Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands

Abstract

Somatostatin receptors are known to be expressed in a large number of human tumours and represent the basis for in vivo tumour targeting. Stable somatostatin derivatives such as octreotide or lanreotide are the most frequently used radiopharmaceuticals acting through specific binding to somatostatin receptors; however, they do not bind with high affinity to all five receptor subtypes. Whereas the mRNAs for most receptor subtypes have been detected in tumours, it is in most cases unclear which of the receptor subtype proteins are expressed. Since in vitro receptor binding methods are close correlates and predictors of in vivo peptide receptor targeting, we took advantage of the recently developed subtype-selective analogues and evaluated approximately 200 tumours for their receptor subtype protein expression in specific binding assays using autoradiography with 125I-[Leu8, D-Trp22, Tyr25]-somatostatin-28 and displacement by subtype-selective analogues. The majority of the tested neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas and hepatocellular carcinomas predominantly expressed sst2. The prostate carcinomas and sarcomas preferentially expressed sstl, while a majority of inactive pituitary adenomas displayed sst3 and, to a lesser extent, sst2. Growth hormone-secreting pituitary adenomas preferentially expressed sst2 and sst5; gastroenteropancreatic tumours and phaeochromocytomas frequently displayed sst2 and/or sstl. Non-neoplastic human tissues such as vessels, nerve plexus, pancreatic islets, prostatic stroma, adrenal medulla, spleen and germinal centres of the lymphoid tissues preferentially expressed sst2. However, the human gastric mucosa predominantly expressed sst1 while colonic mucosa displayed sst2. Interestingly, a minority of tumours showed a strong 125I-[Leu8, D-Trp22, Tyr25]-somatostatin-28 binding, of which less than 50% could be displaced by the sum of the five subtype-selective analogues. This observation suggests the existence of an as yet unknown subtype in selected tumours. This study is the first report to analyse the somatostatin receptor subtype expression in tumours with binding methods. We conclude that sst2, with high affinity for current radiopharmaceuticals such as Octreoscan, is predominantly expressed in a majority of tumours. Fewer tumour types (sarcomas, prostate cancers, inactive pituitary adenomas) preferentially express another subtype. This information is of importance with regard to the clinical applications and development of somatostatin analogues with distinct receptor subtype selectivities.

Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin

“…In this overview, the study with the largest number of patients reported tumour remission in two (1 CR, 1 PR) and stable disease in five out of seven patients with progressive, bronchial carcinoids. Specific data on TTP for patients with foregut carcinoids are lacking in most of these studies ( [29], which is the most frequently expressed subtype on GEP NETs [30] and certainly because the physical properties of 177 Lu are better suited for therapy than those of 111 In when labelled to a somatostatin analogue. However, comparison of these other treatments with treatment using 177 Lu-octreotate is difficult.…”

Production of 177Lu for Targeted Radionuclide Therapy: Available Options

“…The in vivo applications of key 177 Lu radiopharmaceuticals for a variety of therapeutic procedures include peptide receptor radionuclide therapy [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26], bone pain palliation [27][28][29][30][31][32][33], radiation synovectomy [34][35][36][37][38][39] and radioimmonutherapy [40][41][42][43][44][45][46]. There is a steadily expanding list of 177 Lu-labeled radiopharmaceuticals that is currently being evaluated at the preclinical research or at product development stages; these may potentially be used in vivo in humans for evaluation for radionuclide therapy [1][2][3].…”

GPCRs and cancer

“…Somatostatin receptors (SSTRs), particularly SSTR subtype 2, were found highly expressed in many neoplastic cells and in tumoral blood vessels [163] . SST analogues decreased tumor cell growth and angiogenesis as well as stimulated apoptosis in cancer cells [164] .…”