Using a technique called "gene array" that allows them to analyze thousands of genes in one experiment, scientists at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute have identified a new mechanism that may be a critical step in the development of a type of malignant brain tumor that has historically been virtually impervious to treatment.

As a result of this study, scientists are gaining a better understanding of the way these highly malignant tumors (glioblastoma multiforme or GBM) impact and spread to surrounding tissues, how they develop a network of blood vessels that feed their growth, and how lower-grade tumors become transformed into high-grade malignancies.

The discovery may improve the ability of physicians to predict tumor progression and more accurately determine patient prognosis. The researchers also anticipate the findings could lead to improved patient monitoring and the eventual development of effective therapies against these devastating brain tumors. Results of the study are published in the July 15 issue of Cancer Research.

Researchers analyzed the expression of 11,004 genes. They compared the results from 27 tissue samples, including: 15 primary gliomas and adjacent tissues from five of the same patients; three benign brain tumors; three normal brain tissues from trauma patients; and one normal corpus callosum that consisted primarily of normal astrocyte cells. Astrocytes have the potential to be transformed to the tumor.

Among the results, gene-expression patterns of samples taken from tissues adjacent to GBMs -- which looked normal on the cellular (morphological) level -- actually resembled the molecular patterns of the tumors themselves. Also, only two genes were consistently upregulated in all glial tumors and GBM-adjacent tissues. One of those genes was previously known to be over-expressed in gliomas. The other was the a4 chain of laminin, a gene that influences the thin membrane beneath the surface layer of blood vessels.

The laminin a4 chain was over-expressed in glioblastoma multiforme and lower-grade gliomas (astrocytomas), compared to normal brain tissue.

Among the most significant findings, one "isoform" or type of a4 chain-containing laminin -- laminin-8 -- had an increased expression in the majority of GBM, compared to low-grade astrocytoma. Low-grade astrocytoma mainly expressed another isoform -- laminin-9. Theoretically, upregulation of laminin-8 may be a critical step in the development of glioma-induced neovascularization and the progression of low-grade astrocytoma to GBM. On the clinical material from human tumors it has been statistically significantly shown that the presence of laminin-8 was associated with poor prognosis in patients with glial tumors.

The researchers also detected over-expression of 14 out of 11,004 genes in each of five samples of glioblastoma multiforme. And they confirmed, in a single series of experiments, data that had been acquired little by little over a number of years regarding the over-expression of certain growth factors and structural proteins in gliomas.

For some types of tumors, the effects of certain genes can be specifically linked to tumor progression. But for brain gliomas and some other tumors, the known genomic, chromosomal and biochemical changes that occur are nonspecific, providing little help in diagnostics and in designing effective treatments. Therefore, success rates in treating glial tumors have remained unchanged over 20 years, and survival rates have been especially dismal for patients with glioblastoma multiforme, the most deadly type of glioma.

Recent studies have found over-expression of a variety of genes and proteins, and decreased expression of several others, in gliomas. Most studies seeking such glioma markers have been conducted using one gene or protein at a time, perhaps a few at most. In recent years, however, gene array technology has made it possible to directly analyze not only the role of single genes in cancer development but the interactions between multiple genes, according to Julia Y. Ljubimova, M.D., Ph.D, research scientist and the paper's first author.

"Multi-gene study is extremely difficult because in addition to individual genome alterations, another complication is presented by tumor progression that can alter gene expression patterns differently in each tumor," said Dr. Ljubimova.

Scientists attempting to map the human genome first devised gene array techniques, which were quickly adopted by pharmaceutical companies and other scientific interests. The Maxine Dunitz Neurosurgical Institute uses the technology specifically for its brain cancer research, and those efforts have resulted in the discovery of a number of genes implicated in the development of tumors.

A grant from the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai Medical Center supported the current study. In addition to Dr. Ljubimova, authors include Institute Director Keith L. Black, M.D., other Institute scientists, and researchers from the medical center's Department of Pathology and Cedars-Sinai's Ophthalmology Research Laboratories. Scientists from the Renal Division of Washington University School of Medicine in St. Louis, MO, and the Interdisciplinary Center for Clinical Research at the University of Erlangen-Nuremberg in Erlangen, Germany also contributed.

---Cedars-Sinai Medical Center

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