A special enzyme may be a target for future cancer treatments

These mind-alerting findings will help future research to guide or restrict tumor evolution.
Kavita Verma
digital image of enzyme
digital image of an enzyme

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Researchers at Weill Cornell Medicine have uncovered a surprising discovery – an enzyme that normally defends human cells against viruses could contribute to the evolution of cancer towards more malignancy. 

Through its ability to cause mutations in cancerous cells, this newly identified target holds potential for novel treatments aimed at battling deadly diseases.

A special enzyme may be a target for future cancer treatments
The contribution of the APOBEC3G preclinical model

In a recent study by Weill Cornell Medicine, in order to investigate the role of enzymes, scientists used a preclinical model of bladder cancer – APOBEC3G. They have discovered that the enzyme significantly increases the number of mutations in tumor cells. 

Dr. Bishoy M. Faltos, senior study author and assistant professor of medicine in the Division of Hematology and Medical Oncology, emphasized that the APOBEC3G plays a huge role in demonstrating bladder cancer evolution.

The cytosine nucleotide (the letter "C" in the genetic code) can be chemically modified by members of the APOBEC3 family of enzymes to change RNA or DNA. This may lead to an incorrect nucleotide being present there. 

These enzymes, notably APOBEC3G, typically work against retroviruses like HIV by altering the cytosines in the viral genome in an effort to impede viral reproduction.

APOBEC3 enzymes, which are notoriously dangerous to cellular DNA, have been found in high concentrations within cancerous cells. A 2016 study conducted by Dr. Faltas of the Englander Institute for Precision Medicine links these mutations with resistance to chemotherapy treatment methods.

This an unsettling discovery that sheds new light on why certain cancers are hard to treat due to their ability to defend themselves from common treatments.

Such findings create the possibility that cancer generally tackles APOBEC3s in order to change their genomes, helping them not only acquire all the mutations required for malignant growth but also strengthen their ability to do so. This could also enhance the ability to diversify and "evolve" subsequently, allowing for additional growth and spread despite immune defenses, medical treatments, and other negative variables.

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Dr. Faltas and his team demonstrated the specific role of APOBEC3G in bladder cancer

A new study by a team of researchers led by Dr. Faltas, including first author Dr. Weisi Liu, explained the role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

Since mice lack the human enzyme APOBEC3G, the scientists replaced the gene for the only mouse APOBEC3-like enzyme with the gene for human APOBEC3G. 

The researchers found that these APOBEC3G mice were much more likely to develop 76% of this type of cancer than mice whose APOBEC gene (53% developed cancer) was not replaced and were knocked out when they were exposed to a chemical that promotes bladder cancer and mimics the carcinogens in cigarette smoke. 

Additionally, all of the knockout-only mice lived after a 30-week observation period, whereas only around a third of the APOBEC3G mice passed away from cancer.

The researchers were shocked to find out that the APOBEC3G in the mouse cells was present in the nucleus. The nucleus is the place where cellular DNA is kept with the technique known as 'optical sectioning.' On top of that, the APOBEC3G mice's bladder tumors had 2x the number of mutations than the knockout mice's tumors.

It will inform future efforts to lead tumor evolution

By precisely mapping the APOBEC3G mutational signature to tumor genomes, Dr. Liu's team had eye-opening results – abundant evidence that this enzyme was directly responsible for a significantly higher malignancy and mortality rate in mice. 

Unprecedentedly, they spotted a distinct genetic profile within these tumors created by APOBEC3G alone; one which differed from any other member of the family.

Ultimately, in the human tumor DNA database-The Cancer Genome Atlas, the researchers looked for the mutational signature of APOBEC3G. They found mind-blowing results that these mutations are common in bladder cancer and can result in the worst consequences. 

To conclude, these mind-alerting findings will help future research to guide or restrict tumor evolution. This could be done by targeting APOBEC3 enzymes with appropriate drugs.