When we delve into the human genome, amid the multitude of genes essential to life, we find remnants of DNA left behind by viruses that infected our primate ancestors millions of years ago.
In the past, these ancient viral fragments, known as endogenous retroviruses, were considered harmless, often dismissed as ‘junk’ DNA without any harmful capabilities. However, recent research from CU Boulder published in the journal Science Advances on July 17 reveals that when activated, they can play a significant role in aiding cancer growth and survival. Moreover, the study suggests that suppressing specific endogenous retroviruses could enhance the effectiveness of cancer treatments.
Edward Chuong, the senior author of the study and an assistant professor of molecular, cellular, and developmental biology at CU’s BioFrontiers Institute, stated, “Our research demonstrates how present-day diseases can be profoundly influenced by ancient viral infections that previously received little attention from researchers.”
The Human-Virus Hybrid
Research indicates that approximately 8% of the human genome comprises endogenous retroviruses that integrated into the cells of our evolutionary predecessors, compelling their hosts to replicate and retain their genetic material. Gradually, these viruses infiltrated sperm, eggs, and embryos, imprinting their DNA like a historical record into future generations and influencing evolution.
Although they are no longer capable of generating functional viruses, Chuong’s research reveals that endogenous retroviruses can function as “switches” that activate nearby genes. Some have played a role in the evolution of critical elements such as the placenta and our immune responses to modern viruses like COVID-19.
“While there is substantial evidence that these endogenous retroviruses can be beneficial to us, there is limited information on how they could be detrimental,” Chuong commented.
To investigate their involvement in cancer, Chuong and Atma Ivancevic, the study’s first author and a research associate in his laboratory, examined genomic data from 21 types of human cancer sourced from publicly available datasets.
Their analysis revealed that a specific type of endogenous retrovirus called LTR10, which infected some primates around 30 million years ago, exhibited significant activity in various cancers, including lung and colon cancer. Moreover, further examination of tumors from multiple colorectal cancer patients indicated that LTR10 was active in about a third of the cases.
By utilizing the CRISPR gene-editing tool to remove or silence the sequences where LTR10 was found, the researchers noticed a decrease in the expression of crucial genes known to promote cancer development and progression.
Ivancevic explained, “When we silence this retrovirus in cancer cells, it leads to the suppression of neighboring gene expression.”
Experiments conducted on mice produced similar outcomes, indicating that eliminating an LTR10 “switch” from tumor cells resulted in the deactivation of essential cancer-promoting genes, such as XRCC4, thereby enhancing the efficacy of tumor-reducing treatments.
“Many genes that are abnormally active in cancer cells are regulated by these ancient viruses, shedding light on a previously unanswered question,” said Chuong.
Enhancing Our Understanding of Current Treatments
The specific endogenous retrovirus studied by the researchers seems to activate genes within the MAP-kinase pathway, a pivotal cellular pathway that is often disrupted in various cancers. The study suggests that existing drugs, known as MAP-kinase inhibitors, potentially function by deactivating the endogenous retrovirus switch.
The researchers point out that this single retrovirus family may regulate up to 70 genes associated with cancer in this pathway alone. Different retrovirus lineages likely impact diverse pathways that contribute to different types of cancers.
Chuong hypothesizes that as individuals age, their genomic defenses weaken, allowing ancient viruses to reactivate and potentially contribute to other health issues.
“The underlying mechanisms of disease manifestation within cells have always been a puzzle,” Chuong stated. “While endogenous retroviruses may not provide the complete explanation, they could represent a significant piece of the puzzle.”
