Skip to Content

Publications

Research: Major Highlights

Annual Report - 2005-2006

Missing in Action

Thousands of genes reside in every human cell, each one having a specific function. When one goes missing or gets deleted, it can disrupt the natural order of things and cause disease.

A discovery made by Shiaw-Yih Lin, Ph.D., and his team further supports this fact.

They identified a single gene, BRIT1, that plays a pivotal role in launching two DNA damage detection and repair pathways, suggesting that it functions as a previously unknown tumor suppressor gene. They also reported in the journal Cancer Cell that this gene, initially identified as a repressor of an enzyme responsible for cell division, is under-expressed or deleted in several cancers.

“Disruption of BRIT1 function abolishes DNA damage responses and leads to genomic instability, which fuels the initiation, growth and spread of cancer,” says senior study author Lin, assistant professor in the Department of Systems Biology.

A signaling network of molecular checkpoint pathways protects the human genome by detecting DNA damage, initiating repair and halting division of the damaged cell so that it doesn’t replicate.

In a series of experiments, Lin and his colleagues showed that BRIT1 activates two of these checkpoint pathways — ones that respond to damage caused either by ionizing or ultraviolet radiation.

They also discovered that when they inactivated this gene in normal human mammary epithelial cells, chromosomal abnormalities occurred in 21% to 25% of cells. No defects were seen in those cells expressing BRIT1. When these cells were exposed to ionizing radiation, 80% of them had chromosomal defects.

Lin and his team also found reduced expression of BRIT1 in 35 of 87 cases of advanced ovarian cancer, and in breast and prostate cancer tissue, compared with non-cancerous cells. Genetic analysis of breast cancer specimens, for example, revealed a truncated, dysfunctional version of the BRIT1 protein.

Loss of DNA damage checkpoint function and the ability to proliferate indefinitely are two cellular changes required for cancer development. Lin and his colleagues have tied BRIT1 to both factors and are now determining whether current therapies are effective in treating BRIT1-deficient tumors.

Turning on Oneself

If Seiji Kondo, M.D., Ph.D., had any say, tumors would see the error of their ways and self-destruct without provocation.

But as he knows, tumors act on their own volition and will do anything to survive. Simply willing them to die isn’t enough. So Kondo and his colleagues enlisted the help of an engineered virus that they hoped could do the job.

hTERT-Ad, they reported in the Journal of the National Cancer Institute, successfully located and forced malignant glioma cells in mice to devour themselves, a process called autophagy. The modified virus infected and induced autophagy by inactivating a molecular pathway known to prevent cellular self-consumption. This shutdown resulted in prolonged survival and a 20% reduction in tumor volume among mice receiving hTERT-Ad, compared to those getting a different, non-replicating virus.

These mice also lived longer, with those treated with three injections of hTERT-Ad surviving an average of 53 days versus 29 days for those in the control group.

“This virus uses telomerase, an enzyme found in 80% of brain tumors, as a target,” explains senior study author Kondo, associate professor in the Department of Neurosurgery. “Once the virus enters the cell, it needs telomerase to replicate. Normal brain tissue doesn’t have this enzyme, so this virus replicates and functions only in cancer cells.”

Other cancers also are telomerase-positive, and investigators showed that the virus kills both human prostate and cervical cancer cells while sparing normal tissue.

Analyses of dead cancer cells showed telltale signs of autophagy — bits of virus in the cell nucleus and cavities containing residual digested material — but no indication of having been killed by apoptosis, a much better known process of programmed cell death.

Apoptosis and autophagy should be viewed as type 1 and type 2 versions of programmed cell death, Kondo says. He adds that to improve therapeutics, it’s vital to identify molecules that regulate autophagy in cancer cells and to understand how this protective mechanism is associated with cell death, a relatively new field of cancer research.

An Unlikely Pair

Like two peas in a pod, a bacterial and animal virus combine to serve as a vehicle for targeted delivery of genes to tumors and their blood vessels.

In a study reported in the journal Cell, lead author and research scientist Amin Hajitou, Ph.D., says the creation of this new hybrid virus and its ability to find, highlight and transport genes to tumors is an important step forward in making cancer both more visible and accessible to treatment. It may also provide a way to predict and monitor the effects of anticancer drugs.

Under the direction of Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., both professors of medicine in the Departments of Genitourinary Medical Oncology and Cancer Biology, Hajitou created and characterized the hybrid virus by combining genetic elements and biological attributes of an animal virus with those of a bacterial virus. Unlike animal viruses that infect mammalian cells, bacterial viruses have evolved to infect only bacterial hosts. These bacterial viruses, however, can be genetically adapted to bind to specific mammalian cells and then enter them.

In tumor-bearing mice, researchers showed how particles of the hybrid virus, called AAV phage, can target tumors systemically to deliver an imaging or therapeutic agent, thereby providing a strategy for finding tumors and genetically manipulating them for imaging and therapy.

The AAV phage hybrid combines the ability of the adapted bacterial virus to target specific tissues with the capability of the animal virus to actually deliver genes to cells. The crucial vehicles, or vectors, in the AAV phage hybrid retained the properties of their respective parental viruses, which the researchers called a surprising and efficient outcome.

Pleased by the strong effects of this gene transfer in mouse models of breast and prostate cancer, Hajitou next worked with Juri Gelovani, M.D., Ph.D., chair of the Department of Experimental Diagnostic Imaging, who used positron emission tomography to confirm that the reporter and therapeutic genes were efficiently and selectively expressed throughout the animal tumors, and not in normal tissues.

Although researchers have yet to translate these hybrid viruses for use in humans, they’re optimistic that this new system will have future clinical applications in diagnosing, treating and monitoring tumors more accurately.

When Good DNA Goes Bad

Just ask Karen Vasquez, Ph.D., associate professor in the Department of Carcino-genesis, what happens when good DNA goes bad.

She and her team at M. D. Anderson’s Virginia Harris Cockrell Cancer Research Center in Smithville, Texas, reported in the Proceedings of the National Academy of Sciences that when otherwise normal DNA adopts an unusual shape called Z-DNA, it canlead to the kind of genetic instability associated with cancers such as leukemia and lymphoma.

For the first time, they demonstrated that the oddly shaped DNA can cause DNA breaks in mammalian cells. Sequences prone to forming Z-DNA are often found in areas of DNA that are susceptible to the genetic rearrangements associated with cancer.

Analysis of the genome reveals that DNA sequences prone to forming the Z-DNA structure occur in 25% of the genome. This awkward shape puts a strain on the DNA and as Vasquez and her colleagues showed, it can cause the DNA molecule to completely break apart.

To determine whether the presence of Z-DNA could have an effect on DNA stability in a cell, researchers introduced pieces of DNA designed to form the Z-DNA shape into bacterial and human cell lines. They then broke apart the cells and examined what happens to their DNA. They found that in bacterial cells, the Z-DNA caused small deletions or insertions of one or two DNA base pairs, while it led to large-scale deletions and rearrangements of the DNA molecule in human cells.

“We found that DNA itself can act as a mutagen, providing a plausible mechanism for how the chromosome breaks in a particular region to form cancer,” says Vasquez, whose research has been furthered by generous donations from The V Foundation for Cancer Research and the George and Barbara Bush Endowment for Innovative Cancer Research.

“Once we better understand the players involved in the process,” she adds, “we might be able to either prevent the generation of these breaks or even correct them after they occur and before they cause cancer.”


© 2014 The University of Texas MD Anderson Cancer Center