Primary Role for Kinin B₁ and B₂ Receptors in Glioma Proliferation

This study investigated the role of kinins and their receptors in malignant brain tumors. As a first approach, GL-261 glioma cells were injected (2 × 10⁵ cells in 2 μl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B₁ and B₂ receptor knockout (KOB₁R and KOB₂R) and B₁ and B₂ receptor double knockout mice (KOB₁B₂R). The animals received the selective B₁R (SSR240612) and/or B₂R (HOE-140) antagonists by intracerebroventricular (i.c.v.) route at 5, 10, and 15 days. The tumor size quantification, mitotic index, western blot analysis, quantitative autoradiography, immunofluorescence, and confocal microscopy were carried out in brain tumor samples, 20 days after tumor induction. Our results revealed an uncontrolled tumor growing in KOB₁R or SSR240612-treated mice, which was blunted by B₂R blockade with HOE-140, suggesting a crosstalk between B₁R and B₂R in tumor growing. Combined treatment with B₁R and B₂R antagonists normalized the upregulation of tumor B₁R and decreased the tumor size and the mitotic index, as was seen in double KOB₁B₂R. The B₁R was detected on astrocytes in the tumor, indicating a close relationship between this receptor and astroglial cells. Noteworthy, an immunohistochemistry analysis of tumor samples from 16 patients with glioma diagnosis revealed a marked B₁R immunopositivity in low-grade gliomas or in older glioblastoma individuals. Furthermore, the clinical data revealed a significantly higher immunopositivity for B₁R, when compared to a lower B₂R immunolabeling. Taken together, our results show that blocking simultaneously both kinin receptors or alternatively stimulating B₁R may be of therapeutic value in the treatment of brain glioblastoma growth and malignancy.