Atul Butte, MD, PhD is director of the Institute for Computational Health Sciences and a professor of pediatrics at UC San Francisco.
A previously unidentifiable type of low-grade inflammation may explain why common anti-inflammatory drugs such as aspirin have shown promise against some types of cancer – even when patients don’t display typical signs of inflammation.
A team led by researchers in the labs of Atul Butte, MD, PhD, director of the Institute for Computational Health Sciences and a professor of pediatrics at UC San Francisco, and Yinon Ben-Neriah, MD, PhD, a professor of immunology and cancer research at the Lautenberg Center of Immunology of Hebrew University Medical School in Jerusalem, identified the role of a subtle form of inflammation in human and mouse cancer cells. According to the authors, this so-called “parainflammation” may explain how a number of different forms of cancer begin.
“Understanding the initial triggers of tumor formation is one of the main challenges in cancer research,” said Dvir Aran, PhD, a postdoctoral scholar in the Butte lab who was co-lead author of the new paper with Audrey Lasry, a PhD student in Ben-Neriah’s lab. “We think parainflammation could be a big part of this puzzle.”
The research was published online on July 8, 2016, in the open-access journal Genome Biology.
Common Cancer Gene Mutations ‘Turn Off the Brakes’
Growing evidence over the past decade suggests that people who take a regular dose of aspirin or other non-steroidal anti-inflammatory drug (NSAID) are significantly less susceptible to colorectal cancer, breast cancerand a number of other malignancies. This relationship is mysterious, because most of the cancers that aspirin appears to prevent typically show no overt signs of inflammation.
Aran and colleagues hypothesized that there must be some sort of low-level of inflammation, undetectable with standard methods, that could interact with gene mutations to trigger cancer.
In a previous study, Ben-Neriah’s lab showed that they could induce just such a state of low-level tissue inflammation in mice, which they categorized as parainflammation. They found that non-immune cells, including cells known to give rise to cancer, were able to activate some of the same genetic pathways typically used by the immune system. These pathways then interacted with p53, a regulator of cellular division, to prevent the cells from continuing to grow and divide, driving them toward a state known as cellular senescence.
But when p53 becomes mutated, as it does in many different forms of cancer, the researchers found that parainflammation loses its protective role and becomes dangerous for the tissue.
“Without p53, the brakes are off, and the previously protective energy of parainflammation can drive the formation of tumors,” Ben-Neriah said.
The new study identified a specific pattern of gene expression characteristic of carcinogenic parainflammation in mice with both experimentally induced intestinal parainflammation and mutated p53. This newly identified gene-expression signature, which gave the researchers a way to detect the previously invisible phenomenon, allowed them to detect parainflammation in an array of mouse organoid tumors, human cancer cell lines, and human tumor samples.
The new work is an important advance in understanding the link between inflammation and cancer, said Yale School of Medicine immunobiologist Ruslan Medzhitov, PhD, who coined the term parainflammation in 2008 to describe a theoretical state of low-level inflammation, which he hypothesizes could play a beneficial role in helping cells respond to tissue stress or damage. “The ability to molecularly detect parainflammation should help devise cancer treatments that are tailored to these stereotypic paths the tumors follow,” he said.
Linking Parainflammation to Human Cancer Mortality
To determine the role of parainflammation in human cancers, the researchers mined The Cancer Genome Atlas (TCGA), a National Institutes of Health electronic database, and retroactively examined 6523 primary tumors of 18 different cancer types for the molecular signature of parainflammation. They found that more than a quarter of all tumor samples exhibited parainflammation, and that it was much greater in some cancer types than others: for example, more than three quarters of pancreatic adenocarcinomas exhibited parainflammation, while no kidney cancers showed significant signs of parainflammation.