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Immunohistochemical Localization of CCK₁ Cholecystokinin Receptors in Normal and Neoplastic Human Tissues

Departments of Pharmacology and Toxicology (St.S.), Pathology (C.R.), Neuropathology (C.M.), Obstetrics and Gynecology (So.S.), Otto-von-Guericke University, 39120 Magdeburg, Germany

Address all correspondence and requests for reprints to: Stefan Schulz, Department of Pharmacology and Toxicology, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail: Stefan.Schulz{at}Medizin.Uni-Magdeburg.de.

Background: The biological effects of cholecystokinin (CCK) are mediated by two distinct G protein-coupled receptors, CCK₁ and CCK₂. Although it is well established that CCK receptors are widely distributed throughout the normal gastrointestinal tract, little is known about their cellular and subcellular localization in human normal and neoplastic tissues.

Methods: We developed and characterized a novel antipeptide antibody to the carboxyl-terminal region of the human CCK₁ receptor. Specificity of the antiserum was demonstrated by 1) detection of a broad band migrating at a relative molecular mass of 85,000–95,000 in Western blots of membranes from CCK₁-expressing tumors and CCK₁-transfected cells, 2) cell surface staining of CCK₁-transfected cells, 3) translocation of CCK₁ receptor immunostaining after agonist exposure, and 4) abolition of tissue immunostaining by preadsorption of the antibody with its immunizing peptide. The distribution of CCK₁ receptors was investigated in 74 human tumors and their tissues of origin.

Results: The presence of CCK₁ receptors was rarely detected in human tumors except for carcinoids, insulinomas, pituitary adenomas, and meningiomas. CCK₁ receptors were clearly located at the plasma membrane and uniformly present on nearly all tumor cells. In the gastrointestinal tract, CCK₁ receptor immunoreactivity was highly abundant in chief cells of the gastric mucosa, in myenteric ganglion cells, and in myenteric nerve fibers.

Conclusion: This is the first localization of CCK₁ receptors in human formalin-fixed, paraffin-embedded tissues at the cellular level. The overexpression of CCK₁ receptors in a subset of human neuroendocrine tumors may provide a molecular basis for efficient targeting of these tumors with radiolabeled CCK analogs.

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