Bombesin Receptors in Distinct Tissue Compartments of Human Pancreatic Diseases

Abstract

SUMMARY: Overexpression of receptors for regulatory peptides in various human diseases is reportedly of clinical interest.Among these peptides, bombesin and gastrin-releasing peptide (GRP) have been shown to play a physiological and pathophysiological role in pancreatic tissues. Our aim has been to localize bombesin receptors in the human diseased pancreas to identify potential clinical applications of bombesin analogs in this tissue. The presence of bombesin receptor subtypes has been evaluated in specimens of human pancreatic tissues with chronic pancreatitis (n ϭ 23) and ductal pancreatic carcinoma (n ϭ 29) with in vitro receptor autoradiography on tissue sections incubated with 125 ]-bombesin(6 -14) as radioligands and displaced by subtype-selective bombesin receptor agonists and antagonists. GRP receptors were identified in the pancreatic exocrine parenchyma in 17 of 20 cases with chronic pancreatitis. No measurable bombesin receptors were found in the tumor tissue of ductal pancreatic carcinomas, however, GRP receptors were detected in a subset of peritumoral small veins in 19 of 29 samples. Moreover, residual pancreatic islets in these tissues were shown to express the BB3 receptor subtype. These data demonstrate the presence of bombesin receptors in three distinct tissue compartments of the pancreas, namely GRP receptors in the exocrine parenchyma in chronic pancreatitis and in peritumoral vessels around ductal pancreatic carcinomas, and BB3 receptors in residual pancreatic islets. Such a selective expression of bombesin receptor subtypes in pancreatic tissues may not only be of pathophysiological significance but may represent the basis for potential diagnostic and therapeutic clinical applications of bombesin analogs, including GRP receptor scintigraphy to differentiate chronic pancreatitis from ductal pancreatic carcinoma.

Synthesis and Evaluation of Bombesin Derivatives on the Basis of Pan-Bombesin Peptides Labeled with Indium-111, Lutetium-177, and Yttrium-90 for Targeting Bombesin Receptor-Expressing Tumors

“…The extracted supernatant, obtained as described above, was co-injected with the potential "metabolites," synthesized as described above. The metabolism in serum was studied by the addition of EDTA (2.4 mmol/L) or carnosine (22.4 (6 -14) as universal radioligand, as described in detail previously (22,45).…”

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

“…BB 3 receptors have also been shown to exist on normal bronchial epithelial cells (DeMichele et al, 1994;Tan et al, 2006), human islets (Fleischmann et al, 2000), and rat kidney cells ).…”

“…BB 3 receptor knockout mice were shown to have altered taste preference , which was proposed to be due to the lack of BB 3 receptor expression in the medial and central nuclei of the amygdala and the hypothalamic nuclei, which are known to be involved in taste perception and to possibly be a contributory factor to the obesity. BB 3 receptors are present on pancreatic islets (Fleischmann et al, 2000), and BB 3 receptor knockout mice have a 2.3-fold increase in plasma insulin levels (Matsumoto et al, 2003) (Table 2). One study (Matsumoto et al, 2003) concluded that the BB 3 receptor contributes to regulation of plasma insulin concentration/secretion and that dysregulation in this contribution in these mice contributes to obesity (Matsumoto et al, 2003).…”

Enzyme-based visualization of receptor–ligand binding in tissues

“…Normal pancreatic tissue binds bombesin-like peptides while pancreatic cancers do not. 17,19,20 The binding of Fl-BN, and lack of binding of Fl-scrBN, was apparent with normal pancreatic tissue while pancreatic ductal adenocarcinoma failed to bind either peptide. The pancreatic array consisted of 13 ductal adenocarcinomas and five normal samples, all of which were evaluated with results tabulated in Figure 4d.…”