By Daniel Stolte, University Communications
An enzyme that normally establishes a sense of direction in developing brain cells might be a poorly understood cause of glioblastoma, the most common and devastating type of brain cancer.
The National Institutes of Health awarded $1.6 million to the University of Arizona to investigate ways to get the deranged signaling mechanism back on track and test whether the protein could serve as a candidate target for new cancer-fighting drugs.
The project is led by Sourav Ghosh, an assistant professor in the department of cell biology and anatomy at the UA's College of Medicine, in collaboration with Joseph C. Loftus at the Mayo Clinic in Scottsdale, Ariz.
"We discovered a connection between this signaling protein, called atypical Protein Kinase C, and the spread of glioblastoma," said Ghosh, who is also a member of the UA's BIO5 Institute and the Arizona Cancer Center. "We believe that by inhibiting the protein, we might be able to stop the cancer cells from invading the brain."
Of all brain cancers, glioblastoma is the most deadly: Nine out of 10 patients do not survive much longer than a year following the diagnosis. In its most malignant form, the tumor cells force their way deep into the nervous tissue of the brain, making it all but impossible to target and completely remove the cancer.
Cancers involving glia cells account for the most common primary tumor affecting the central nervous system. Approximately 17,000 new cases are reported each year and of these, 11,500 patients die.
The human brain consists of about 100 billion nerve cells, or neurons, and their supporting cells, the glia. In order to assemble into what scientists have called the most complex structure in our solar system, the brain cells must embark on extensive migrations. Glia cells (Greek for "glue") offer mechanical support to neurons, give them directional clues and thus help organize the structure of the brain.
To build an organ as complex as the brain, each cell must have what cell biologists call polarity: a sense of direction in which to move and how it is positioned with respect to neighboring cells in a tissue.
"In most cases, a cell is not just a ball," Ghosh said. "Many cells are polarized, meaning they have a ‘front end' and a ‘back end.'"
This is where the enzyme Atypical Protein Kinase C, or aPKC for short, comes in. Ghosh and his co-workers have identified a signaling pathway in which the protein plays an important role directing where neural stem cells are located within the developing brain.
"During brain development, there is a lot of cell migration," Ghosh said. "aPKC tells those cells which is the front end and which is the back. The protein also tells them which way to go."
When Ghosh altered the function of aPKC in chicken embryos, he found characteristics reminiscent of tumors: abnormal proliferation of less differentiated cells that were reluctant to stay put. Instead, they invaded places they shouldn't go: mature brain tissue.
The same appears to be true for humans: "We studied samples of brain tissue from glioblastoma patients and found that levels of this protein are too high," Ghosh said. "In cancer, a lot of these developmental pathways are altered and misexpressed, improperly activated or not regulated correctly."
"About 90 percent of glioblastoma patients show enhanced activity in a cancer-promoting signaling pathway," he said. "We see that our kinase is a part of this cancer-causing cascade and regulates the ability of cells to migrate and to invade."
"We have reason to believe that ultimately glioblastoma goes back to stem cells in the brain losing their polarity, their sense of direction," Ghosh said. "With this grant, we are going to further study this kinase protein. We hope to come up with targets for potential new drugs that could prevent the brain tumor from growing and spreading."
Although glioblastomas do not metastasize, the kinase has also been implicated in lung cancer and ovarian cancer, where it might function in metastasis.
The team hopes to identify aPKC as drug target and add it to existing cancer treatments and to prevent relapse.
"Kinases make excellent pharmacological targets because they are easy to block," said Ghosh. "Our rationale is that if we inhibit aPKC, we could stop the invasion of those glioma cells that were missed in the surgery."