Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways

Abstract

Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

Fig 1

A simplified diagram of the Ras/ERK pathway and SST effects through PTPs, SHP-1 and SHP-2. Yellow lines show activation, red lines show inhibition of the corresponding protein. Note SHP-1 and SHP-2 inhibition of growth factor receptors, SHP-1 inhibition of ERK 1/2, SHP-2 inhibition of Raf kinase shown in blue lines. Src and SHP-2 activates SHP-1. As a result, SHP-1 and SHP-2 lead the cells to accumulate in G1 phase and inhibit entry in the S phase of the cell cycle. For simplicity the SSTR subtype-specific effects has not been shown separately. Abbreviations: ATF1, activating transcription factor; CcnD1, cyclin D1; CREB, cAMP responsive element binding protein; ERK, extracellular signal-regulated protein kinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GRB2, growth factor receptor binding protein 2; KSR, kinase suppressor of Ras; mTOR, mammalian Target of Rapamycin; MEK, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase; MSK, mitogen and stress activated kinase; NF-κB, nuclear factor-κB; p90RSK, p90 ribosomal S6 kinase; RTK, receptor tyrosine kinase; Src, cytosolic tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SHP-2, SH-2 domain containing cytosolic tyrosine phosphatase 2; SOS, mammalian son-of-sevenless; SST, somatostatin; SSTR, somatostatin receptor.

Fig 2

A simplified diagram of PI3K/Akt pathway and SST effects through PTP SHP-1. Arrowheads show activation, bold lines with rounded heads show inhibition of the corresponding protein. Note direct inhibition of growth factor receptor and p85 regulatory subunit of PI3K, and indirect inhibition of Akt pathway by SHP-1 shown in dotted lines. As a result, SHP-1 cause up-regulation of p21^cip1/waf1 and p^27kip1 and the tumour suppressor gene Zac1 and activation of caspase 8 and pro-apoptotic protein Bax. For simplicity, the SSTR subtype-specific effects has not been shown separately. Abbreviations: BAD, BCL2-antagonist of death; CcnD1, cyclin D1; CcnE, cyclin E; ERK, extracellular signal-regulated protein kinases; HDM2, human homolog of murine double minute ubiquitin ligase; GSK-3, glycogen synthase kinase-3; IKK, IκB kinase; mTOR, mammalian target of Rapamycin; NF-κB, nuclear factor-κB; p21, cyclin dependent kinase inhibitor p21^Cip1/WAF1; p27, cyclin dependent kinase inhibitor p27^Kip1; PDK1, phosphoinositide-dependent kinase 1; RTK, receptor tyrosine kinase; SHP-1, SH-2 domain containing cytosolic tyrosine phosphatase 1; SST, somatostatin; SSTR, somatostatin receptor.