Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 9 of 12 Recently, the high expression of SSTRs on gastrinomas has been considered as an opportunity to use radiola- beled somatostatin analogues, in order to achieve a cyto- toxic effect [111In-labelled analogues, 90yttrium or 177lutetium] [111]. Novel strategies based on SSTRs 2 receptor gene transfer to target tumour growth and angiogenesis represents a new advance in the treatment of unresect- able pancreatic tumours. Buscail et al initially demonstrated that in human pan- creatic adenocarcinoma SSTR 2 expression was specifi- cally los[8]. Once gene defect corrected, cell growth as well as tumorigenicity, were significantly reduced in the absence of exogenous ligand [112]. The synthesis and secretion of the natural ligand somatostatin-14 by sst2-transfected cells was responsible for an autocrine/paracrine inhibi- tory loop [57]. Several study conducted on pancreatic adenocarci- noma animal models demonstrated that intratumoural SSTR 2 gene transfer (using polyethylenimine synthetic vector) inhibited intratumoural production of somatos- tatin that was critical for the SSTR 2 antitumoral effect. Primary tumour growth and angiogenesis were highly decreased and associated with a reduction in microves- sel density, inhibition of intratumoural production of VEGF and up-regulation of antiangiogenic SSTR 3 receptor expression in peripheral tumour vessels [32,113,114]. Conclusion Neuroendocrine tumors of the gastroenteropancreatic (GEP NETs) system comprise a rare group of malignant neoplasms. The somatostatin analogues have been shown to be very useful for symptomatic and biochem- ical improvement in patients with these tumours while preclinical and clinical studies provide conflicting results on their antitumour effects. The mechanisms of these effects are unknown, but probably are in part due to direct effects on proliferative signalling pathways, activa- tion of apoptosis, and effects on angiogenesis. Biological response to somatostatin analogs depends on distribution and level of expression of SSTRs sub- types in tumours, and the expression of selective soma- tostatin receptor-signaling pathway molecules. The high density of SSTR2 in endocrine tumours explains the use of SSTR 2 specific analogues in the diag- nosis and treatment of these tumours. However, the role of SSTR1,3 and 5 appears to be of increasing interest. The development of new peptidic and non-peptidic somatostatin analogues, subtype selective agonists, chimae- ric analogues, or pan-somatostatin analogues will probably improve the diagnosis and treatment of GEP NETs, which express somatostatin receptors other than SSTR 2. The combination of SSAs and IFN seems of benefit in patients where the treatment with somatostatin analo- gues alone failed to achieve a biochemical and sympto- matic control while their synergistic effect on tumour growth is still unknown. The analysis of the SSTR status specifically for each patient, and studies of individual tumour biological behaviour, might be of therapeutic interest and could help to optimise treatment expecially in unresectable tumours. Peptide-receptor-targeted radiotherapy for advanced disease using radiolabeled octapeptide analogues appears to be a significant progress in the treatment of GEP NETs but data are limited, mainly about the best time for its administration, or what is the most appropriate radioligand/combination to be used for each patient, and if and how the doses should be fractionated. Novel strategies based on SSTR 2 receptor gene trans- fer to target tumor growth and angiogenesis might offer new prospectives of therapeutic interest mainly to treat unresectable tumours. Prospective studies including large number of patients regarding the optimal dosage and modes of administra- tion of somatostatin analogues and the development of new slow release, SSTR subtype specific compounds are needed. Conflict of interest statement We disclose any financial and personal relationships with other people or organisations that could inappro- priately influence (bias) their work. Authors’ contributions MA and RB read and approval the final manuscript. Received: 16 November 2009 Accepted: 2 March 2010 Published: 2 March 2010 References 1. 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