Bradykinin Promotes the Chemotactic Invasion of Primary Brain Tumors

Abstract

Primary brain tumors, gliomas, diffusely invade the brain by active cell migration either intra-parenchymal, along white matter tracts or along blood vessels. The close relationship of glioma with the vasculature assures a continuous supply of oxygen and nutrients essential for cell growth, and exposes cells to a variety growth factors, chemokines, cytokines and kinins. Signals that attract glioma cells to blood vessels are poorly understood. It has been shown that vascular endothelial cells can initiate the bradykinin (BK) signaling cascade and two bradykinin receptors, B1 and B2 have been identified and cloned. In this study we show that glioma cells isolated from patient biopsies express bradykinin 2 receptors (B2R) whose activation causes intracellular Ca2+-oscillations. Through time-lapse video-microscopy experiments we show that BK significantly enhances glioma cell migration/invasion. We further show that BK acts as a chemo-attractant guiding glioma cells toward blood vessels in acute rat brain slices. The number of cells associated with blood vessels is decreased when B2R are either pharmacologically inhibited or B2R eliminated through shRNA knockdown. These data strongly suggest that bradykinin, acting via B2R, acts as an important signal directing the invasion of glioma cells toward blood vessels. A clinically approved B2R antagonist is available that could be used as anti-invasive drug in glioma patients in the future.

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…By the same token, increased levels of kinin receptor expression would not support previously observed inhibition of invasion of GBM cells in indirect interactions with MSC (9). With respect to the underlying mechanism, Montana and Sontheimer (16) showed that bradykinin via B2R-induced [Ca 21 ] i transients enhanced and directed invasion of glioma cells toward blood vessels. Moreover, Seifert and Sontheimer (15) recently revealed that bradykinin through [Ca 21 ] i transients in GBM cells in vitro induced the formation of small bleb-like protrusions at the plasma membrane, which stimulated an amoeboid phenotype of cell migration.…”

“…In vivo studies on kinin B1 (B1R) and B2 receptors (B2R) revealed that B2R was increasingly expressed with augmenting malignancy of glioma (16) and GBM cells (26). Reportedly, B1R was not relevant for GBM cell invasion (15); however, B1R expression upregulation in GBM cells was confirmed by Lu et al (27).…”

“…At the same time, recent studies demonstrate the influence of kinin B1 (B1R) and B2 receptors (B2R) on proliferation, chemotaxis, and tumor invasion (11), such as in melanoma (12), bladder cancer (13,14), and glioblastoma (15,16 (17) recently reported that the human GBM cell line U373 produced and bound kininogens, synthesized kallikreins, as well as carboxypeptidases M and E, resulting in the production of B1R and B2-activating kinins, affecting cell invasion. Therefore, considering the effects of GBM-MSC interaction and of kinin receptor activation on proliferation, chemotaxis, and tumor invasion of glioma cells, here we investigate whether direct and indirect co-cultures of bone marrow derived MSC with malignant GBM cells U87-MG would affect B1R and B2R expression, as well as consider possible inductions of protease mediated increase in GBM progression and invasion.…”

Molecular Mechanisms of Glioma Cell Motility

“…Furthermore, glioma cells overexpress components of the basal membrane of the cerebral vasculature, for example, tenascin (TN)-C, which is associated with glioma progression (15). Glioma cells are recruited to the perivascular space around blood vessels by chemoattractants like bradykinin, which is produced by endothelial cells (16). Also, overexpression of chemokine receptors on glioma cells has been associated with perivascular invasion (17).…”

“…It is a critical attractor of glioma cells toward the vasculature, and an activator of ion channels (127,129). Binding of bradykinin to B 2 R leads to increases in intracellular Ca 2 + which induces the opening of the KCa3.1 and ClC-3 channels, resulting in the efflux of Cl − , K + , and water (16,127,130). As a result, the glioma cells shrink which enable them to migrate through the narrow space of the brain.…”