RESUMO
BACKGROUND: Complete tumor removal by transsphenoidal surgery is usually difficult for large nonfunctioning pituitary adenomas (NFPAs). A validated medical treatment may be useful for their management. This study evaluates the clinical efficacy of the dopaminergic agonist cabergoline for residual NFPA. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized, parallel, open-label clinical trial that compared cabergoline with nonintervention in patients with residual NFPA after transsphenoidal surgery over 2 years. The primary outcome was clinical efficacy (tumor reduction). The secondary outcome was the relationship between tumor dopamine D2 receptor (D2R) expression and clinical responsiveness. Tumor measurements and clinical evaluations were performed every 6 months. RESULTS: In total, 59 and 57 individuals were randomly assigned to the study and control groups, respectively. At the end of the study, residual tumor shrinkage, stabilization, and enlargement were observed in 28.8%, 66.1%, and 5.1% of patients, respectively, in the medical-therapy group and in 10.5%, 73.7%, and 15.8% of patients, respectively, in the control group (P=0.01). The progression-free survival rate was 23.2 and 20.8 months for the study and control groups, respectively (P=0.01). D2R was not associated with cabergoline responsiveness. No major side effects were related to cabergoline use. CONCLUSIONS: Cabergoline was an effective drug for treating residual NFPA, and its use was associated with a high rate of tumor shrinkage (ClinicalTrials.gov NCT03271918).
Assuntos
Adenoma/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Cabergolina/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Adenoma/metabolismo , Adenoma/patologia , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/metabolismo , Neoplasia Residual/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prognóstico , Receptores de Dopamina D2/metabolismo , Taxa de SobrevidaRESUMO
OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n=10), somatotrophinomas (n=8), and nonfunctioning adenomas (n=6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r=0.49, p=0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.
Assuntos
Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas com Domínio T/metabolismo , Fator de Transcrição Pit-1/metabolismo , Adenoma Hipofisário Secretor de ACT/genética , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/genética , Adenoma/patologia , Adolescente , Adulto , Idoso , Diferenciação Celular , Feminino , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Hipófise/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas com Domínio T/genética , Fator de Transcrição Pit-1/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .
Assuntos
Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas com Domínio T/metabolismo , Fator de Transcrição Pit-1/metabolismo , Adenoma Hipofisário Secretor de ACT/genética , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/genética , Adenoma/patologia , Diferenciação Celular , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Proteínas de Neoplasias/genética , Hipófise , Reação em Cadeia da Polimerase em Tempo Real , RNA Mensageiro/metabolismo , Proteínas com Domínio T/genética , Fator de Transcrição Pit-1/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Pituitary tumors can be morphologically classified as microadenomas (diameter<1 cm) or macroadenomas (>1 cm), which can be enclosed, invasive and/or expansive. Functionally, they are classified as secreting tumors and clinically non-secreting or 'non-functioning' tumors. Several molecular mechanisms have been studied acting in uncontrolled cell proliferation and the acquisition of resistance to apoptosis. A potential mechanism related to apoptosis control has been found following the isolation and characterization of the ASPP proteins family. All these proteins share sequence similarities in their C-termini, which contains their signature sequences of Ankyrin repeats, SH3 domain and proline-rich region. Recent investigations reported that the expression of iASPP mRNA and protein was increased in non-transformed cells induced to undergo apoptosis and inhibition of iASPP expression in these cells by siRNA reduced apoptosis. Thus, modulation of iASPP expression seems to be an integral part of the apoptotic response. The ASPP proteins family binds to proteins that are key players in controlling apoptosis (P53 and NFkappaB p65 subunit). It has been speculated that the iASPP protein product induces apoptosis by blocking NFkappaB or inhibits apoptosis by blocking P53. By either mechanism, the gene could influence the survival of precancerous lesions.
