Remnants of ancient retrovirus may drive aggressiveness and resilience of malignant brain cancers

The median length of survival after diagnosis of glioblastoma is 14 months, but some of these brain tumors are more aggressive and resistant to treatment than others, and a new study suggests reactivation of an ancient retrovirus may be at least partly to blame.

“Our lab found that an evolutionary dormant retrovirus from 6 million years ago – HML-2, a subtype of HERV-K– contributes to brain tumor formation. We demonstrated for the first time that this virus, when reactivated, plays a role in defining the stem-cell state of high-grade gliomas, promoting an aggressive form of cancer,” said the principal investigator first author of a paper in the Journal of Clinical Investigation

Cancer stem cells, a subpopulation of cells in cancers, drive tumor initiation and development and influence how aggressive and resistant to treatment a cancer will be. This study, conducted by researchers found that HML-2 altered stem cell programming by activating a gene-regulating protein called OCT4. HML-2 was previously implicated in the genesis and development of other cancers, but this is believed to be the first study showing the virus’ effects in gliomas and describing the molecular and cellular mechanisms involved.

“Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem-cell niche, the microenvironment that supports stem cells and determines their fate,” said  the senior author.

“We conducted a comprehensive translational investigation of HML-2 expression in glioblastoma and its role in maintaining the cancer stem cell phenotype,” said the article’s senior author. Results were based on analyses of patient-derived glioblastoma cells and mouse model studies.

The team’s findings give researchers targets for developing therapies; and in their work, an anti-retroviral drug significantly reduced HML-2 activity and reduced tumor stem-cell markers, said the principal investigator.

“Targeting the glioblastoma stem cell niche is an attractive option to prevent alterations in stem cells and reduce tumor recurrence and treatment resistance,” the author said.

HML-2, a subtype of HERV-K, is one of many human endogenous retroviruses (HERVs), ancestral relics of retroviral infections that occurred throughout history and led to the integration of viral sequences into the human genome. HERVs, making up about 8% of the human genome, are usually silent – unable to cause infection – but scientists have recently discovered that some can be reactivated in certain cancers.