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In lab studies, blocking expression of gene reduces invasion of deadly brain tumor cells


In July 2001, scientists at Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute published their findings that one "isoform" or variant of a specific gene was significantly upregulated in high-grade, malignant brain tumors called glioblastoma multiforme (GBM). They theorized that this increased activity might be a critical step in the development, progression and spread of these highly aggressive tumors.

Now, in laboratory experiments designed to mimic the environment of a brain tumor and its abnormal influence on surrounding normal blood vessel cells, the researchers have found that by blocking the expression of this gene, laminin-8, they were able to reduce the tumor’s ability to invade neighboring tissue. The new study supports the hypothesis that laminin-8 is involved in the spread of these malignancies, and it reinforces the possibility that a therapy may be developed to arrest the tumors by targeting the gene.

In the original study, published in Cancer Research, the scientists used "gene array" technology to rapidly and efficiently analyze the expression of 11,004 genes in samples of low-grade tumors; high-grade tumors; brain tissue that had been located in close proximity to high-grade tumors; and unrelated normal brain tissue.

Two genes were consistently up-regulated in all high-grade and low-grade gliomas and in tissues adjacent to GBMs, the most aggressive gliomas. One of the genes was already known to be over-expressed in gliomas. The other was the alpha-4 chain of laminin, a gene that influences the thin "basement membrane" that lies beneath the surface layer of blood vessels.

One of the alpha-4 chain-containing laminin isoforms, laminin-9, was expressed mainly in the blood vessel walls of low-grade tumors and normal brain. Laminin-8 was expressed primarily in the vessel walls of the high-grade GBMs and the tissue adjacent to these types of tumors. There were some exceptions. In those cases, it was noted that an overexpression of laminin-8 correlated with a shorter time to tumor recurrence than when there was an overexpression of laminin-9. Overexpression of laminin-8 was, therefore, identified as a predictor of glioma recurrence and a potential target of intervention strategies.

These observations were reinforced by the new study, which used short strands of genetic code (Morpholino™ antisense oligonucleotides) to block the messenger RNA (mRNA) carrying the gene’s "instructions." As a result, the gene’s "protein product," laminin-8, was not produced and the invasiveness of glioma cells was significantly reduced.

Although antisense intervention was introduced more than two decades ago, new technology has overcome many earlier limitations. Unlike its predecessors, for example, Morpholino is stable in plasma.

New-generation antisense oligos are being used in studies to find effective medications and treatments for many disorders, including viruses and cancers. By blocking a gene’s effects in a laboratory setting, they enable scientists to study the gene, its control, and the interactions between gene products.

"Antisense technology is being refined not only for drug validation and diagnostic purposes but also for the development of future treatments for patients. It may become an effective tumor therapy because it offers efficiency, specificity and ease of delivery to tumor cells," said Keith L. Black, M.D., director of Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute. Dr. Black directs the medical center’s Division of Neurosurgery and the Comprehensive Brain Tumor Program and holds the Ruth and Lawrence Harvey Chair in Neuroscience.

According to Julia Y. Ljubimova, M.D., Ph.D., research scientist at the Institute, the researchers decided not to conduct the experiments using glioma cells alone because laminin-8 appears to be produced both by glioma cells and by endothelial cells. By co-culturing glioma cells and brain endothelium, they were better able to mimic the situation as it would exist in actual patient tissue. Although scientists cannot say with certainty how laminin-8 promotes the spread of gliomas, this and previous studies suggest that it reduces cell adhesion and enhances cell migration – both in glioma cells and in adjacent vascular cells – circumstances that are necessary for local tumor invasiveness.

"Antisense oligos to laminin-8 chains significantly inhibited invasion of two different glioma cell lines in vitro," said Dr. Ljubimova. "If these laboratory studies can be translated into patient therapy, antisense oligos may slow the growth and spread of aggressive gliomas. Perhaps it will be used in combination with more traditional therapies or with other genetic targeting to prolong disease-free periods and increase survival."

The study was supported by a grant from the Maxine Dunitz Neurosurgical Institute. It was conducted by scientists from the Institute, the Ophthalmology Research Laboratories at Cedars-Sinai, Osaka (Japan) University Medical Center, the Interdisciplinary Center for Clinical Research at the University of Erlangen-Nuremberg (Germany), and the Institute of Biomedicine/Anatomy at the University of Helsinki (Finland).

Cedars-Sinai is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, it has been named Southern California’s gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthroughs in biomedical research and superlative medical education. It ranks among the top 10 non-university hospitals in the nation for its research activities.

Sandra Van | Van Communications
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