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Immunocytochemical Identification of VPAC₁, VPAC₂, and PAC₁ Receptors in Normal and Neoplastic Human Tissues with Subtype-Specific Antibodies

Departments of ¹ Obstetrics and Gynecology, ² Pathology, ³ Neuropathology, and ⁴ Pharmacology and Toxicology, Otto-von-Guericke-University, Magdeburg, Germany

Human tumors frequently overexpress receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP). However, none of the VIP/PACAP receptor proteins has been visualized individually in human tumors. Here, we developed and characterized a panel of antipeptide antibodies to the carboxyl-terminal regions of the VIP/PACAP receptor subtypes vasoactive intestinal peptide receptor (VPAC)₁, VPAC₂, and pituitary adenylate cyclase-activating peptide receptor (PAC)₁. Specificity of the antisera was shown by the following: (1) detection of broad bands migrating at M_r 50,000 to 70,000 in Western blots of membranes from receptor-expressing tumors and receptor-transfected cells; (2) cell surface staining of VIP/PACAP receptor-transfected cells; (3) translocation of VIP/PACAP receptor immunostaining in transfected cells after agonist exposure; and (4) abolition of tissue immunostaining by preadsorbtion of the antibodies with their immunizing peptides. The distribution of VIP/PACAP receptors was investigated in 98 human tumors and their tissues of origin. VPAC₁, VPAC₂, and PAC₁ receptors were clearly located at the plasma membrane of the tumor cells in a variety of human neoplasms. In the gastrointestinal tract, VPAC₁ receptor immunoreactivity was abundant in the mucosa and myenteric neurons; VPAC₂ receptor immunoreactivity was detected in neuroendocrine cells, blood vessels, and smooth muscle; and PAC₁ receptor immunoreactivity was found in myenteric neurons. This is the first localization of all of the VIP/PACAP receptor subtypes in human formalin-fixed, paraffin-embedded tissues. VIP/PACAP receptor visualization with this simple and rapid immunohistochemical method will facilitate identification of tumors with a sufficient receptor overexpression for diagnostic or therapeutic intervention.

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