Abstract
Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed.
Highlights
Human endogenous retroviruses are replication-defective proviruses comprising a portion of human genome (∼8%)
human endogenous retroviruses (HERVs) activation appears to influence the aggressiveness of different cancers, including seminoma, melanoma, leukemia, hepatocellular carcinoma, sarcoma, prostate, breast and colon cancer (Cegolon et al, 2013; Kassiotis, 2014; Pérot et al, 2015; Suntsova et al, 2015; Giebler et al, 2018)
One of the most important events for the development and progression of cancer is global DNA hypomethylation (Ehrlich, 2009; Sandoval and Esteller, 2012); the expression of HERV-K is strongly associated with hypomethylation (Stengel et al, 2010; Kreimer et al, 2013), and with increased genomic instability and transcriptome activity (Romanish et al, 2010)
Summary
Human endogenous retroviruses are replication-defective proviruses comprising a portion of human genome (∼8%). Most of the HERV sequences have been inactivated over time, some of them remain active and, with LTRs, retain the genes encoding the structure, replication, and accessory proteins of retroviruses (Wildschutte et al, 2016). The research activity focused on the “omics” characterization of tumor from the primary site to the metastasis, the molecules that act as intermediaries between the epigenetic effect mediated by the microenvironment and cell fate haven’t been completely identified. On the basis of the genetic predisposition, both differentiated and stem cells are driven toward transformation by the epigenetic pressure of the tumor niche and the microenvironmental changes (van den Hurk et al, 2012; Taddei et al, 2013). We suggest future perspectives on their potential therapeutic uses
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