Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

Abstract

Numerous peptide receptors are overexpressed in human cancer, permitting in vivo tumor targeting. Among such receptors, those for the neurotransmitter neuropeptide Y (NPY) are overexpressed in various tumors. Since NPY can play a role in the kidney, NPY receptor expression and/or endogenous production of peptides of the NPY family (NPY, PYY, PP) were evaluated in 40 renal cell carcinomas (RCCs) and 18 nephroblastomas. NPY receptor protein expression was investigated by in vitro autoradiography using 125 I-labeled PYY in competition with NPY receptor subtype-selective analogs. NPY, PYY and PP production was assessed immunohistochemically. Fifty-six percent of RCCs expressed the Y1 receptor subtype in moderate density, and 80% of nephroblastomas expressed Y1 and Y2 subtypes in moderate to high density. Y1 was also highly expressed in intratumoral blood vessels. In selected cases, NPY was observed in nerve fibers in close association with intratumoral blood vessels and in the vicinity of tumor cells, while no PYY or PP was detected immunohistochemically in these sites. NPY receptors on renal tumor cells and tumor blood vessels may therefore be the molecular targets of endogenous NPY released by intratumoral nerve fibers. With regard to clinical applications, NPY receptors may act as in vivo targets for receptor-directed therapy of RCCs and nephroblastomas for which alternative therapeutic approaches are still required. ' 2005 Wiley-Liss, Inc.Key words: NPY receptor; renal cell carcinoma; nephroblastoma; receptor autoradiography Peptide hormone receptors are overexpressed in a wide variety of human tumors.1 Like other cell surface molecules, these receptors become increasingly important for clinical applications. In particular, they allow receptor-targeted tumor imaging and therapy with corresponding peptide hormone analogs. For instance, scintigraphy using the somatostatin analog Octreoscan is highly sensitive at detecting gastroenteropancreatic neuroendocrine tumors which express somatostatin receptors in high amounts.2,3 Moreover, targeted radiotherapy of these tumors with 90 Y-or 177 Lu-labeled somatostatin analogs is also promising. 4,5 Another peptide hormone receptor family with a potential future role in this field is the NPY receptor family. It belongs to the G protein-coupled receptor superfamily and comprises various subtypes. Subtypes Y1, Y2, Y4 and Y5 are expressed in humans. 6 They are present mainly in the central and peripheral nervous systems as well as other tissues, such as the cardiovascular system. Their physiologic ligands are the neurotransmitter NPY and the 2 hormones PYY and PP. Among many other sites, NPY has been localized to perivascular nerves in the human kidney. 7 NPY receptors may also play a role in human neoplasia. High incidence rates of subtypes Y1 and Y2 were found in tumors related to steroid hormone metabolism (adrenal cortical tumors, ovarian sex cord-stromal tumors, breast carcinomas), 8,9 in neuroendocrine tumors (pheochromocytomas and paragangliomas) 10

Red-fluorescent argininamide-type NPY Y1 receptor antagonists as pharmacological tools

“…1). 5 Thus, with regard to the lower affinity of 1 compared to 13, the guanidine-acylguanidine bioisosteric approach is more efficient for BIBP 3226 (1), and it may be speculated about a slightly different orientation of the parent compounds BIBO 3304 (13) and BIBP 3226 at the Y 1 receptor. Due to lack of advantages in terms of potency and unexpectedly low solubility (org.solvents) of compounds derived from 13, the preparation of fluorescent Y 1 R antagonists was carried on using BIBP 3226 as the preferred building block.…”

“…12-Amino-4,7,10-trioxadodecanoic acid tert-butyl ester (18), N-Boc-3,6-dioxaoctane-1,8-diamine (22), N-Boc-8-amino-3,6-dioxaoctanoic acid (35, as dicyclohexylamine salt), N-Boc-propane-1,3-diamine (15) and N-Boc-butane-1,4-diamine (26) were purchased from Fluka (Sigma-Aldrich Chemie GmbH, Munich, Germany). D-Ornithine hydrochloride (5) was obtained from Iris Biotech GmbH (Marktredwitz, Germany).…”

“…The Y 1 R was selected as a representative model of a peptidergic GPCR, for instance, as this receptor subtype was recently associated with diagnosis and treatment of tumours. [11][12][13][14][15][16][17][18][19] For the synthesis of non-peptidic fluorescent ligands, the argininamidetype Y 1 R selective antagonists BIBP 3226 20 and BIBO 3304 21 ( Fig. 1) were considered appropriate parent molecules to construct high affinity fluorescent probes with reduced propensity to induce internalisation compared to (peptidic) agonists.…”

Breast‐Cancer Diagnosis by Neuropeptide Y Analogues: From Synthesis to Clinical Application

“…This approach might be further extended to a tumor-specific targeting by using NPY derivatives for carrier of chemotherapeutic agents and might not be limited to breast cancer, because Y-receptor expression has been identified in other tumors, such as neuroblastoma, glioblastoma, ovarian adenocarcinoma, gastrointenstinal stromal tumor, nephroblastomas, renal cell carcinoma, and pheochromocytoma. [5,23,24] Experimental Section See Supporting Information for details. All animal and human studies were done at the Institute of Nuclear Medicine and Oncology …”

Neuropeptid‐Y‐Analoga zur Brustkrebsdiagnostik: von der Synthese zur klinischen Anwendung

“…[17][18][19] Der Tc-MDP-Knochenszintigraphie diente als Kontrolle; bei diesem Verfahren reichert sich radiochemisch markiertes Methylendiphosphat (MDP) in den Osteoblasten an, sodass mögliche Knochenmetastasen detektiert werden können. [21,22] Des Weiteren erfolgte als Negativkontrolle die intravenöse Injektion des Peptids 2 a in eine gesunde Probandin, die bei der szintigraphischen Untersuchung [5,23,24] ) nicht ausschließlich auf Bruskrebs beschränkt. …”