Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

21.10.2003


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
Further information:
http://www.csmc.edu/

More articles from Health and Medicine:

nachricht Microgel powder fights infection and helps wounds heal
14.11.2018 | Michigan Technological University

nachricht Spread of deadly eye cancer halted in cells and animals
13.11.2018 | Johns Hopkins Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Massive impact crater from a kilometer-wide iron meteorite discovered in Greenland

15.11.2018 | Earth Sciences

When electric fields make spins swirl

15.11.2018 | Physics and Astronomy

Discovery of a cool super-Earth

15.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>