Endocrine Abstracts

Introduction

Cushing’s disease is the result of prolonged exposure to excess cortisol caused by a pituitary tumor, known as corticotropinoma, which hypersecretes adrenocorticotropin (ACTH). Treatment with somatostatin analogs (SSA) has been shown to reduce hormone secretion and, to a lower extent, tumor growth in some subtypes of pituitary tumors, such as growth hormone secreting tumors. However, SSA are commonly ineffective in corticotropinomas. Previous studies indicated that the presence of the truncated receptor variant SST₅TMD4 is associated with a lack of response to SSA in growth hormone secreting tumors. However, its presence and functional role in corticotropinomas is still poorly defined.

Aims

The aim of this study was to explore the molecular and functional role of somatostatin receptors (SSTs) in corticotropinoma cells, and in particular to assess the contribution of SST₅TMD4 to SSA response.

Methods

The expression levels of SSTs were evaluated in 28 corticotropinomas and 8 normal pituitary samples. Functional assays (free cytosolic calcium kinetics, ACTH secretion and cell viability) were assessed in response to SSA in primary corticotropinoma cultures. Moreover, cell viability was evaluated after transiently SST₅TMD4 overexpression.

Results

In general, a lower expression of the receptors SST₁/SST₂/SST₃ was observed in corticotropinomas compared to normal pituitary samples. A more detailed analysis revealed the existence of two subpopulations of corticotropinomas that differed in the presence of high (n = 7) or low levels (n = 17) of expression of SST₅TMD4. The named ’high’ population expresses all SSTs, presenting a higher expression of SST₂/SST₃/SST₅TMD4 compared to the ’low’ subpopulation, which predominantly expresses SST₅. Furthermore, SST₅TMD4 was significantly over-expressed in the ’high’ population compared to normal samples. Pilot functional studies in cell cultures derived from corticotropinomas revealed that both ’high’ and ’low’ corticotropinomas differentially respond to in vitro treatment with SSA, octreotide and pasireotide. Finally, SST₅TMD4 overexpression increased cell viability.

Conclusions

Our data indicate that there might be two discinct subpopulations of corticotropic tumors, one expressing most SSTs and another that predominantly expresses SST₅, which could confer differential responsiveness to SSA. Furthermore, the trasfection assay revealed that the presence of SST₅TMD4 seems to be associated with a higher proliferative rate in corticotropinomas. Consequently, a detailed expression profile of all the SSTs in corticotropinomas, especially SST₅ variants, could assist the prediction of response to SSA in patients with Cushing’s disease.

Funding

MICINN (PID2019–105201RB-I00, PID2019–105564RB-I00), Junta de Andalucía (BIO-0139) and CIBERobn.