Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas
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Published on: August 25, 2021
Raúl M Luque1, Alejandro Ibáñez-Costa1, Leonardo Vieira Neto2
1Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and Hospital Universitario Reina Sofia.; CIBER Fisiopatología de la Obesidad y Nutrición; Campus de Excelencia Internacional Agroalimentario (ceiA3), 14014, Córdoba, Spain.
Abstract:
The GH/IGF1 response of somatotropinomas to somatostatin analogues (SSA) is associated with their pattern of somatostatin receptor (sst1-sst5) expression. Recently, we demonstrated that expression of a truncated sst5-variant (sst5TMD4) can influence the secretory response of somatotropinomas to SSA-therapy; however, its potential relationship with aggressive features (e.g. invasion/proliferation) is still unknown. Here, we show that sst5TMD4 is present in 50% of non-functioning pituitary-adenomas (NFPA) (n = 30) and 89% of somatotropinomas (n = 36), its expression levels being highest in somatotropinomas > > NFPAs > > > normal pituitaries (negligible expression; n = 8). In somatotropinomas, sst5TMD4 mRNA and protein levels correlated positively, and its expression was directly associated with tumor invasiveness (cavernous/sphenoid sinus), and inversely correlated with age and GH/IGF1 reduction after 3-6 months with octreotide-LAR therapy. GNAS+ somatotropinomas expressed lower sst5TMD4 levels. ROC analysis revealed sst5TMD4 expression as the only marker, within all sst-subtypes, capable to predict tumor invasiveness in somatotropinomas. sst5TMD4 overexpression increased cell viability in cultured somatotropinoma (n = 5). Hence, presence of sst5TMD4 associates with increased aggressive features and worse prognosis in somatotropinomas, thereby providing a potentially useful tool to refine somatotropinoma diagnosis, predict outcome of clinical response to SSA-therapy and develop new therapeutic targets.
Insights
The truncated somatostatin receptor variant sst5TMD4 is linked to aggressive pituitary tumors called somatotropinomas. Its presence predicts invasiveness and poorer response to therapy, offering a new diagnostic and therapeutic target.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Somatotropinomas, pituitary tumors secreting growth hormone (GH), are often treated with somatostatin analogues (SSAs).
- The efficacy of SSAs is linked to somatostatin receptor (sst) expression patterns.
- A truncated sst5 variant, sst5TMD4, was previously shown to affect SSA treatment response, but its role in tumor aggressiveness was unknown.
Purpose of the Study:
- To investigate the expression of sst5TMD4 in somatotropinomas and non-functioning pituitary adenomas (NFPAs).
- To determine the association between sst5TMD4 expression and aggressive tumor features, including invasiveness.
- To evaluate sst5TMD4 as a potential predictor of clinical response to SSA therapy and patient prognosis.
Main Methods:
- Quantification of sst5TMD4 mRNA and protein levels in pituitary adenomas (somatotropinomas, NFPAs) and normal pituitary tissue.
- Correlation analysis of sst5TMD4 expression with tumor invasiveness (cavernous/sphenoid sinus invasion), clinical parameters, and GNAS mutation status.
- Receiver Operating Characteristic (ROC) analysis to assess sst5TMD4's predictive value for invasiveness.
- In vitro studies assessing the effect of sst5TMD4 overexpression on somatotropinoma cell viability.
Main Results:
- sst5TMD4 was highly expressed in somatotropinomas (89%) and NFPAs (50%), with significantly higher levels in somatotropinomas compared to NFPAs and normal pituitaries.
- In somatotropinomas, sst5TMD4 expression correlated positively with tumor invasiveness and negatively with age and reduction in GH/IGF1 levels after octreotide-LAR treatment.
- ROC analysis identified sst5TMD4 as the sole sst subtype marker capable of predicting tumor invasiveness in somatotropinomas; overexpression increased cell viability in vitro.
Conclusions:
- The presence and overexpression of sst5TMD4 are associated with increased aggressiveness and poorer prognosis in somatotropinomas.
- sst5TMD4 serves as a valuable marker for predicting tumor invasiveness and clinical response to SSA therapy.
- sst5TMD4 represents a potential novel therapeutic target for aggressive somatotropinomas.
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