Downregulation of laminin α4 chain expression inhibits glioma invasionin vitro andin vivo

Abstract

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.

Gadd45a inhibits cell migration and invasion by altering the global RNA expression

“…Laminin-4 (LAMA4) has been reported to be highly upregulated in hepatocellular carcinoma and the downregulation of LAMA4 could inhibit glioma invasion. 22,23 Interestingly, in our study, we found LAMA4 was overexpressed in Gadd45a -/-MEF cells. As another important component of BM, collagens also play curial roles in tumorigenesis.…”

Downregulation of SPARC expression inhibits cell migration and invasion in malignant gliomas

“…The brain slice model enabled us to evaluate the invasion of glioma cells into the surrounding brain tissue in conditions analogous to those of normal brain in situ. We implanted a rhodamine-labeled spheroid of each glioma cell onto the corpus callosum of the cerebral hemisphere (22). Glioma cells transfected with control siRNA or without siRNA actively migrated and infiltrated into the brain tissue around tumor spheroids, whereas glioma cells treated with SPARC siRNA showed decreased migration into the surrounding normal brain tissue (Fig.…”

Alpha4 chain laminins are widely expressed in renal cell carcinomas and have a de-adhesive function

“…[27][28][29][30] Furthermore, Lm a4 chain is characteristic of invasive gliomas, and inhibition of Lm a4 chain by antisense RNA seems to prevent tumor invasion and angiogenesis. 32,35,36 A similar characteristic has as also been described for SPARC. 69 In summary, the results of present study show that a4 chain Lms are widely expressed in oncocytomas and RCCs.…”

“…[27][28][29][30] Overexpression of Lm a4 chain, on the other hand, has been suggested to promote angiogenesis, 31,32 and to correlate with malignancy and invasive capacity in human gliomas. [33][34][35][36] Tissue-specific inhibition of Lm a4 chain expression with antisense oligonucleotides has been suggested to be a potential new treatment for gliomas and tumor angiogenesis. 32,37 The role of a4 chain Lms in carcinomas has remained largely unresolved.…”