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

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.

The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer

“…sst5TMD4 immunohistochemical analysis sst5TMD4 analysis by immunohistochemistry (IHC) was performed by using a custom-made and previously validated polyclonal rabbit anti-human sst5TMD4 Ab (clone name: 66498; 1:400) (20) using standard procedures (15,17,20). The validity and specificity of this Ab are further supported by the results presented in Supplemental Fig.…”

“…Details of real-time quantitative PCR (qPCR) analysis are reported elsewhere (15,21). Specifically, expression levels-absolute mRNA copy number/50 ng of sample-of sst5TMD4, b-actin, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were measured by using validated primers as previously reported (15,17,20,21). For fresh samples and PCa cell lines, a normalization factor was calculated with the expression levels of ACTB and GAPDH using GeNorm 3.3 (22).…”

“…In addition, in contrast to the predominant plasma membrane localization of other ssts, sst5TMD4 demonstrates a preferential intracellular localization wherein it may disrupt the function of other ssts, mainly sst2 and sst5 (14). Of more interest, sst5TMD4 is barely expressed in normal tissues but is highly overexpressed in several tumors and cancers, including pituitary adenomas (15,16), breast cancer (17), thyroid carcinoma (18,19), and NETs (20), where it correlates with aggressive clinical parameters and promotes cell proliferation, migration, invasion, and hormone secretion (15,17,19,20). Indeed, sst5TMD4 expression is negatively correlated with the ability of SSAs to reduce growth hormone secretion in pituitary adenomas (16) and inhibits the ability of sst2-transfected cells to respond to SST and/or SSAs (17).…”

E‐cadherin expression is associated with somatostatin analogue response in acromegaly

“…In (B,C) data points represent values for each individual patient. 26,31 Hence, it seems that the potential connection negative linking E-cadherin and SSTR5 expression (and, perhaps, function) deserves to be explored in more detail. The Mann-Whitney test was used.…”

Analgesic effect of long-acting somatostatin receptor agonist pasireotide in a patient with acromegaly and intractable headaches

“…The pituitary adenomas in these patients were found to not only express sst 2 and sst 5 receptors, but a truncated sst 5 variant which was thought to account for the poor response to treatment with octreotide 15. Expression of these variants of sst 5 on GH-secreting adenomas has been associated with more aggressive features and worse prognosis 20. The alleviation of headaches and achievement of biochemical control in our patient were likely mediated via the effect of pasireotide on multiple receptors, including sst 1 , sst 2 and sst 5 .…”