Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

Peptide receptors have been found to represent excellent targets for in vivo cancer diagnosis and therapy. Recent in vitro studies have shown that many cancers can overexpress not only one but several peptide receptors concomitantly. One of the challenges for nuclear medicine in this field in the coming decade will be to take advantage of the co-expression of peptide receptors for multireceptor tumour targeting. In vitro receptor studies can reveal which peptide receptor is overexpressed in which tumour and which receptors are co-expressed in an individual tumour; such knowledge is a prerequisite for successful in vivo development. One group of tumours of particular interest in this respect is the neuroendocrine tumours, which have previously been shown often to express peptide receptors. This review summarises our investigations of the concomitant expression of 13 different peptide receptors, in more than 100 neuroendocrine tumours of the human intestine, pancreas and lung, using in vitro receptor autoradiography with subtype-selective ligands. The incidence and density of the somatostatin receptors sst1–sst5, the VIP receptors VPAC1 and VPAC2, the CCK1 and CCK2 receptors, the three bombesin receptor subtypes BB1 (NMB receptor), BB2 (GRP receptor) and BB3, and GLP-1 receptors were evaluated. While the presence of VPAC1 and sst2 was detected in the majority of these neuroendocrine tumours, the other receptors, more differentially expressed, revealed a characteristic receptor pattern in several tumour types. Ileal carcinoids expressed sst2 and VPAC1 receptors in virtually all cases and had CCK1, CCK2, sst1 or sst5 in approximately half of the cases; they were the only tumours of this series to express NMB receptors. Insulinomas were characterised by a very high incidence of GLP-1, CCK2 and VPAC1 receptors, with the GLP-1 receptors expressed in a particularly high density; they expressed sst2 in two-thirds and sst1 in approximately half of the cases and lacked CCK1 and NMB receptors. All gastrinomas had sst2 and GLP-1 receptors; they expressed GRP receptors in three-quarters of the cases and CCK1 or VPAC1 in approximately half of the cases. Most bronchial carcinoids had VPAC1, while sst1, sst2 and CCK2 were found in two-thirds of the cases and BB3 in one-third of the cases. These data provide evidence for the vast biological diversity of these neuroendocrine tumours. Moreover, the results represent a basis for starting and/or optimising the in vivo targeting of these tumours by selecting the suitable radiopeptides for tumour diagnosis and/or therapy. Finally, the data strongly encourage concomitant application of several radiopeptides to permit more efficient targeting of these tumours.