Gene has Jekyll and Hyde role in brain cancer
Researchers have discovered a gene that may play a key role in a form of brain cancer that is nearly always fatal.
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BOSTON, Mass.—Researchers have discovered a gene that may play a key role in a form of brain cancer that is nearly always fatal.
The brain cancer glioblastoma is relatively uncommon. It tends to strike people in the prime of their lives, and the limited treatment options have changed little over decades.
As a result, many researchers are driven to find new ways to treat a poorly understood form of cancer.
One approach focuses on a gene called STAT3. In several tumors, STAT3 takes the role of an oncogene, that is, a gene whose normal functions are derailed and, as a result, becomes a driving force in a tumor's development. Clearly then, blocking STAT3 would deal a major blow to such tumors.
In a new study led by a team at Harvard Medical School, however, it has been determined STAT3 isn't always the villain. While it does behave as an oncogene in certain types of glioblastoma, in others it becomes what's called a "tumor suppressor gene," a type of gene often responsible for keeping the renegade cancer cells in check.
That means the same gene in the same cancer can play a completely different role from one person to the next, depending on genetic nuances between individuals. The results appear online Feb. 6 in Genes and Development.
"This discovery lays the foundation for a more tailored therapeutic intervention," says Azad Bonni, an associate professor of pathology at Harvard Medical School, and senior author on this study. "And that's really important. You can't just go blindly treating people by inhibiting STAT3."
A neurologist and neuroscientist by training, Bonni decided to investigate the genetic etiology of glioblastoma by studying whether certain regulatory genes that control the generation of astrocytes during normal development also play a role in these tumors.
Taking advantage of previously published data, the researchers looked closely at how two genes, EGFR and PTEN—whose mutated forms are associated with glioblastoma—affect the function of STAT3 in astrocytes. Bonni's group found when EGFR is mutated, STAT3 is an oncogene; with a PTEN mutation, STAT3 is a tumor suppressor.
"EGFR, in its normal state, is a transmembrane receptor, usually performing its functions at the cell surface," says Bonni. "However, when it's mutated, we find it in the cell's nucleus interacting with STAT3—and turning it into an oncogene. STAT3 itself is not mutated or damaged. It's the process of regulating STAT3 that gets damaged."
With PTEN, it's a completely different story. PTEN is itself a tumor suppressor gene. When PTEN becomes disabled in astrocytes, these potential tumors still have STAT3 standing in their way. This is because STAT3 acts as a tumor suppressor normally in astrocytes. However, as more PTEN becomes disabled, a cascade of molecular events is set in motion with the express purpose of inhibiting STAT3 function and thus turning the tide in the cells toward tumor formation.
The researchers confirmed these findings in human glioblastoma tumors as well.
In addition, the findings contribute to the growing body of evidence for "personalized medicine," showing that many types of cancers contain subgroups that require different treatments.
