Overexpression of alpha 4 chain-containing laminins in human glial tumors identified by gene microarray analysis

Differential gene expression in tumors often involves growth factors and ex tracellular matrix/basement membrane components, Here, 11,000-gene microarr ay was used to identify gene expression profiles in brain tumors including high-grade gliomas [glioblastoma multiforme (GBM) and anaplastic astrocytom a], low-grade astrocytomas, or benign extraaxial brain tumors (meningioma) in comparison with normal brain tissue. Histologically normal tissues adjac ent to GBMs were also studied. All GBMs studied overexpressed 14 known gene s compared with normal human brain tissue. Overexpressed genes belonged to two broad groups: (a) growth factor-related genes; and (b) structural/extra cellular matrix-related genes. For most of these 14 genes, expression level s were lower in low-grade astrocytoma than in GEM and were barely detectabl e in normal brain, Despite normal-appearing histology, gene expression patt erns of tissues immediately adjacent to GEM were similar to those of their respective primary GBMs, Two genes were consistently up-regulated in both h igh-grade and low-grade gliomas, as well as in histologically normal tissue s adjacent to GBMs, These genes coded for the epidermal growth factor recep tor (previously reported to be overexpressed in gliomas) and for the alpha4 chain of laminin, a major blood vessel basement membrane component, Change s in expression of this laminin chain have not been previously associated w ith malignant tumors. Overexpression of laminin alpha4 chain in GBM and ast rocytoma grade II by gene microarray analysis was confirmed by semiquantiti ve reverse transcription-PCR and immunohistochemistry, Importantly, an alph a4 chain-containing laminin isoform, laminin-8 (alpha4 beta1 gamma1), was e xpressed mainly in blood vessel walls of GBMs and histologically normal tis sues adjacent to GBMs, whereas another a4 chain-containing laminin isoform, laminin-9 (alpha4 beta2 gamma1), was expressed mainly in blood vessel wall s of low-grade tumors and normal brain. GBMs that overexpressed laminin-8 h ad a shorter mean time to tumor recurrence (4.3 months) than GBMs with over expression of laminin-9 (9.7 months, P = 0.0007). Up-regulation of alpha4 c hain-containing laminins could be important for the development of glioma-i nduced neovascularization and glial tumor progression. Overexpression of la minin-8 may be predictive of glioma recurrence.