Peptide receptors involved in pathophysiological processes represent promising therapeutic targets. Neuropeptide somatostatin (SST) is produced by specialized cells in a large number of human organs and tissues. SST primarily acts as inhibitor of endocrine and exocrine secretion via the activation of five G-protein-coupled receptors, named sst1–5, while in central nervous system, SST acts as a neurotransmitter/neuromodulator, regulating locomotory and cognitive functions. Critical points of SST/SST receptor biology, such as signaling pathways of individual receptor subtypes, homo- and heterodimerization, trafficking, and cross-talk with growth factor receptors, have been extensively studied, although functions associated with several pathological conditions, including cancer, are still not completely unraveled. Importantly, SST exerts antiproliferative and antiangiogenic effects on cancer cells in vitro, and on experimental tumors in vivo. Moreover, SST agonists are clinically effective as antitumor agents for pituitary adenomas and gastro-pancreatic neuroendocrine tumors. However, SST receptors being expressed by tumor cells of various tumor histotypes, their pharmacological use is potentially extendible to other cancer types, although to date no significant results have been obtained. In this paper the most recent findings on the expression and functional roles of SST and SST receptors in tumor cells are discussed. 1. Somatostatin and Somatostatin Receptors: An Overview Somatostatin (SST) is a cyclic neuropeptide containing a disulfide bond linking the cysteine residues at positions 3 and 14 (Cys3-Cys14). Native SST has two molecular forms, SST-28 and SST-14, consisting of 28 or 14？a.a., respectively, derived from proteolysis of a larger precursor molecule, pre-pro-SST. SST is ubiquitously expressed in humans, with high concentrations in brain, liver, lungs, pancreas, thyroid, gastrointestinal tract, and adrenal gland mainly acting as an inhibitor of exocrine and endocrine secretions on target organs. For example, SST suppresses GH, prolactin, and TSH production from pituitary gland, insulin, glucagon and exocrine secretions from pancreas, and several gastrointestinal peptides [1]. In the brain, SST acts as neuromodulator, with physiological effects on neuroendocrine, motor, and cognitive functions, and as neurotransmitter, exerting both stimulatory and inhibitory effects [2]. Moreover, the synthesis of many growth factors (insulin-like growth factor 1, IGF-1; epidermal growth factor, EGF; fibroblast growth factor, FGF; vascular-endothelial growth
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