Human endogenous retroviruses (HERVs), which are critical to normal embryologic development and downregulated during normal maturation, have been implicated in a variety of cancers. Abnormal persistent production of HERVs has been suggested to play a role in oncogenesis and to confer stem cell properties to cells. We recently demonstrated that the most recently incorporated HERV element (HERV-K HML-2) has been associated with the pathogenesis of the embryonal atypical teratoid rhabdoid tumor (AT/RT), shifting our understanding of embryonal tumor development. HML-2 expression is vital for proper human development and its expression is suppressed via methylation or chromatin remodeling as cells differentiate. We previously found that dysfunctional chromatin remodeling due to loss of SMARCB1 expression induces HML-2 envelope (env) expression, impairing cellular differentiation and migration, and facilitating tumor growth in AT/RT. Epigenetic dysregulation in other embryonal tumors with concomitant expression of stem-cell markers may facilitate HML-2 expression. Future studies could utilize HML-2 as potential diagnostic criteria, use its expression as a treatment biomarker, and investigate the efficacy of therapies targeting cells with high HML-2 expression.

The role of extracellular vesicles (EVs), including retroviral-like particles (RVLPs), in pathogenic processes is currently a subject of active investigation. Several studies have identified mechanistic links between the increased presence of EVs and the process of senescence. A recent study reveals that the reverse transcribed complementary DNA (cDNA) of a human endogenous retroviral sequence can activate the innate immune system and result in tissue damage and/or the spread of cellular senescence to distant tissues. Several studies have linked EVs to age-related diseases, such as Alzheimer’s disease and Parkinson’s disease, and have included isolation of EVs from individuals with these diseases. Loss of epigenetic regulation, immune activation, and environmental stimuli can all lead to the expression of endogenous retroviruses and the incorporation of their proteins and transcripts into EVs. In addition, EVs disseminating these endogenous retroviral components have now been shown to act in a paracrine manner in multiple human diseases. Further investigation of the connection between EVs containing endogenous retroviral protein products or nucleotides should be pursued in models of age-related diseases.