Differential gene expression in
tumors often involves
growth factors and extracellular matrix/basement membrane components. Here, 11,000- gene microarray was used to identify gene expression profiles in
brain tumors including high-grade
gliomas [
glioblastoma multiforme (GBM) and
anaplastic astrocytoma], low-grade
astrocytomas, or benign extra-axial
brain tumors (
meningioma) in comparison with normal brain tissue. Histologically normal tissues adjacent to GBMs were also studied. All GBMs studied overexpressed 14 known genes compared with normal human brain tissue. Overexpressed genes belonged to two broad groups: (a)
growth factor-related genes; and (b) structural/extracellular matrix-related genes. For most of these 14 genes, expression levels were lower in low-grade
astrocytoma than in GBM and were barely detectable in normal brain. Despite normal-appearing histology, gene expression patterns of tissues immediately adjacent to GBM were similar to those of their respective primary GBMs. Two genes were consistently up-regulated in both high-grade and low-grade
gliomas, as well as in histologically normal tissues adjacent to GBMs. These genes coded for the
epidermal growth factor receptor (previously reported to be overexpressed in
gliomas) and for the alpha4 chain of
laminin, a major blood vessel basement membrane component. Changes in expression of this
laminin chain have not been previously associated with malignant
tumors. Overexpression of
laminin alpha4 chain in GBM and
astrocytoma grade II by gene microarray analysis was confirmed by semiquantitive reverse transcription-PCR and immunohistochemistry. Importantly, an alpha4 chain-containing
laminin isoform,
laminin-8 (alpha4beta1gamma1), was expressed mainly in blood vessel walls of GBMs and histologically normal tissues adjacent to GBMs, whereas another alpha4 chain-containing
laminin isoform,
laminin-9 (alpha4beta2gamma1), was expressed mainly in blood vessel walls of low-grade
tumors and normal brain. GBMs that overexpressed
laminin-8 had a shorter mean time to
tumor recurrence (4.3 months) than GBMs with overexpression of
laminin-9 (9.7 months, P = 0.0007). Up-regulation of alpha4 chain-containing laminins could be important for the development of
glioma-induced neovascularization and glial
tumor progression. Overexpression of
laminin-8 may be predictive of
glioma recurrence.