New research shows that two types of per-and polyfluroalkyl substances (PFAS), or ‘forever chemicals,’ spurred cancer cells to migrate to new positions in lab and mouse studies, an indication that the chemicals could contribute to cancer metastasis. The work was spurred by the fact that firefighters experience this type of cancer at higher rates than the general population and are heavily exposed to PFAS at work.
PFAS make up the prevalent group of persistent forever chemicals—organic pollutants that do not break down in the environment and can build up in the body. In a study in Environmental Science and Technology, a team from Yale University studied the link between PFAS and colorectal cancer to learn more about the relationship between the two.
In a series of experiments led by the lab of senior author Caroline Johnson, the team observed the effects of colorectal cancer cells immersed in low-dose and high-dose PFAS solutions for up to seven days, including perflurooctanesulfonic acid (PFOS) and perflurooctanoic acid (PFOA). Both have been used in firefighting foam and many other products. Notably, the researchers used exposure levels similar to those detected in firefighters and others in frequent contact with PFAS, such as people living near landfills, airports, military bases, or wastewater treatment plants.
The researchers also used two types of colorectal cancer cells—one with a normal wild-type KRAS gene (SW48 KRAS wild-type), and the other KRAS-mutated (SW48 KRAS G12A). KRAS mutations are known as a common driver of some colorectal cancers. The SW48 KRAS G12A genetic mutation is linked with a lower survival rate among all KRAS mutation types and is representative of an aggressive form of colorectal cancer for which no therapies are currently available.
During immersion, the cells formed into tiny balls called spheroids. While the lowest PFAS levels did not induce migration, the highest 10μM dosage did cause migration of the colorectal cancer spheroids, showing a tendency to spread and penetrate membranes. When the SW48 KRAS G12A cells were exposed to higher PFOS/PFOA doses for 24 hours, their migration ability significantly increased from 28% to 50%.
In another experiment mimicking wound healing, researchers grew the cells in a flat, two-dimensional layer, then drew a scratch down the middle, separating half of the cells from the other half. When they added PFAS, the cell lines grew and migrated back together again.
“It doesn’t prove it’s metastasis, but they have increased motility, which is a feature of metastasis,” Johnson says.
The team also noted metabolic changes that were consistent with cancer metastasis. The spheroids produced a variety of fatty acids, amino acids, and signaling proteins in patterns previously linked to metastasis. In contrast, small-chain fatty acids, which can protect against tumors and inflammation, were downregulated.
The study revealed up- and down-regulation of specific signal proteins associated with metastasis during the epithelial-mesenchymal transition (EMT). EMT has been shown to occur in wound healing, organ fibrosis, and the initiation of metastasis in cancer progression.
For example, when exposed to either chemical at higher levels, both cell types expressed less E-cadherin, rendering them less adhesive—a key step in EMT-related metastasis. The results added to the team’s confidence that the cell was behaving in vitro like a metastatic cell in the body.
Since some changes were more pronounced in the KRAS-mutated line, the researchers theorize that cancers with this mutation may be especially prone to spread after PFAS exposure.
“This work provides insights into the metabolic response of colorectal cancer cells to PFAS exposure and provides evidence of their metastatic potential,” the authors write.
The team emphasizes that their study results are also important for vulnerable populations that may be occupationally exposed to high levels of PFOS and PFOA including firefighters and those who work in fluorochemical manufacturing. “These results provide valuable insights into the potential impacts of PFOS and PFOA exposure on colorectal cancer progression, highlighting the importance of monitoring these environmental chemicals to reduce harmful effects on human health.”
