Targeted virus compels cancer cells to eat themselves

May 2, 2006

An engineered virus tracks down and infects the most common and deadly form of brain cancer and then kills tumor cells by forcing them to devour themselves, researchers at The University of Texas M. D. Anderson Cancer Center report this week in the Journal of the National Cancer Institute.

The modified adenovirus homed in on malignant glioma cells in mice and induced enough self-cannibalization among the cancer cells -- a process called autophagy -- to reduce tumor size and extend survival, says senior author Seiji Kondo, M.D., Ph.D., associate professor in the Department of Neurosurgery at M. D. Anderson.

''This virus uses telomerase, an enzyme found in 80 percent of brain tumors, as a target,'' Kondo says. ''Once the virus enters the cell, it needs telomerase to replicate. Normal brain tissue does not have telomerase, so this virus replicates only in cancer cells.''

Other cancers are telomerase-positive, and the researchers showed in lab experiments that the virus kills human prostate and human cervical cancer cells while sparing normal tissue.

In addition to demonstrating the therapeutic potential of the virus, called hTERT-Ad, Kondo says the international research team also clarified the mechanism by which such conditionally replicating adenoviruses (CRAs) infect and kill cancer cells.

Autophagy is a protective process that cells employ to consume part of themselves when nutrients are scarce or to destroy some of their organelles to recycle their components. A double membrane forms around the material to be consumed, then everything inside is digested.

Kondo and colleagues showed that hTERT-Ad (short for human telomerase reverse transcriptase promoter regulated adenovirus) infected the glioma cells and induced autophagy by inactivating a molecular pathway -- the mammalian target of rapamycin (mTOR) pathway -- that is known to prevent cellular self-cannibalization.

The result was a huge difference in tumor volume among mice with subcutaneous malignant glioma that got hTERT-Ad and those that received a different, non-replicating virus. Average tumor size in the hTERT-Ad group was 39 cubic millimeters, while those receiving the other virus had an average tumor volume of 200 cubic millimeters.

Among mice with malignant gliomas in the brain, those treated with three injections of hTERT-Ad on average lived 53 days. Those receiving the control adenoviruses lived on average 29 days. Two of the hTERT-Ad mice survived 60 days and had no detectable brain tumors.

Analyses of dead cancer cells showed telltale signs of autophagy: bits of virus in the cell nucleus and autophagic vacuoles -- cavities with residual digested material.

The cells showed no sign of having been killed by apoptosis -- a much better known process of programmed cell death. A normal biological defense mechanism that systematically kills defective cells, apoptosis is suppressed or dysfunctional in cancer cells. Many cancer therapies focus on restoring or enhancing apoptosis to combat the disease.

''We believe that autophagy, but not apoptosis, mediates the principal anti-tumor effect of conditionally replicating adenoviruses,'' Kondo says.

Cells killed by apoptosis show specific damage to the cell nucleus and DNA, with other cellular organelles preserved, Kondo explains. Cells killed by autophagy have little damage to the nucleus but heavy degradation of the cells' organelles.

Apoptosis and autophagy should be viewed as type 1 and type 2 versions of programmed cell death, Kondo says. In a Nature Reviews Cancer paper last September, Kondo and colleagues reviewed therapies and molecules that cause or inhibit the self-cannibalization process and compared autophagy and apoptosis, which has been more heavily studied.

To improve cancer therapeutics, Kondo and colleagues concluded that it is vital to identify molecules that regulate autophagy in cancer cells and to understand how autophagy is associated with cell death, a relatively new field in cancer research.

The research group is following up the malignant glioma findings by studying ways to improve the efficiency of viral infection of cancer cells.

Source: University of Texas

Explore further: Study boosts hope of 'liquid biopsies' for cancer screening

Related Stories

Study boosts hope of 'liquid biopsies' for cancer screening

August 9, 2017
Scientists have the first major evidence that blood tests called liquid biopsies hold promise for screening people for cancer. Hong Kong doctors tried it for a type of head and neck cancer, and boosted early detection and ...

Clinical trial shows ready-to-use cells are safe and effective to treat viral infections

August 8, 2017
Patients who receive a hematopoietic stem cell transplant are at risk of developing potentially lethal viral infections. Some of the infections can be treated with available drugs, but they are not always effective and side ...

Partnering cells turn off immune attack on pancreatic tumors

July 18, 2017
Two cell types work together to protect pancreatic tumors from destruction by the immune system. But, blocking this partnership may restore the system's ability to attack these same tumor cells.

How DNA damage turns immune cells against cancer

July 31, 2017
Cancer is essentially a disease of the cell replication cycle. The goal of treating the disease is to permanently kill off the cells that replicate with abandon without any molecular brakes. Chemotherapy and radiation cause ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

Novel RNA nanodevices in living cells can sense and analyze multiple complex signals

July 26, 2017
The interdisciplinary nexus of biology and engineering, known as synthetic biology, is growing at a rapid pace, opening new vistas that could scarcely be imagined a short time ago.

Recommended for you

Despite benefits, half of parents against later school start times

August 18, 2017
Leading pediatrics and sleep associations agree: Teens shouldn't start school so early.

Population health impact of infants born small for gestational age in low- and middle-income countries

August 18, 2017
In low-and middle-income countries, it is common for babies to be born of low birth weight, due to either inadequate growth in utero (fetal growth restriction) and/or preterm birth, (birth before 37 weeks gestation). Maternal ...

Researchers find monkey brain structure that decides if viewed objects are new or unidentified

August 18, 2017
A team of researchers working at the University of Tokyo School of Medicine has found what they believe is the part of the monkey brain that decides if something that is being viewed is recognizable. In their paper published ...

Researchers investigate the potential of spider silk protein for engineering artificial heart

August 18, 2017
Ever more people are suffering from cardiac insufficiency, despite significant advances in preventing and minimising damage to the heart. The main cause of reduced cardiac functionality lies in the irreversible loss of cardiac ...

New study rebuts the claim that antidepressants do not work

August 18, 2017
A theory that has gained considerable attention in international media, including Newsweek and the CBS broadcast 60 minutes, suggests that antidepressant drugs such as the SSRIs do not exert any actual antidepressant effect. ...

How whip-like cell appendages promote bodily fluid flow

August 18, 2017
Researchers at Nagoya University have identified a molecule that enables cell appendages called cilia to beat in a coordinated way to drive the flow of fluid around the brain; this prevents the accumulation of this fluid, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.