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 A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

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: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>