Malignant gliomas are characterized by active invasiveness, necrosis, and vascular proliferation. These pathological features have been speculated to be caused by tissue hypoxia. Hypoxia-inducible factor-1 (HIF-1), which is controlled by rapid stabilization of the HIF-1• subunit, is a pivotal transcriptional factor in the cellular response to hypoxia. Although many studies have described the relationship between tumor angiogenesis and hypoxic environment, the roles of HIF-1 in cell invasion have been barely elucidated in malignant gliomas. We investigated the role of HIF-1• in the motile and invasive activities of human glioma cells under hypoxia. Four malignant glioma cell lines, U87MG, U251MG, U373MG, and LN18, were cultured under 21 and 1% oxygen concentration. Expression of HIF-1• under hypoxia was observed to be much higher than that under normoxia in all cell lines. Introducing HIF-1•-targeted small interfering RNA (HIF-1• siRNA) into the glioma cell lines resulted in downregulation of HIF-1• expression, and significantly suppressed glioma cell migration in vitro. Furthermore, invasiveness was significantly reduced in the cells transfected with HIF-1• siRNA compared with those transfected with the control siRNA. Co-culture of glioma spheroids and rat brain slices showed that HIF-1• siRNAtransfected glioma cells failed to invade the surrounding normal brain tissue in an organotypic brain slice model. These effects of HIF-1• siRNA were more conspicuous under hypoxia than under normoxia. In addition, under hypoxic conditions, the level of matrix metalloproteinase (MMP)-2 mRNA was upregulated, and that of tissue inhibitor of metalloproteinase (TIMP)-2 was downregulated in all glioma cell lines. Treatment with HIF-1• siRNA resulted in downregulation of MMP-2 mRNA and upregulation of TIMP-2 mRNA. Furthermore, the enzyme activities of MMP-2 and MMP-9, both of which were activated by hypoxia, decreased with the introduction of HIF-1• siRNA. These findings suggest that overexpression of HIF-1• induced by hypoxic stress is an essential event in the activation of glioma cell motility through alteration of invasion-related molecules. Targeting the HIF-1• molecule may be a novel therapeutic strategy for malignant gliomas.
Image-guided neurosurgery using navigation systems is an essential tool to increase accuracy in brain tumor surgery. However, brain shift during surgery has remained problematic. The present study evaluated the utility of a new ultrasound (US)-linked navigation system for brain tumor surgery in 64 patients with intracranial tumors. The navigation system consisted of a StealthStation TM navigation system, a SonoNav TM system, and a standard US scanner. This system determines the orientation of the US images and reformats the images from preoperative computed tomography (CT) or magnetic resonance (MR) imaging to match the US images. The system was used intraoperatively to measure brain shift several times, using the results to guide tumor resection. US-linked navigation provided information regarding brain shift, and extent of tumor resection during surgery. Evaluation of brain shift was easily achieved in all patients, without using intraoperative CT or MR imaging. Accurate information regarding the true anatomical configuration of the patient could be obtained in all phases of the operation. Magnitude of brain shift increased progressively from pre-to post-resection and depended on the type of cranial structure. Integration of the US scanner with the navigation system allowed comparisons between the intraoperative US and preoperative images, thus improving interpretation of US images. The system also improved the rate of tumor resection by facilitating the detection of remnant tumor tissue. This US-linked navigation system provides information on brain shift, and improves the accuracy and utility of image-guided surgery.
The laminin family is a structural constituent of the extracellular matrix that plays an essential role in promoting the motility of infiltrative tumor cells. We investigated the role of laminin a4 chain, a subset of laminin-8, -9 and -14, in the motile and invasive activities of human glioma cells. All malignant glioma cell lines examined expressed more mRNA for the laminin a4 and b1 chains than for the b2 chain, indicating that these cells predominantly express the laminin-8 isoform. Introducing an antisense oligonucleotide for laminin a4 chain (AS-Ln-a4) into the glioma cells resulted in downregulation of laminin a4 expression. AS-Ln-a4 also significantly suppressed glioma cell adhesion and migration. Furthermore, invasiveness was significantly reduced in cells transfected with AS-Ln-a4 compared to those transfected with the sense oligonucleotide (S-Ln-a4). Indeed, when glioma spheroids were implanted into rat brain slices, AS-Ln-a4-transfected cells failed to invade surrounding normal brain tissues. In addition, intracerebral injection of glioma cells transfected with AS-Ln-a4 into nude mice resulted in the formation of a noninvasive tumor, whereas injection of cells transfected with S-Ln-a4 resulted in diffuse invasion of brain tissue. These results suggest that mainly laminin-8 is essential for the invasive activity of human glioma cells; thus, a novel therapeutic strategy could target this molecule to treat patients with malignant glioma. ' 2005 Wiley-Liss, Inc.
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