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.