Genetic Hijacking May Lead to New Tests for Brain Cancer

by Aalok Mehta

February 24, 2009

An unusual form of cell hijacking may offer doctors ways to improve blood tests and treatments for one of the deadliest brain cancers.

Scientists have discovered that glioblastoma tumors release microvesicles—tiny membrane-covered sacs containing proteins and forms of ribonucleic acid (RNA)—that help the cancer spread by co-opting the molecular machinery of nearby cells.

Enough of these microvesicles, also known as exosomes, cross the blood-brain barrier to show up on blood tests, researchers report in the December issue of the journal Nature Cell Biology.

Scientists knew that some cancers send off and fuse with microvesicles that contain growth-assisting proteins, though many of the details remain hazy. The new study is the first to characterize the genetic contents of a cancer exosome.

“These microvesicles are filled with messenger RNAs (mRNAs) and micro RNAs, and they’re an indicator of what’s going on genetically inside a cell,” says study senior author Xandra Breakefield, a professor of neurology at Massachusetts General Hospital and Harvard Medical School. “We think normal cells use this for cell communication. But tumor cells use this with a vengeance—probably for taking over their environment.”

The glioblastoma exosomes contained mutated RNAs associated with the growth of new blood vessels, immune suppression and other processes that contribute to cancer cell survival, Breakefield says. In lab tests with healthy cells, these RNAs were transcribed into proteins, suggesting that the cancer cells are coercing assistance directly from their neighbors.

Genetic profiling

To assess potential diagnostic tools, the scientists tested the blood of 25 people with glioblastoma and found evidence of exosomes in many of the samples. The researchers also were able to do detailed genetic workups; for example, in several instances the team found a mutation in the epidermal growth factor receptor (EGFR) that characterizes one common subtype of glioblastoma.

“This is the first study where we enabled mutational profiles in serum from tumors,” says study lead author Johan Skog, a neurology instructor at Harvard Medical School. “Before we had to do a biopsy; now we can do this in blood.”

The blood tests may even be more precise. In two cases, the researchers found EGFR mutations not detected during a biopsy. The authors suggest that many such abnormalities could be missed during sampling because tumors are heterogeneous mixes of different populations of cells; the tiny sample sites might not contain each type of cell.

Since some mutations are linked with vulnerabilities to certain kinds of drugs, better genetic profiles could allow doctors to choose more effective cancer treatment plans. Regular blood testing could also allow scientists to see how cancer cells are responding to therapy, which might prompt refinements in treatment, Breakefield says.

The tests may also be useful in detecting relapse: Many cancer cells return with similar genetic profiles, often months before they can be seen via brain scanning.

“We desperately need ways to tell if a tumor is coming back or not,” Breakefield says.

The team is now planning to study whether exosomes are involved in other types of solid tumors.

Better than the alternatives?

Other scientists are cautiously hopeful about the new techniques, noting that exosomes remain a poorly understood form of cell communication.

“The paper is potentially important because it illuminates a rather underappreciated—but not previously unknown—mechanism by which tumor cells can communicate with each other and with their microenvironment,” says Sean Lawler, a neurosurgery professor and brain tumor researcher at Ohio State University.

“If it is possible to enrich tumor-specific mRNAs, then this would be an important breakthrough, particularly for brain tumors, in which it is difficult to monitor treatment response or recurrence.”

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