (bFGF) is a potent mitogenic and angiogenic factor that is known to regulate GH, PRL, and TSH secretion. Sequences within a bFGF gene family member have been detected in transforming DNA samples derived from human PRL-secreting tumors. Furthermore, elevated serum concentrations of bFGF have been noted in patients with multiple endocrine neoplasia-1. To further examine the significance of bFGF in sporadic human pituitary adenomas, we investigated the expression of bFGF by these tumors. Using an enzyme-linked immunoassay that recognizes all 16-24 kilodalton molecular mass forms of bFGF, we measured circulating serum concentrations in 21 patients with sporadic pituitary adenomas; they ranged from less than 0.5-84 pg/mL and declined following surgical adenomectomy. To confirm the pituitary source of this growth factor, we determined in vitro bFGF release from 43 adenomas (10 GH, 7 PRL, 10 ACTH, 14 gonadotrope adenomas/oncocytomas, and 2 silent subtype 3 adenomas). bFGF was present with wide variability (0.75-2100 pg/24 h.10(5) cells) in conditioned culture media of all adenomas examined. The adenohypophysial source of this growth factor was further demonstrated by the reverse hemolytic plaque assay. Variable bFGF messenger RNA expression was identified by the reverse-transcription polymerase chain reaction technique in 9 functional (2 PRL, 5 GH, 2 ACTH) and 7 nonfunctional (1 oncocytoma, 2 null cell, 2 gonadotrope, 2 Silent Subtype 3) adenomas examined. bFGF levels were unaltered in vitro following hypothalamic hormone stimulation/inhibition. The lack of a bFGF signal peptide sequence and hypothalamic hormone-independence suggest that secretion of this factor may be independent of pituitary hormone regulation. Immunocytochemistry failed to localize bFGF in tumors that released this factor in vitro, suggesting that storage of this peptide does not correlate with its synthesis and release. In conclusion, the heterogenous expression of bFGF suggests that it may play a specific and selective role in the tumorigenic process of some pituitary adenomas.