Genesis of pituitary adenomas: state of the art

In recent years, remarkable progress has been made in the understanding of the pathogenesis of pituitary tumors. Pituitary tumors originate from the u ncontrolled proliferation of a single transformed cell in which an initiati ng event has caused a gain of proliferative function. After the initiation, promoting factors cooperate in the clonal expansion. Common oncogenes, suc h as ras, are only exceptionally involved. The only activating mutations id entified so far are gsp mutations causing the constitutive activation of cA MP pathway. However, gsp-positive adenomas are not associated to a more agg ressive tumoral phenotype. The oncogenic potential of gsp mutations is limi ted by a more rapid degradation of the mutant Gs alpha with respect to the wild-type protein, and by a faster removal of cAMP due to increased phospho diesterase activity. Estrogen-inducible gene sequences with transforming pr operties (pituitary tumor-transforming gene (PTTG)) have been identified in human pituitary tumors. Human pituitary tumor-transforming gene (hPTTG) is involved both in early pituitary tumorigenesis, as it causes in vitro and in vivo transformation acting as a transcription activator, and in tumor pr ogression, as it regulates the production of basic fibroblast growth factor (bFGF), a potent activator of angiogenesis and mitogenesis. Moreover, a ro le of cyclin D1 in pituitary tumorigenesis is emerging. The allelic loss of loci for unknown oncosuppressor genes are currently under investigation, w hile an exceedingly limited role for menin gene and RB1 has been demonstrat ed for sporadic pituitary tumors. Abnormal methylation that predisposing to ward genetic instability may favor the allelic loss or the reduced expressi on of oncosuppressor genes, is also an emerging field of investigation. Sev eral promoting factors, including the excessive action of physiological sti mulators, the defective action of inhibitors, the susceptibility to respond to inappropriate stimuli and the locally produced growth factors, help in tumor progression. The study of homeobox genes that intervene in pituitary cell differentiation may help in expanding our knowledge in pituitary tumor cell genealogy.