Cancer cells invade the surrounding tissue, making many cancers difficult to isolate and treat. If we determine how cancer cells become invasive, then we may be able to develop new therapeutic or diagnostic opportunities. Good models for cancer invasion in humans are rare, but remarkably, the human placenta presents an excellent model for cellular invasion and may help in the discovery of new invasion-associated genes.
In early pregnancy, placental cells invade into the uterine wall to establish a blood supply for the fetus, just as cancer cells invade into surrounding tissues and initiate angiogenesis. As placental and cancer cells invade, they also exhibit control over the immune system to prevent rejection. Intriguingly, placental and cancer cells share a genetic phenomenon that we do not understand – they fail to silence viral DNA sequences that lie embedded within the human genome, known as retrotransposons. Retrotransposons comprise 42% of the human genome, and due to their potentially destructive ‘viral’ nature, they are silenced (turned off) in healthy tissues so that the cells can behave normally. The silencing of DNA in our genome is regulated by a chemical (epigenetic) modification, known as DNA methylation.
Curiously, the placenta – a healthy tissue – has evolved in humans and some primates so that certain retrotransposons are allowed to escape epigenetic silencing. This has created new genes in the placenta that are essential for placental growth and a healthy pregnancy. We and others have documented the specific unsilenced (unmethylated) state of retrotransposons in the placenta and their silenced (methylated) state in other human tissues. Distributed among large numbers of retrotransposons in the human genome are a relatively small number of recently evolved, epigenetically unsilenced genes called “retrotransposon-derived genes” (referred to henceforth as RDGs). Interestingly, the evolutionary conservation of certain RDGs in the placentas of humans and some primates suggests that these new genes may contribute to the highly invasive phenotype of placentas in these species. Apart from the observation that retrotransposon activity has created new genes that expanded the functionality of the placental genome, very few other features are known to commonly characterize RDGs.
Tumour cells undergo a huge loss of DNA methylation across the genome, and the specific loss of silencing at viral DNA sequences is a hallmark of many cancers. Moreover, active retrotransposons cause genomic instability and cellular malfunction in tumor cells, which presents a conundrum, because active retrotransposons are therefore likely to have both good and bad consequences for the placenta. Further, no published studies have addressed a relationship between placental RDG unsilencing and the shared invasive properties of placental and cancer cells. We were surprised to recently discover that some unsilenced (unmethylated) RDGs in the placenta are also unsilenced in melanoma, one of the most invasive cancers. Our work suggests that similar to the permissive state of unsilenced viral DNA in the placenta, the unsilencing of viral DNA in cancer is important for cancer cell invasion. So we ask: do these RDGs promote early life through the placenta and death through malignancy?
The aim of our current research at the University of Otago (in Dunedin, New Zealand) is to generate a catalog of recently evolved placental RDGs and determine whether these genes play a role in driving cancer invasion. This will determine whether essential placental genes are activated in cancer cells, and if so, whether they drive cancer cell invasion. Understanding the epigenetic rather than mutational activation of RDGs in cancer may be key to determining how a healthy somatic cell becomes malignant and invasive. At present, RDGs have not yet been associated with generating an invasive phenotype. In the placenta, early developmental programmes require the unsilencing and activation of retrotransposons to support fetal growth and normal development. In cancer, invasion and metastasis are suggested to be induced by processes such as epithelial to mesenchymal transition (EMT), essentially shifting differentiated cells back to an early developmental programme. We believe that placental and cancer cells are similar, whereby early developmental programmes may be (re)activated to unsilence retrotransposons.
Because retrotransposons comprise a large portion (42%) of the human genome, retrotransposon activation in cancer is unsurprising and well documented. However, in the placenta, we suspect that RDGs with a role in invasion and immunosuppression is a small subset of all retrotransposons, only a fraction of which have so far been identified. The identification of a common set of activated RDGs in the placenta and in cancer may reveal a catalog of potential “retro-oncogenes”, which could lead to novel diagnostic biomarkers and therapeutic targets for cancer. Such a discovery would enable the early detection of cancer cells that are at risk of spreading, which will improve a patient’s prognosis and provide opportunities to develop targeted therapies. By using the placenta as a model for human malignancy and focusing on the activation of retrotransposons, this work will reveal new mechanisms that have evolved in our genome that simultaneously influence health and disease.
This study, The Genes of Life and Death: A Potential Role for Placental-Specific Genes in Cancer: Active retrotransposons in the placenta encode unique functional genes that may also be used by cancer cells to promote malignancy was recently published in the journal Bioessays.