Conversion of brain tumor cells into blood vessels thwarts treatment efforts

Jan 24, 2011
Glioblastoma tumor cells (shown in green) can transform into endothelial cells (shown in red), which line the interior surface of a tumor vessel. Credit: Courtesy of Dr. Yasushi Soda, Salk Institute for Biological Studies

Glioblastoma, the most common and lethal form of brain cancer and the disease that killed Massachusetts Senator Ted Kennedy, resists nearly all treatment efforts, even when attacked simultaneously on several fronts. One explanation can be found in the tumor cells' unexpected flexibility, discovered researchers at the Salk Institute for Biological Studies.

When faced with a life-threatening oxygen shortage, glioblastoma cells can shift gears and morph into blood vessels to ensure the continued supply of nutrients, reports a team led by Inder Verma, Ph.D., in a feature article in this week's issue of the .

Their study not only explains why cancer treatments that target angiogenesis--the growth of a network of blood vessels that supplies nutrients and oxygen to cancerous tissues--routinely fail in glioblastoma, but the findings may also spur the development of drugs aimed at novel targets.

"This surprising effect of anti-angiogenic therapy with drugs such as Avastin tells us that we have to rethink glioblastoma combination therapy," says senior author Verma, a professor in the Laboratory of Genetics and holder of the Irwin and Joan Jacobs Chair in Exemplary Life Science. "Disrupting the formation of tumor blood vessels is not enough; we also have to prevent the conversion of tumor cells into blood vessels cells."

To grow beyond one to two millimeters in diameter--roughly the size of a pinhead--tumors need their own independent blood supply. To recruit new vasculature from existing blood vessels, many tumors overexpress growth factors, predominantly vascular endothelial growth factor, or VEGF. This led to the development of Avastin, a monoclonal antibody that intercepts VEGF.

"In a recent phase II clinical trial, 60 percent of patients with glioblastoma responded to a combination of Avastin and , which directly interferes with the growth of ," explains Verma, "but in most patients this effect was only transient." In fact, studies have shown that tumor cells often become more aggressive after anti-angiogenic therapy, but the reason had been unclear.

To find out, postdoctoral researcher and first author Yasushi Soda, Ph.D., took advantage of a mouse model of glioblastoma that recapitulates the development and progression of human brain tumors that arise naturally. "The tumors in these mice closely resemble glioblastomas, including the typically messy and highly permeable tumor vessels, which allowed us to study the tumor vasculature in great detail," he explains.

The glioblastoma mice, the concept for which was developed in the Verma laboratory, grow brain tumors within a few months of being injected with viruses that carry activated oncogenes and a marker gene that causes all tumor-derived cells to glow green under ultraviolet light. By simply tracking the green glow under the microscope, the Salk researchers can then follow the fate of tumor cells.

When Soda peered at the tumor cells, he found--much to his surprise--that about 30 percent of vascular endothelial cells--specialized cells that line the interior surface of blood vessels--appeared green. "This indicated to us that they most likely originated from tumor cells," he says.

Further experiments revealed that TDECs, short for tumor-derived endothelial cells, are not specific to mouse tumors but can also be found in clinical samples taken from human glioblastoma patients. "This was really strong evidence for us that glioblastoma cells routinely transdifferentiate into endothelial cells," he explains.

The transformation is triggered by hypoxia, or low oxygen levels, which signals tumor cells that the time has come to start their shape-shifting stunt. But unlike regular vascular endothelial cells, TDECs don't require VEGF to form functional blood vessels. "This might explain why, despite being initially successful, anti-angiogenic therapy ultimately fails in glioblastomas," says Verma.

interrupts normal blood vessels, but eventually they are replaced with tumor-derived vessels, which are now treatment-resistant. "Once again, we are confronted with the versatility of , which allows them to survive and thrive under adverse conditions," says Verma. "But as we learn more about tumors' molecular flexibility, we will be able to design novel, tailor-made combination therapies to combat deadly brain tumors."

Explore further: Is genetic instability the key to beating cancer?

Related Stories

Precancerous stem cells can form tumor blood vessels

Feb 20, 2008

Tumors require a blood supply to grow, but how they acquire their network of blood vessels is poorly understood. A new study here shows that tumor blood vessels can develop from precancerous stem cells, a recently discovered ...

'Normalizing' tumor vessels leaves cancer more benign

Feb 12, 2009

A report publishing online on February 12th in the journal Cell, a Cell Press publication, suggests a counterintuitive new method to make cancer less likely to spread: by normalizing the shape of tumors' blood vessels to ...

Combinatorial therapy allows viruses to destroy tumors

Apr 01, 2010

For several years, researchers have been developing a new approach to treating cancer that uses viruses to infect and kill cancer cells while leaving normal cells unharmed. Recent data have indicated that this approach, which ...

Recommended for you

New breast cancer imaging method promising

5 hours ago

The new PAMmography method for imaging breast cancer developed by the University of Twente's MIRA research institute and the Medisch Spectrum Twente hospital appears to be a promising new method that could ...

Palliation is rarely a topic in studies on advanced cancer

5 hours ago

End-of-life aspects, the corresponding terminology, and the relevance of palliation in advanced cancer are often not considered in publications on randomized controlled trials (RCTs). This is the result of an analysis by ...

Breast cancer replicates brain development process

5 hours ago

New research led by a scientist at the University of York reveals that a process that forms a key element in the development of the nervous system may also play a pivotal role in the spread of breast cancer.

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

XQZME
1 / 5 (1) Feb 03, 2011
This is 80 year old news, but the scientists need to keep repeating the same experiments to stay employed. The secret is to restrict sugar and increase oxygen to cells. COQ10 and omega 3 increase O2. Garlic and Cayenne increase circulation to cells. Resveratrol penetrates and repairs cells and stimpulates apoptosis. Other supplements to stimulate apoptosis include Cayenne, COQ10, Curcumin, Limonene, Quercetin, Rosemary. Anti-inflamatories are essential - Bromelain, Cucumin, Gingko Biloba, Resveratrol, Lycopene, Ginger Root, Hawthron Berry. Good foods include orange, grape, cranberry, and apple juices, potatoes, tomatoes, onions, garlic, ginger. Avoid red meat and fluoridated water.

More news stories

Autism Genome Project delivers genetic discovery

A new study from investigators with the Autism Genome Project, the world's largest research project on identifying genes associated with risk for autism, has found that the comprehensive use of copy number variant (CNV) genetic ...

Team reprograms blood cells into blood stem cells in mice

Researchers at Boston Children's Hospital have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors. The reprogrammed ...

Study links California drought to global warming

While researchers have sometimes connected weather extremes to man-made global warming, usually it is not done in real time. Now a study is asserting a link between climate change and both the intensifying California drought ...