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

• Presence of sst5TMD4 increases aggressive features in acromegaly.
• Lower sst2/sst5TMD4 ratio is associated with poorer GH/IGF response to SSA.
• sst5TMD4 provides a plausible predictive marker for tumor invasiveness in acromegaly.
• In vitro overexpression of sst5TMD4 enhanced cell viability in somatotropinomas.
• sst5TMD4 expression may provide an attractive target for therapeutic research.

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.