GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting

Abstract

Peptide hormone receptors overexpressed in human tumors, such as somatostatin receptors, can be used for in vivo targeting for diagnostic and therapeutic purposes. A novel promising candidate in this field is the GLP-1 receptor, which was recently shown to be massively overexpressed in gut and lung neuroendocrine tumors-in particular, in insulinomas. Anticipating a major development of GLP-1 receptor targeting in nuclear medicine, our aim was to evaluate in vitro the GLP-1 receptor expression in a large variety of other tumors and to compare it with that in nonneoplastic tissues. Methods: The GLP-1 receptor protein expression was qualitatively and quantitatively investigated in a broad spectrum of human tumors (n 5 419) and nonneoplastic human tissues (n 5 209) with receptor autoradiography using 125 I-GLP-1(7-36)amide. Pharmacologic competition experiments were performed to provide proof of specificity of the procedure. Results: GLP-1 receptors were expressed in various endocrine tumors, with particularly high amounts in pheochromocytomas, as well as in brain tumors and embryonic tumors but not in carcinomas or lymphomas. In nonneoplastic tissues, GLP-1 receptors were present in generally low amounts in specific tissue compartments of several organs-namely, pancreas, intestine, lung, kidney, breast, and brain; no receptors were identified in lymph nodes, spleen, liver, or the adrenal gland. The rank order of potencies for receptor binding-namely, GLP-1(7-36)amide 5 exendin-4 GLP-2 5 glucagon(1-29)-provided proof of specific GLP-1 receptor identification. Conclusion: The GLP-1 receptors may represent a novel molecular target for in vivo scintigraphy and targeted radiotherapy for a variety of GLP-1 receptor-expressing tumors. For GLP-1 receptor scintigraphy, a low-background signal can be expected, on the basis of the low receptor expression in the normal tissues surrounding tumors. G protein-coupled peptide hormone receptors play an increasing role in cancer medicine. This role is based primarily on the peptide receptor overexpression on tumor cells, which allows specific receptor-targeted scintigraphic tumor imaging and tumor therapy with radiolabeled peptide analogs (1). The somatostatin receptors were the first peptide receptors identified for these purposes, and somatostatin receptor targeting has now become an integral part of the routine management of patients with gastroenteropancreatic neuroendocrine tumors. Somatostatin receptor scintigraphy (OctreoScan [ 111 In-pentetreotide]; Mallinckrodt, Inc.) detects these tumors with extremely high sensitivity and specificity (2). Moreover, recent results from clinical studies performing somatostatin receptor radionuclide therapy of these tumors are very promising (3,4).Prompted by the success of somatostatin receptor targeting, we have evaluated the overexpression of other peptide receptor families in tumors in vitro (1), with the aim, eventually, of being able to target in vivo a larger spectrum of tumors or individual tumors more efficiently with multiple pepti...

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

“…The results of our ex vivo autoradiography are in line with the quantitative PCR analysis on rat tissues: high GLP-1R expression was observed in the endocrine pancreas, while low expression was apparent in the exocrine pancreas. The differences observed between our results and the previously published data [13,33] may be explained by differences between binding characteristics of 125 I-labelled glucagon-like peptide 1 and GLP-1R antibodies in an in vitro assay as compared with the binding characteristics of 111 In-labelled exendin in vivo. Of note, in vivo 111 In-labelled exendin also shows internalisation and metabolic trapping [34], which makes this technology highly sensitive and specific for the detection of GLP-1R-positive tissues.…”

“…Previous studies suggested that GLP-1R expression is detected in the exocrine pancreas by in vitro autoradiography with 125 I-GLP-1 and immunohistochemistry on human pancreatic sections [13,33]. Our ex vivo autoradiographic analysis showed scattered focal hotspots throughout the pancreas that were co-localised with the islets in immunohistochemical staining with only low background activity in the exocrine pancreas.…”

“…Alternative nuclear medicine imaging modalities, such as single photon emission computed tomography (SPECT) or positron emission tomography (PET), offer a very high sensitivity, which may be sufficient for the detection of the relatively low number of pancreatic islet cells by using a highly beta cell-specific radiolabelled tracer molecule. A potential target for measurement of the BCM is the glucagon-like peptide 1 receptor (GLP-1R) as it is abundantly expressed in rat, mouse and human pancreatic beta cells but not in α, δ and pp cells [13,14]. Exendin is a stable agonist of the GLP-1R and it has been used for in vivo targeting of the GLP-1R after labelling with various radionuclides [15][16][17][18][19].…”

The Human GLP-1 Analogs Liraglutide and Semaglutide: Absence of Histopathological Effects on the Pancreas in Nonhuman Primates

“…However, valid studies are available documenting GLP-1R expression (49). These studies measure receptor expression by ligand binding and show that pancreatic adenocarcinomas do not express GLP-1R (49,50). Thus, from a molecular target point of view, it seems unlikely that GLP-1R agonism should directly worsen or induce pancreatic adenocarcinomas when such tumors do not express GLP-1R.…”

“…Some scientific journals have provided new guidance for validation experiments that must be available for reliable documentation of expression of a G-protein-coupled receptor (48). However, valid studies are available documenting GLP-1R expression (49). These studies measure receptor expression by ligand binding and show that pancreatic adenocarcinomas do not express GLP-1R (49,50).…”