by If you were to ask the average person on the street how cancer develops, most would know that it involves a mutation in a cell in some part of our body. Many would guess that those mutations are caused by chemicals or inherited genetics.
A recent article in The New Yorker by Siddhartha Mukherjee, author of the Pulitzer Prize winning book The Emperor of All Maladies, expands on that simple explanation. Citing historical research from the 1940s to 2023, the article looks beyond known carcinogens and inherited mutations as the sole culprit for the development of cancer.
Mukherjee’s conversation with Allan Balmain, a cancer geneticist at the University of California, San Francisco, is a jumping off point for exploring what might be going on outside of the “cancer cell” that could promote cancer. He points out that “cancer cells live and grow surrounded by normal cells – buried in a landscape of normal tissue.” Knowing that, should we not be looking at the larger “ecosystem” in which cancer develops?
Mutations can be inherited, caused by viruses, random copying errors in an otherwise healthy, dividing cell or by physical/chemical agents. Some human studies of exposures to carcinogens seem to explain increases in certain cancers, however not all of those carcinogens act as mutagens in lab tests. Carcinogens can cause cancer through a number of different mechanisms. Mutagens cause disease (not just cancer) by causing permanent genetic damage to cells. Not all carcinogens are mutagens. So what else, besides the carcinogen, could be influencing the trajectory from a normal cell to one that is mutated to the point of uncontrolled cell division and tumor development? Could a cell that’s been exposed to a carcinogenic compound just sit silently, harmlessly, until an external trigger is pulled – a “sleeper cell”? The author asks, “Could there be a universe of promoters” being missed in research because we haven’t “been looking in the right place?”
Balmain relates the results of a study in his lab that resulted in an accidental discovery. In a mouse study where they expected to see tumors develop from a chemical trigger, none of the mice developed tumors. The mutated cells were present, but not tumors. Following incisions made in each of the mice, staples were used to close the incisions. All three mice developed inflammation around these poorly healing wounds and all three mice subsequently developed tumors there. The mutant cells were dormant until they were “irritated” and were awakened. He says, “It’s the inflammation that awakens them.”
Inflammation is not always a bad thing. It’s our immune system sending up a flag that something is wrong. The role of inflammation is to resolve injury or infection. (Read more about inflammation here). However, if something goes wrong in this normal immune system response, it can lead to chronic inflammation, which can promote the formation of tumors.
Mukherjee asks Balmain, “But what if that irritation is caused by an environmental insult, like air pollution?” Using the same logic that the staples in the mice, which aren’t mutagenic, “caused” tumor formation, couldn’t the irritant be a chemical, or some other environmental exposure?
Balmain sends the author to London to speak with another researcher, Charles Swanton. His lab, in 2019, began to look at lung cancer in non-smokers and any correlation to air pollution. In people who have never smoked but developed lung cancer, the cancerous cells often carry a mutation in a gene called EGFR. So far, air pollution in and of itself hasn’t been shown to be notably mutagenic. But in experiments using mice engineered to have this mutation and who were then exposed to a solution of dust and soot, they in fact did see increasing numbers of lung tumors as the dose of “air pollution” was increased.
As they dove deeper into the research, they found that the treated mice didn’t have significantly more mutations than the control mice, so whatever had caused such an explosion of tumors in the treated mice wasn’t also producing mutations INSIDE the cancer cells – as one might expect. What they found was that the cancerous lungs of the mice treated with “air pollution” were full of inflammatory cells. They found that a malfunction in the normal immune response to the malignancies was actually promoting tumor development.
The original mutant cells existed before the exposure to an environmental irritant. In the long run, the lesson is that a lot of bad luck has to happen for that mutant cell to “find its footing” in the inflammation that causes it to become cancerous. The researcher explains: “You have to have a bad cell at the bad place at the bad time, and over a long period.” Nature and nurture.
Reading this, I was reminded of the 2013 Breast Cancer and The Environment Research Program’s annual scientific conference, during which a researcher explained to us that “genetics loads the gun; environment pulls the trigger.” Since cancer is such a complex interaction of genes, the environment and behavior, you may have a predisposition for a disease and be fine if the “trigger” isn’t pulled. The trigger will likely be a combination of exposures and will likely be different for every person.
After reading “All the Carcinogens We Cannot See,” I find myself even more frustrated and convinced that, while it seems like researchers are on the right track, there will never be a silver bullet to cure or prevent all cancers. Prevention research lags behind treatment research. We need to better understand the mechanisms by which cancer flourishes – and if we continue to find that the environment in which tumors develop is just as, or more, important than the inherent genetic mutation from which they grow, then we need to advocate for policies that protect our health from potentially deadly environmental irritants.
I gained an even deeper appreciation for the complexity of our biological systems after reading this article several times. In breast cancer, our best known risk factors are not modifiable: being a woman, aging, pubertal onset, menopausal onset, genetic mutations. We should know how to modify what we CAN modify to reduce our risk. The idea that we could keep mutated cells “asleep” by reducing our exposure to things that can cause chronic inflammation is hopeful, maybe pie-in-the-sky thinking, but certainly something we should try to do.
As I’ve noted in many other articles since my involvement in the BCERP project, we live in a soup of environmental irritants. Some chemicals may not be mutagenic by themselves, but in combination with others (practically unavoidable outside of a lab), they may become cancer causing. Our exposures are many and are different for each of us. Some of us may have genetic mutations that are priming the pump, some of us may not. What can we do? Start at home. Start with your young children, particularly your daughters if there is an enhanced risk of breast cancer in your family. Here are some links to previous articles on our website – most with excellent resources you can use for even more information.
Breast Cancer and the Environment Research Program
Reducing Environmental Cancer Risks: Progress and Challenges
It’s time to clean out and clean up!
PFAs in Food Packaging