Search

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences, and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases, the presence of germline mutations in specific genes predisposes to PitNET formation, as part of syndromic diseases or familial isolated pituitary adenomas, and associates to more aggressive, invasive, and drug-resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the α subunit of the stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNET drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNET clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNET clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

Pituitary tumors, that origin from excessive proliferation of a specific subtype of pituitary cell, are mostly benign tumors, but may cause significant morbidity in affected patients, including visual and neurologic manifestations from mass-effect, or endocrine syndromes caused by hormone hypersecretion. Dopamine (DA) receptor DRD2 and somatostatin (SS) receptors (SSTRs) represent the main targets of pharmacological treatment of pituitary tumors since they mediate inhibitory effects on both hormone secretion and cell proliferation, and their expression is retained by most of these tumors. Although long acting DA and SS analogs are currently used in the treatment of prolactin (PRL)- and growth hormone (GH)-secreting pituitary tumors, respectively, clinical practice indicates a great variability in the frequency and entity of favourable responses. The molecular basis of the pharmacological resistance are still poorly understood, and several potential molecular mechanisms have been proposed, including defective expression or genetic alterations of DRD2 and SSTRs, or an impaired signal transduction. Recently, a role for cytoskeleton protein filamin A (FLNA) in DRD2 and SSTRs receptors expression and signalling in PRL- and GH- secreting tumors, respectively, has been demonstrated, first revealing a link between FLNA expression and responsiveness of pituitary tumors to pharmacological therapy. This review provides an overview of the known molecular events involved in SS and DA resistance, focusing on the role played by FLNA.