Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 2 of 12 some of them can have an aggressive behaviour (poorly- differentiated carcinomas). The clinical picture depends on the site of the primary tumour and its ability to secrete neuroamines and pep- tides at supra-physiological levels (functioning tumours), able to cause a symptomatic response (clinical syn- dromes). Among functioning tumours, major clinical entities are: carcinoid syndrome, hypoglycaemic syn- drome, Zollinger-Ellison syndrome, WDHA (Water Diarrhea-Hypo-kaliemia-Achlorydria) syndrome, gluca- gonoma syndrome. However, 90% of GEP NETs do not produce biologi- cally active hormones (non functioning tumours) and therefore the diagnosis is often made too late, in pre- sence of symptoms due to the mass effect and/or the presence of metastases, mainly hepatic metastases [1]. In cases at advanced stages, with a diagnostic confir- mation of metastasis, as well as in case of disease pro- gression, the prognosis gets worse. In patients with localised well differentiated neuroendocrine carcino- mas, 5-year survival is 60-100%. With regional disease or distant metastases 5-year survival is 40% and 29%, respectively [6]. As a matter of fact, the median survival in these cases is approximately 1 or 2 years. Around 80% of GEP NETs express somatostatin receptors (SSTRs), located on the cell membrane. There are five different G-protein coupled receptor subtypes (SSTRs 1-5) that are differently expressed in the various types of tumour (Table 1 and 2). Tumours expressing SSTRs often contain one or more receptor subtypes. In addition, recent studies have shown that such receptors are preferably expressed in well-differentiated forms, that some advanced tumours loose particular receptor subtypes while keeping others [7,8], that SSTR subtypes can form homo/heterodimers at the membrane level, to develop new receptors with different functional features [9], and that this receptor “association” may be induced by addition of either dopamine or somatostatin. In a study examining 81 functioning and non-func- tioning GEP NETs the large parte of the tumours Table 1 Somatostatin receptorsa in neuroendocrine gastroenteropancreatic tumours [%] SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 All Insulinoma Gastrinoma Glucagonoma VIPoma N-F 68 33 33 67 100 80 86 100b 50 100 100 100 46 33 17 67 100 40 93 100 83 67 100 100 57 67 50 67 100 60 VIP, vasoactive intestinal polypeptide; N-F, Non functioning; aUsing receptor subtype antibodies; bMalignant insulinoma [Modified from Oberg K, Annals of Oncology, 2004] Table 2 Somatostatin receptor subtypes mRNA in neuroendocrine tumours Tumor Gastrinoma Insulinoma N-F Carcinoid (gut) SSTR1 79%a 76% 58% 76% SSTR2 SSTR3 SSTR4 SSTR5 93% 81% 88% 80% 36% 38% 42% 43% 61% 58% 48% 68% 93% 57% 50% 77% SST, somatostatin receptor; N-F, Non functioning;a Indicates the percentage of positive tumours for each sst. mRNA expression may overestimate the number of receptors present, depending on the technique used [PR-polymerase chain reaction, Northern blot, in-situ hybridization]. [Data from Plöckinger U. Biotherapy. Best Practice & Research Clinical Endocrinology & Metabolism 2007; Vol. 21, No. 1, pp. 145-162] expressed SSTRs 1, 2, 3 and 5, while SSTR 4 was detected only in a small minority [10]. Somatostatin receptors have been extensively mapped in different pancreatic tumours by means of autoradio- graphy, reverse-transcription polymerase chain reaction, in situ hybridization and immunohistochemistry; SSTRs 1, 2, 3 and 5 are usually expressed in pancreatic NETS. Pancreatic insulinomas had heterogeneous SSTRs expression while 100% of somatostatinomas expressed SSTR 5 and 100% gastrinomas and glucagonomas expressed SSTR 2 [11]. Somatostatin (SST) is a natural peptide hormone secreted in various parts of the human body, including the digestive tract, able to inhibit the release of numer- ous endocrine hormones, including insulin, glucagon, and gastrin. The biological effects of somatostatin are mediated through its specific receptors (SSTR 1-5) with a high degree of sequence similarity (39-57%) and which have been cloned in the early 1990s. They all bind nat- ural peptides, somatostatin 14, somatostatin 28 and cor- tistatin with similar high affinity (nM range). However, endogenous somatostatin short half-life in circulation (1-3 min), makes it difficult to use it continuously and has resulted in the development of synthetic analogues. By the early 1980s a number of short synthetic analo- gues of somatostatin including SMS201-995 (octreotide), RC-160 (vapreotide), BIM 23014 (lanreotide), and MK 678 (Seglitide) were developed. These cyclic octapeptides are more resistant to pepti- dases and their half-lives and hence their biological activities are substantially longer than native somatosta- tin (1.5-2 h vs 1-2 min) [12]. The development of a depot formulation of octreotide, Sandostatin LAR (Novartis) (long-acting repeatable), administered up to 30-60 mg once every 4 weeks has to a large extent eliminated the need for daily injections. Lan- reotide (Somatuline; Ipsen, Slough, UK), a long-acting somatostatin analogue administered every 10-14 days, has a similar efficacy to octreotide in the treatment of carci- noid tumors, but its formulation is easier and more