Chronic inflammation is cause for alarm! Could be cancer's right-hand man
International Business Department Liu Bojia September 13, 2023
When the body senses the invasion of a pathogen, it produces a defense response, which is often referred to as inflammation. When inflammation occurs tissues may exhibit symptoms such as pain and fever accompanied by elevated white blood cells and tissue infiltration. Although these acute reactions are uncomfortable, they are important in restoring health.
Acute inflammation subsides as the infection ends, but there is another category of chronic inflammation that persists over time. In recent years, many studies have gradually linked chronic inflammation to aging and cancer. For example, senescent cells that chronically release pro-inflammatory molecules into the microenvironment can leave surrounding tissues in a chronic state of inflammation, which can lead to faster aging of the tissues and elevate the risk of cancer.
In a new paper in Nature Genetics, scientists from the University of Oxford confirm that chronic inflammation is an important driver of leukemia, and they find direct evidence of a link between inflammation and cancer development, a link that is linked to the familiar TP53 gene.
TP53 is a classic oncogene that encodes the p53 protein, which helps regulate the cell cycle and apoptosis, and is involved in DNA repair, cell differentiation, etc. When TP53 is mutated, the cell fails to maintain genomic integrity and divides uncontrollably, resulting in cancerous cells, and TP53 mutations are detected in many types of tumors.
When a TP53 mutation occurs in an individual cell in a tissue, it is equivalent to a hole in the house. When there are fewer holes, the house doesn't collapse, and the immune system may be able to monitor and remove these mutated cells to repair the holes. But the onset of chronic inflammation throws a monkey wrench into things, like pouring gasoline on a fire, allowing the starry-eyed cancer cells to expand exponentially.
One of the most vulnerable to chronic inflammation belongs to hematopoietic stem cells (HSC). When inflammation occurs, HSC receive signals to differentiate towards white blood cells to help fight infection. However, if some of the cells in the HSC have a TP53 mutation, these cells turn around and proliferate as they are unable to differentiate due to an incomplete genome.
After collecting HSC samples from a subset of leukemia patients, the authors were able to distinguish the TP53-mutated population with the help of targeted sequencing, and they confirmed that inflammation-related genes are upregulated in this subset of cells and that they are more likely to develop into blood cancer cells. And in mice, the number of HSC with TP53 mutations rose significantly when artificially induced to produce inflammation.
When inflammation occurs, HSC with TP53 mutations rarely produce leukocytes and acquire greater resistance to apoptosis compared to healthy HSC. In addition, TP53-mutated HSC carry additional genes that promote cell growth, allowing them to expand their populations faster and eventually evolve into cancer cells.
According to the paper's summary, wild-type HSC are suppressed in the presence of chronic inflammation, which acts like a selective condition that gives TP53-mutated HSC an adaptive advantage. Inflammation regulates HSC function and also influences the direction of the fates of different HSC populations, with normal HSC causing HSC depletion due to constant differentiation, while TP53-mutant HSC that don't do the right thing expand the population size, a role never before found for TP53 mutations to date.
The authors note that discovering the link between inflammation and cancer gives us a new direction for cancer prevention, and how to stop chronic inflammation may be the key to effectively reducing cancer risk.