Impact of <i>gsp</i> Oncogene on the mRNA Content for Somatostatin and Dopamine Receptors in Human Somatotropinomas

Abstract

Introduction: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine’s actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. Objectives: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. Methods: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. Results: The response to LAR did not significantly differ between patients with gsp+ and gsp– tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. Conclusion: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.

Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors

“…Toboada et al reported that elevated tumor expression of SSTR1, SSTR2, and dopamine receptor 2 may help improve responsiveness to SSA in somatotropinomas. 45 In other study of 21 advanced well-differentiated pancreatic neuroendocrine carcinoma treated with SSA, there was no significant association between expression of SSTR2 or SSTR5, and patient survival. 46 …”

Truncated somatostatin receptor variant sst5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas

“…None of the patients belongs to pituitary adenoma kindred. In acromegalic patients, only 3 patients were treated with octreotide-LAR before surgery, and prevalence of GNAS oncogene was 10% [15]. In line with this last point, we have previously reviewed [16] that the prevalence of the GNAS oncogene in somatotropinomas is approximately 40%; however it has been shown that this prevalence dramatically varies between studies (ranging from 4.4 to 55%) considering previous series from several countries.…”

“…For in vivo studies, we used a set of 74 pituitary samples (66 pituitary adenomas and 8 normal pituitaries; Tables 1–3), in which demographic/clinical data of patients, profile of sst1-5, and presence of GNAS oncogene in somatotropinomas were previously characterized [13,15]. Briefly, somatotropinoma (n = 36; median age: 38 years old; Table 1) and NFPA (n = 30; median age: 51 years old; Table 2) samples were obtained during transsphenoidal surgery of pituitary adenoma (PA) tumors.…”

AIP and the somatostatin system in pituitary tumours

“…The implication of gsp mutation in SSA response has been widely discussed (Larkin et al 2013); nevertheless, a recent meta-analysis revealed that GNAS-positive patients have an approximately 10% greater reduction in GH levels in response to an acute octreotide suppression test (Efstathiadou et al 2015). Additionally, GNAS positive patients show high levels of SSTR2 mRNA (Taboada et al 2011) and low levels of sst5TMD4 .…”