In a new study, researchers at the Johns Hopkins Kimmel Cancer Center have shown that the epigenetic alterations associated with cancer evolve in an erratic manner during the early stages of tumor formation . These tumor-associated epigenetic changes ultimately focus on a subset of genes that are also observed in aging.
Cancer and senescent cells are epigenetically very different
This means that these genes could be used as a potential biomarker for cancer risk, and screening for them could help identify the individuals most at risk. Aging is the leading risk factor for the majority of cancers, and as epigenetic changes have been shown to be reversible in lab animals, these researchers are thinking that the same reversals might be applied to humans and that periodically targeting these age-related epigenetic alterations could potentially reduce cancer risk.
During the study, the researchers looked at the DNA methylation patterns, which cause genes to be expressed or silenced as we age, in fibroblast cells. They used Weinberg’s classical transformation system to convert these cells to cancer cells by infecting them with genes known to encourage tumor development. They then introduced these newly transformed cells into mice and monitored them.
A second test group of fibroblasts was allowed to age and naturally reach senescence, a state in which the cells no longer divide, having reached their replicative limit. The researchers recorded the methylation changes observed in both groups of cells over time.
Senescence occurs during the aging process, and it is thought to be an anti-cancer safety measure that prevents aged and potentially damaged cells from replicating without limit by giving them a set number of replications before retiring the cells into a senescent, non-dividing state. Senescence also occurs when cells become damaged, such as from excessive DNA damage or when they are exposed to cancer-inducing stress.
Scientists have generally thought that because senescent cells and cancer cells share DNA methylation patterns, tumor-promoting epigenetic patterns arise due to cellular senescence. However, it was puzzling for the researchers that senescence would encourage the formation of tumors, the very things that it is supposed to prevent. What exactly was going on?
The researchers set out to solve this mystery. They began by mapping out how epigenetic methylation patterns evolved during both cancer transformation and senescence. They discovered that while the changes in methylation were similar between transformed cells and senescent cells, how they evolved and what genes were methylated were mostly different.
The researchers showed that in the case of senescence, the DNA methylation changes that developed did so in a highly programmed manner; this was so much so that additional replications of the senescent cell group all had the same epigenetic pattern, which mostly affected genes that regulate metabolic processes.
In stark contrast to this, the cells subjected to cancer transformation had very random epigenetic patterns and evolution. Also, the transformation process mostly affected regulatory genes that are key to cancer survival and that allow these cells to maintain themselves as cancer cells.
They also attempted to encourage senescent cells to transform into cancer cells but could not do so, showing that senescence was indeed acting as a protective system against cancer development. They identified a subset of transformation-associated genes that were most likely to become methylated during early tumor development as well as aging.
Their research shows that transformation-associated changes to methylation are random, while senescent cells follow a programmed pattern. This further confirms the anti-cancer purpose of cellular senescence.
This research does not discount the role of senescent cells in cancer development via other mechanisms, such as inflammation from accumulated senescent cells that are not cleared by the immune system, but these mechanisms are only indirectly related to the epigenetic changes that induce cancer.
The next step for the researchers will be to investigate tissue-specific DNA methylation pattern changes that affect senescence and transformation genes. The hope is to then use that information to help develop cancer biomarkers and potential therapies that target cancer at the root cause: aging.
 Xie, W., Kagiampakis, I., Pan, L., Zhang, Y. W., Murphy, L., Tao, Y., … & Sen, S. (2018). DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk. Cancer cell, 33(2), 309-321.