Somatostatin, Somatostatin Analogs and Somatostatin Receptor Dynamics in the Biology of Cancer Progression

Abstract

The pharmacological effects (i.e., inhibition of endocrine secretion and cell proliferation) mediated by the hormone somatostatin (SRIF) are derived from its universal high-affinity binding to five different G proteincoupled receptors (GPCRs), named sst1-5. However, SRIF has a half-life of less than 3 min, whereas the available mono- and bi-specific SRIF preferential analogs show prolonged half-life and increased potency. These compounds may control tumor development, cell proliferation and metastatization by direct actions, including cell division arrest in G0/G1 phase (i.e., induction of cyclin-dependent kinase inhibitor p27(kip1) or p21(Cip1)), induction of apoptosis (i.e., induction of p53 and Bax) and suppression of cell invasion. Along with these direct actions on the biology of cancer progression, in vivo SRIF analogs may also regulate tumor growth through indirect actions, by suppressing the secretion of growth-promoting hormones and growth factors and angiogenesis. Interestingly, when ssts are co-expressed, they may interact forming homo- or heterodimers, also with other GPCRs such as type 2 dopamine receptor and the μ-opioid receptor 1, altering their original pharmacological and functional properties. Dimers can be not only constitutive, but perhaps also ligandpromoted: hence, compounds with high affinity for different ssts isoforms may be used to achieve effects elicited by specific dimers. Future developments in the knowledge of ssts dynamics upon SRIF and SRIF analogs binding in neoplastic tissues may allow the full elucidation of the pathophysiological role of this system and the exploitation of the therapeutic potential of its modulation.

Obesity- and gender-dependent role of endogenous somatostatin and cortistatin in the regulation of endocrine and metabolic homeostasis in mice

“…SST3 is a pleiotropic neuropeptide widely distributed throughout the organism, which regulates a plethora of physiological functions, including inhibition of basal and stimulated secretion from endocrine and exocrine cells, inhibition of gastrointestinal motility, modulation of neurotransmission, metabolism and immune function, as well as inhibition of cell proliferation and differentiation13456. In contrast, CORT7 is mainly produced in the cerebral cortex and was originally identified for its role in the modulation of sleep cycles, neuronal activity and immune system7891011.…”

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes

“…Somatostatin receptors (SSTR) have been recognised as dynamic regulators of tumour development, cell proliferation and apoptosis (Ruscica et al , 2012). Somatostatin secretion is known to negatively influence VEGF production (Mentlein et al , 2001), and in vitro work has shown that the administration of the somatostatin analogue octreotide can antagonise Hif-1 α transcriptional activity in NET cells (Villaume et al , 2010).…”

Somatostatin and prostate cancer: role of somatostatin receptors in the control of tumor growth

“…Somatostatin system SRIF is a cyclic polypeptidic hormone largely expressed in hypothalamus which displays inhibitory functions on hormone secretion (5-18) and cell proliferation (14,19,20). SRIF acts on target cells through its binding with five specific receptor subtypes codenamed SS1R-SS5R (21,22,44,45).…”

“…Improved understanding of PCa biology has led to new promising treatment strategies, in particular peptide-based agonists and antagonists, including somatostatin (SRIF) analogs (SSAs), alone or in combination with other treatments (2)(3)(4). SRIF is a cyclic polypeptidic hormone largely expressed in hypothalamus which displays inhibitory functions on hormone secretion (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and cell proliferation (14,19,20). SRIF acts through the binding with five specific membrane receptors (SSRs) codenamed SS1R-5 (21).…”