Researchers here use organoid models of tissue to recapitulate some of the epigenetic changes that occur in the bodies of old individuals, as a way to investigate how those changes alter the risk of cancer. There are of course numerous factors involved in the fact that cancer risk is age-related: rising levels of mutational damage; the above mentioned epigenetic changes that diminish protective anti-cancer mechanisms inside cells; inflammatory tissue environments that support the very early growth of precancerous cells; the declining ability of the immune system to find and destroy cancerous cells. Evidence suggests that the latter item, the aging of the immune system, is the most important factor over the course of the present human life span, but until the research community can repair or reverse that process, it will be hard to say in certainty.
Most cancers contain epigenetic and genetic alterations, but how they work together to cause cancer was not well understood. Researchers have found that epigenetic alterations characterized by changes in DNA methylation - a process by which cells add a tiny methyl group to a beginning region of a gene's DNA sequence, often silencing the gene's activation - are a key component of cancer initiation. In their laboratory model, known cancer-driving gene mutations did not cause colon cancers to form unless epigenetic methylation changes to the DNA were also present.
Cancer is primarily a disease of aging, with the majority of cancers occurring in people over age 60. To study colon cancer in the setting of aging, researchers used a mouse colon organoids derived from six- to eight-week old mice. Organoids are lab-grown cells that clump together and resemble specific normal organs, such as the colon in this case, and can grow indefinitely. The researchers compared colon organoids with and without mutations in the BRAFV600E, a known cancer-driving gene mutation common particularly to human right sided colon cancer. As the organoids aged, they remained genetically stable but became epigenetically unstable, even without the BRAF mutation being introduced. The scientists found that acquired DNA methylation during "aging" of the organoids, silenced cancer protective genes in a pattern similar to human aging that associates with risk for colon cancer by decade.
The team engineered the colon organoids to contain a transgenic BRAF mutation they could activate on demand. In all of the BRAF-activated organoids, DNA methylation was necessary for the mutation to initiate tumor development. Without this epigenetic change, the mutation did not initiate cancer in mice. "Essentially, we 'aged' young cells to become old, methylation-wise. In general, the risk of cancer increases with age, but if we can shift the epigenetic landscape through lifestyle changes to limit the impact of methylation fluctuations, we might be able to prevent cancer from developing. Although these studies were done to examine BRAFV600E-mediated tumorigenesis, we believe our findings apply to the cancer driver roles of other oncogenic mutations."