Extraordinary new research led by scientists from the Francis Crick Institute presents a new hypothesis as to how cancer develops. Inspired by a forgotten body of study from 75 years ago, the research looked at how air pollution drives the development of lung cancer in non-smokers, revealing pre-existing mutations in healthy tissue can be prompted into tumorous proliferation by environmental triggers.
The new research initially set out to explore the relationship between air pollution and lung cancer. Plenty of epidemiological studies have reported higher rates of lung cancer in non-smokers who live in areas with greater air pollution. But this correlation never exactly gelled with current theories on how cancer develops.
The general idea in modern science is that most tumors begin from a healthy cell that undergoes mutational damage to its DNA which then leads to cancerous growth. This is how tobacco smoke, for example, is thought to lead to lung cancer by damaging the DNA in lung cells.
The problem with this theory is that researchers have never been able to conclusively demonstrate how air pollution directly damages cellular DNA. Lab tests have struggled to show general air pollution causing DNA mutation damage in lung cells.
In fact, a number of known carcinogens have been found to not directly damage human DNA, adding to the mystery of how these substances lead to cancer. Alongside this mystery, cancer-causing mutations have been regularly found in lung tissue from healthy subjects, suggesting these mutations alone may not be enough to lead to the development of tumors.
"If you would have asked me two years ago how a tumor starts, I would have said it is obvious," explained lead investigator Charles Swanton in a recent presentation at the European Society for Medical Oncology (ESMO) annual congress. "Due to environmental carcinogens, this causes mutations in DNA, activates a driver event, and the tumor starts."
The 75-year-old hypothesis
In looking for clues to understanding how air pollution could increase a person’s risk of lung cancer without directly acting as a carcinogen, Swanton turned to the writings of Israeli biochemist Isaac Berenblum. In the first half of the 20th century Berenblum was studying how cancer develops and came across this same paradox while investigating how some non-carcinogenic oils tend to trigger skin tumors in mice.
Across several key articles, published over 75 years ago, Berenblum ultimately posited some cancers likely require two triggers to develop. The first trigger is what Berenblum dubbed the “Initiating Process.” Here, an undefined factor causes a healthy cell to turn into a latent tumor cell.
At this point the latent tumor cells can sit quietly for an indeterminate amount of time without ever progressing into cancer. To develop further a second trigger was necessary, and this was dubbed the “Promoting Process” by Berenblum.
Berenblum ultimately concluded it is important to understand the carcinogenic potential of any substance or environmental condition from the perspective of both its capacity to initiate a cellular mutation and its capacity to promote that cell to progress into cancer.
For example, some substances could be very potent both as initiator and promotor, while others may be powerful at promoting but weak at initiating. In Berenblum's early experiments he found croton oil was a powerful promoter of skin cancer in mice but it was a weak initiator, with little cellular carcinogenic potential.
So in the case of Swanton’s research, could air pollution be a potent promoter, awakening latent cancerous cells that otherwise would remain quiet?
The 21st century experiments
The first step in the new research was to look at one of the most common types of lung cancer seen in non-smokers, notable for mutations in a gene called epidermal growth factor receptor (EGFR). Studying epidemiological data encompassing nearly half a million people, the researchers found higher rates of EGFR lung cancer in areas with greater concentrations of airborne particulate matter measuring 2.5 micrometers (PM2.5).
This direct finding gave the researchers something to closely focus on in the lab. Looking at mouse models the researchers found exposure to PM2.5 pollution did explicitly trigger cancerous growth in cells with EGFR mutations.
William Hill, co-first author on the new research, said many people may carry lung cells with EGFR mutations, but these mutations are rare and don’t automatically progress into cancer without a secondary trigger. In fact, an investigation into healthy lung tissue revealed 15% of samples carried EGFR mutations and 50% had KRAS mutations, a similar lung cancer trigger.
“Air pollution needs to wake up the right cells, at the right time, for lung cancer to start and grow,” said Hill. “EGFR mutations are an essential step towards cancer forming, but they are rare, affecting around 1 in 600,000 cells in the lung. These rare cells are dormant until a trigger, such as air pollution, causes them to start growing.”
So, the million-dollar question: How could PM2.5 exposure activate these latent cancer cells in the lung?
This question will surely be subject to a huge amount of future study but the new research did detect a few clues that could reveal this cancer-causing trigger. Considering prior findings indicated PM2.5 pollution triggers an inflammatory response in the lungs, the researchers homed in on a certain immune signaling molecule called interleukin-1 beta.
This particular inflammatory molecule was found to drive the proliferation of cells with EGFR mutations following exposure to PM2.5 pollution. And, perhaps most promisingly, blocking interleukin-1 beta activity seemed to disrupt the link between PM2.5 pollution and the latent cancer cells activating.
A 2017 clinical trial that tested an interleukin-1 beta inhibitor designed to reduce risk of cardiovascular disease reported the strange side effect of low rates of lung cancer in the active drug cohort. That unusual finding is somewhat explained by this new research and suggests disrupting this particular mechanism may reduce a person’s risk of lung cancer.
Reframing the origins of cancer
While this new research offers compelling insights into the relationship between air pollution and lung cancer, perhaps the more groundbreaking finding is its rekindling of a 75-year-old cancer hypothesis that had been forgotten by many scientists. Speaking to the BBC, Swanton said its likely this two-pronged cancer activation mechanism will be discovered in a number of other cancers beyond this initial PM2.5 to EGFR association.
"Pollution is a lovely example, but there are going to be 200 other examples of this over the next 10 years,” Swanton speculated.
Some researchers are already wondering what role inflammation may play in triggering certain cancers that previously had been completely attributed to a single carcinogen. Smoking, for example, is known to lead to lung cancer by directly causing DNA damage in lung cells. But what if a similar inflammatory pathway triggered by tobacco smoke is playing some part in these lung cancers?
Allan Balmain, a cancer geneticist at the University of California, San Francisco who did not work on this new research, said to The Guardian this raises the possibility of electronic cigarettes influencing lung cancer. E-cigs may not induce DNA damage in cells like tobacco smoke but there is evidence of inflammation in the lungs can be triggered by vaping, according to Balmain.
“The tobacco companies are now saying that smokers should switch to vaping as this reduces exposure to mutagens, and therefore the cancer risk is going to go away,” said Balmain. “This is not true, as our cells get mutations anyway, and there is evidence that vaping can induce lung disease and cause inflammation similar to promoters.”
Sources: Francis Crick Institute, ESMO
