Identification of bradykinin receptors in clinical cancer specimens and murine tumor tissues

Bradykinin (BK) has multiple pathophysiologic functions such as induction of vascular permeability and mitogenesis, and it triggers the release of other mediators such as nitric oxide in inflammatory and cancer tissues. To explore the pathophysiologic roles of BK in tumor, we examined the distribution of BK B, receptors in human adenocarcinoma (lung, stomach), lymphoma (lymph node), hepatoma, squamous cell carcinoma (lung) and carcinoid (duodenum), and in mouse colon adenocarcinoma 38 (C-38) and sarcoma 180 (S-180) tumor tissues. Immunohistochemical staining of tumor tissues with an anti-BK B-2 receptor antibody, or autoradiography with the B-2 receptor antagonist [I-125]HOE 140 (D-Arg-[Hyp Thi D-Tic Oic(8)]-BK) and the B-2 receptor agonist [H-3]BK indicated the presence of B receptors in all human tumor cells and murine S-180 and C-38 cells. Specific binding of [H-3]HOE 140 was observed in S-180 cells with a Kd of 2.1 nM. Binding of [I-125]HOE 140 to S-180 cells was competed by an excess amount (20-100 times) of nonradiolabeled HOE 140 or BK, but not by BK B, receptor agonist des-Arg(9)-BK. These results provide direct evidence that the BK B-2 receptor is expressed in human cancer and experimental murine tumors, which suggests a potential role for BK in inducing pathologic signal transduction in cancer growth and progression, nitric oxide production and vascular permeability enhancement in tumors. BK antagonists may thus have applications in the modulation of cancer growth and in paraneoplastic syndromes. (C) 2002 Wiley-Liss, Inc.