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[Cancer Research 61, 5601-5610, July 15, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

Overexpression of {alpha}4 Chain-containing Laminins in Human Glial Tumors Identified by Gene Microarray Analysis1

Julia Y. Ljubimova2, Alexander J. Lakhter, Anna Loksh, William H. Yong, Mary S. Riedinger, Jeffrey H. Miner, Lydia M. Sorokin, Alexander V. Ljubimov and Keith L. Black

Maxine Dunitz Neurosurgical Institute [J. Y. L., A. J. L., A. L., M. S. R., K. L. B.], Department of Pathology [W. H. Y.], and Ophthalmology Research Laboratories [A. V. L.], Cedars-Sinai Medical Center, Los Angeles, California 90048; Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110 [J. H. M.]; and Interdisciplinary Center for Clinical Research, University of Erlangen-Nuremberg, Erlangen 91054, Germany [L. M. S.]

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 {alpha}4 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 {alpha}4 chain in GBM and astrocytoma grade II by gene microarray analysis was confirmed by semiquantitive reverse transcription-PCR and immunohistochemistry. Importantly, an {alpha}4 chain-containing laminin isoform, laminin-8 ({alpha}4ß1{gamma}1), was expressed mainly in blood vessel walls of GBMs and histologically normal tissues adjacent to GBMs, whereas another {alpha}4 chain-containing laminin isoform, laminin-9 ({alpha}4ß2{gamma}1), 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 {alpha}4 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.




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Copyright © 2001 by the American Association for Cancer Research.