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Vasoactive Intestinal Peptide/Pituitary Adenylate Cyclase-activating Peptide Receptor Subtypes in Human Tumors and Their Tissues of Origin¹

Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland [J. C. R., U. L., B. W., J. A. L.]; Institute of Pathology, Kantonsspital Luzern, CH-6000 Luzern, Switzerland [J-O. G.]; and Departement de Chimie Biologique et de la Nutrition, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium [P. R.]

The evaluation of peptide receptors in man is needed not only to discover the physiological target tissues of a given peptide but also to identify diseases with a sufficient receptor overexpression for diagnostic or therapeutic interventions. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors have been evaluated in human tumors and in their tissues of origin using in vitro receptor autoradiography with ¹²⁵I-VIP or ¹²⁵I-acetyl-PACAP-27 in tissue sections. The VIP/PACAP receptor subtypes VPAC₁, VPAC₂, and PAC₁ were evaluated in these tissues by determining the rank order of potencies of VIP and PACAP as well as VPAC₁- and VPAC₂-selective analogues. The VIP/PACAP receptors expressed in the great majority of the most frequently occurring human tumors, including breast (100% receptor incidence), prostate (100%), pancreas (65%), lung (58%), colon (96%), stomach (54%), liver (49%), and urinary bladder (100%) carcinomas as well as lymphomas (58%) and meningiomas (100%), are predominantly of the VPAC₁ type. Their cells or tissues of origin, i.e., hepatocytes, breast lobules and ducts, urothelium, prostate glands, pancreatic ducts, lung acini, gastrointestinal mucosa, and lymphocytes, also predominantly express VPAC₁. Leiomyomas predominantly express VPAC₂ receptors, whereas paragangliomas, pheochromocytomas, and endometrial carcinomas preferentially express PAC₁ receptors. Conversely, VPAC₂ receptors are found mainly in smooth muscle (i.e., stomach), in vessels, and in stroma (e.g., of the prostate), whereas PAC₁ receptors are present in the adrenal medulla and in some uterine glands. Whereas the very wide distribution of VIP/PACAP receptors in the normal human body is indicative of a key role of these peptides in human physiology, the high VIP/PACAP receptor expression in tumors may represent the molecular basis for clinical applications of VIP/PACAP such as in vivo scintigraphy and radiotherapy of tumors as well as VIP/PACAP analogue treatment for tumor growth inhibition.

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