Hit man: A suspect emerges in the chaos of aggressive brain cancer

New research from UAB oncologist Markus Bredel identifies the splicing enzyme PTBP1 as a key factor
in the spread of glioblastoma multiforme.  

Glioblastoma multiforme is one of the deadliest human cancers. "The tumor can double in size within a few weeks," says Markus Bredel, M.D., Ph.D., a professor in the UAB Department of Radiation Oncology and senior scientist in the neuro-oncology program at the UAB Comprehensive Cancer Center. "Usually, by the time we see a patient, they often have apple-size lesions."

That explosive growth "comes with a substantial amount of genetic chaos," Bredel says. "If you look at the whole genome in a brain tumor, out of the 30,000 genes, you very often have changes in up to 50 percent; they're up or down, lost, amplified, mutated."

A Change for the Worse

Markus Bredel

But in that chaos, patterns emerge with surprising regularity, Bredel says. "When Gene A is up, Gene B is very often down." In two papers published in JAMA in 2009, Bredel's research team argued that "there needs to be a reason why glioblastomas co-select for certain genetic events. The tumor cells must benefit."

In those papers, Bredel's lab identified dozens of gene-gene links that were candidates for additional scrutiny. They focused on one particular pair: The oncogene EGFR, or epidermal growth factor receptor, which is crucial for normal cell growth and wound healing, and the tumor-suppressor ANXA7 or annexin A7. EGFR is of interest in many cancers, because it is often hijacked to fuel the aggressive growth of tumor cells.

"We found that ANXA7 is probably a regulator of EGFR," Bredel says. "So it's to the benefit of the tumor cell to knock down this regulator." But it wasn't clear at the time how this was happening. "ANXA7 resides on a different chromosome from EGFR, so it's a completely independent event, but somehow the tumor cells were disabling it," says Bredel.

Image post 8: mapping live brains

This image from UAB Research illustrates the improving brain maps that promise to reveal the mechanisms behind complex, neurological diseases.


























A MRI technology called diffusion tractography captured this image of a living rat brain. Tractography is a 3-D modeling technique that visually represents nerve pathways in the brain using data collected by diffusion tensor imaging (DTI).

DTI visualizes nerve pathways known collectively as white matter that connect the various parts of the brain via long bundles of nerve cells. It shows whether or not bundles of white matter fibers run in the same direction, but not in which direction. Tractography does that.

Since developed by researchers at Washington University School of Medicine in St. Louis, it has given the field a more detailed look at brain structures, especially living brains. Taken together, these new MRI technologies promise to improve understanding of neurological disorders like schizophrenia and Alzheimer's disease and the consequences of head trauma. They also may one day help neurosurgeons better avoid cutting nerves during surgeries.

In particular, tractography reveals connections that can be measured in living human subjects and measurements that can be made simultaneously across the entire brain. The Human Connectome Project is capitalizing on these strengths to build more accurate brain maps. The image was created in the lab of Hyunki Kim, Ph.D., associate professor in the departments of Radiology and Biomedical Engineering and faculty in the UAB Comprehensive Cancer Center.

Image post 6: spinal cord cell reaches for its neighbor

While many posts from The Mix feature a science story, we also share images coming out of UAB research. Below is a description of what we are looking at and related hints about how the brain forms in the womb. 

Pictured here is one star-shaped astrocyte "reaching out" to another in a dish. The most abundant cell type in the brain and spinal cord, astrocytes are not nerve cells, but instead provide support, nutrients and protection to nerve cells. Recent work has shown that astrocytes help to shape the messages being passed from nerve cell to nerve cell, and that problems with astrocyte function may throw off nerve cell performance.

In her research, Michelle Olsen, Ph.D., assistant professor in the UAB Department of Cell, Developmental and Integrative Biology, seeks to determine how the overlap between nerve cells and astrocytes contributes to normal brain development, and to brain abnormalities when something goes wrong.

Dr. Olsen's experiments with isolated cells seek to model processes underway in the brain as it forms during development. Nerve cells are known to put out "roots" that reach out, find nearby cells and link up to form signaling networks. The above picture suggests that astrocytes do something similar.

Named for their star shape, astrocytes put out extensions that wrap around synapses, the gaps between nerve cells in signaling pathways. Each nerve cell in a pathway sends an electric pulse down itself until it reaches a synapse, a gap between itself and the next cell in line. When it reaches the cell's end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Arriving at the other side, they cause the downstream nerve cell to “fire” and, depending on the synapse type, to either pass on or stop the message.

In this way, each synapse between nerve cells “decides” whether or not a message continues down that pathway. The balance of messages passed on (excitation) and messages halted (inhibition) is crucial to brain function. One theory has it that astrocytes influence that balance at synapses with their own set of extensions and transmitters.

Dr. Olson captured the image using an inverted Zeiss Observer microscope.