Role of Somatostatin Signalling in Neuroendocrine Tumours

Abstract

Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.

Abiraterone acetate for treatment of ectopic Cushing syndrome caused by ACTH-producing neuroendocrine tumor: a case report

“…SSA inhibitor effects are mediated through SSTR subtypes 2 (inhibit hormone secretion), 3 and 5 (both modulate tumor growth suppression and apoptosis). SSAs primarily bind to SSTR-2, primarily associated with temporizing hormonal and modest downstream SSTR effects of apoptosis and cell growth with variable interaction with SSTR 3 and 5, though low rates of durable radiologic response are reported ( 9 , 10 ).…”

Advances in Radionuclides and Radiolabelled Peptides for Cancer Therapeutics

“…A different subtype may occupy tumour regions devoid of the expression of a given subtype. Furthermore, in advanced illness stages, the deletion or downregulation of SST2 is linked to a poorer prognosis, less sensitive imaging, and unsuccessful therapy with SST2-specific analogues due to poor tumour targeting [ 150 ]. For this reason, somatostatin analogues with an affinity for several receptor subtypes are of considerable interest since they can tackle the problems of receptor subtype co-expression and heterogeneous expression patterns.…”

Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms

“…Hence, SSAs are now used as a treatment option for patients with progressive well-differentiated pancreatic and midgut NENs, preferably with a Ki-67 of ≤10%, regardless of the functional status of the tumour, to either prevent or inhibit tumour growth [ 158 ]. First-generation SSAs, octreotide and lanreotide, the only two SSAs approved for NENs, bind specifically to SSTR2 and with lesser affinity to SSTR5, with lower to no affinity for the other SSTRs, while the new SSA pasireotide is also able to bind to the other SSTRs with greater affinity [ 12 ]. The effect of octreotide seems to be mediated mainly by the interaction with SSTR2, and SSTR2 is the target for receptor-based imaging and RLT in NENs.…”

“…The hallmark of NENs is their expression of somatostatin receptors (SSTRs), as somatostatin inhibits cell growth and hormone secretion in normal and cancerous neuroendocrine cells [ 12 ]. Somatostatin receptors are G-protein-coupled receptors with a typical transmembrane domain that includes five distinct subtypes named 1 to 5, with the gene encoding for the SSTR2 also producing two splice variants, SSTR2 isoform A and B.…”