Abnormal Transduction Mechanisms in Pituitary Adenomas

Abstract

Pituitary adenomas are differentiated tumors expressing their appropriate mature hormone. Tumoral cells sometimes present with a defective physiological inhibitory or stimulatory control, resulting in paradoxical responses or nonresponsiveness to regulatory neurohormones. These abnormalities can be explained by defects at the intracellular transduction mechanism level. Knowledge of these defective pathways has made progress in the understanding of the pathogenesis of pituitary adenomas possible. The discovery of mutations of Gsα named gsp oncogenes in 40% of human somatotropinomas represents one of the most important advances in this field. Other molecular alterations were identified but are rare and sporadic and the pathogenesis of pituitary adenomas remains largely unknown.Abnormal transduction mechanisms may also result in a variable sensitivity of tumors to pharmacological therapy. The dopamine agonist, bromocriptine, is able to normalize blood PRL levels and to reduce tumor size in the majority of patients with prolactinoma, but is ineffective in 8-15% of them. Under physiological conditions, PRL secretion is under the tonic inhibitory control of dopamine which binds D2 receptors negatively coupled to adenylyl cyclase. Several defects in the dopaminergic transduction pathways participate in this bromocriptine resistance. The mean D2-binding site density is decreased to 50% as compared to responsive tumors. This loss of D2 receptors can account for a lower transcription level of its gene and is accompanied by modifications in the messenger alternative splicing; the D2 short isoform receptor expression decreases preferentially. A reduction in Gi2α protein expression is also observed and is correlated to that of the D2 receptor. Finally, the pituitary-specific transcription factor Pit-1 expression is affected. A highly significant correlation was seen between the D2 receptor mRNA and Pit-1 mRNA levels. These defects observed on many levels of the dopaminergic transduction cascade may be the first steps in the loss of the functional features of differentiated tumors toward more proliferative tumors.

Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels

“…Our present study could not demonstrate clear correlation between the proportion of D 2 S mRNA and the responsiveness to dopamine agonists, failing to confirm the findings in previous studies (11,12). Changes in the ratio of the receptor isoforms alone are unlikely to determine the spectrum of dopamine agonist responsiveness observed among prolactinomas (34). Nonetheless, the pathophysiological significance of D 2 R isoforms in prolactinomas requires further investigation (35).…”

Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report

“…This finding can explain a previous report of Kovacs et al in which D2R mRNA was present in a rapidly growing and invasive PRL-producing tumor which failed to respond to DA medication (13). These findings indicate that in some cases of DA resistance, posttranscriptional defects can explain the failure of the medical therapy (14,15). At present, there is no report providing an explanation for the absence of D2R protein in the presence of gene expression.…”

Matrix Metalloproteinase-9 Is Differentially Expressed in Nonfunctioning Invasive and Noninvasive Pituitary Adenomas and Increases Invasion in Human Pituitary Adenoma Cell Line

“…Mutations identified in a significant proportion of pituitary tumors, particularly in growth hormone-secreting adenomas, have been discovered in the gene encoding the ␣-subunit of Gs G-protein (GNAS1), causing constitutive activation of the cAMP pathway (gsp oncogene). 3 A point mutation of protein kinase C (PKC)-␣ and a higher overall PKC activity and expression have been documented in invasive PAs. 4,5 However, other investigators have failed to detect such a change.…”