Might brushing your teeth protect against cancer? The suggestion looks like it belongs in the pages of an unreliable tabloid, but scientific evidence for the link is strong and growing.
Take head and neck cancer, which kills some 450,000 people worldwide every year. It’s associated with smoking and drinking alcohol, which is one reason why the most common form of the disease, oral squamous cell carcinoma (OSCC), tends to cluster in under resourced areas. But plenty of people diagnosed with OSCC say they never drank nor smoked, so researchers have been looking for other possible causes.
One likely candidate is gum disease. A series of studies have identified periodontitis, a bacterial infection that eats away soft tissue and eventually bone around teeth, as a risk factor for OSCC. That might be because the disease changes the behavior of usually benign bugs that live in the mouth.
A study published late last year, for example, showed that mice infected with oral bacteria developed significantly larger and more numerous tumors compared to those not infected.
“The moment they sense that there’s some problem in the mouth, or that there is a decrease in the immune system, they respond and attack, because they’re looking for food,” says Jorge Frias-Lopez, a microbiologist at the University of Florida’s school of dentistry who studies the link between the oral microbiome and cancer.
And of the 700 or so bacterial species typically found in our mouths, scientists studying OSCC have zeroed in on a spindle-shaped suspect called Fusobacterium nucleatum. It’s early days, but researchers think F. nucleatum could explain why gum disease is linked to the development of oral tumors.
“All of the signs are leaning towards that this bacterium is in some way involved,” says Daniel Slade, a biochemist at Virginia Tech who studies the role bacteria play in cancer. “But it’s still an open question and needs more research on whether it can initiate cancer, or whether or not it’s accelerating cancer.”
Bacteria and tumors
Infectious microbes are reckoned to contribute to some 20 percent of human tumors. Viruses tend to soak up most of the blame, from the common human papillomaviruses that lead to cervical cancer to hepatitis B and C, which raise the risk of liver cancer.
“The concept that bacteria are important in cancer is new,” says Yvonne Hernandez-Kapila, a periodontologist at the University of California, San Francisco. When a link between colon cancer and the bacteria H. pylori was discovered in the 1990s, it triggered a search for other pathogenic and perhaps carcinogenic types, she says. “Then large population studies began to see some associations between bacteria, especially oral bacteria, and some cancers.”
Such association studies make up the bulk of the evidence that currently links OSCC to F. nucleatum. Starting in 1998, research on people with cancer has shown time and again that levels of the bacteria and bacterial gene expression are higher in OSCC tumors than in normal tissue.
“Fusobacterium nucleatum is actually present in many people,” says Hernandez-Kapila. “However, the relative numbers increase in cancer patients. We’ve shown that in oral and head and neck cancer patients.”
Association studies can only identify a correlation between the bacteria and disease, and famously, correlation does not equal causation. Without longitudinal studies to examine whether people with higher numbers of the bacteria go on to develop higher rates of cancer, scientists struggle to determine whether the bugs perhaps cause and worsen the disease, or if they are simply found alongside tumors. “There might be a role for Fusobacterium in promoting cancers, but I think it’s a kind of chicken and egg question,” says Miguel Reis Ferreira, a clinical oncologist at Guys and St Thomas NHS Foundation Trust in London.
But scientists like Slade and Hernandez-Kapila believe that F. nucleatum does contribute to cancer. That’s because studies have made connections between elevated F. nucleatum numbers and cancer in other parts of the body where the bacteria isn’t normally found. Scientists think F. nucleatum gets from the mouth to the colon, breast, and other places where it is linked to cancer when it enters the bloodstream through bleeding gums.
In 2012, well before the association between the bacteria and OSCC was spotted, F. nucleatum was found to be prevalent in human colorectal carcinoma (CRC). “The link is really strong in gastrointestinal cancer,” says Frias-Lopez. Reis Ferreira agrees that the evidence that the bacteria plays a role in CRC is relatively strong, both because of the number of studies that have made the connection and for a very simple physiological reason: “The bacteria shouldn’t be there.”
Compared with other cancers, there has since been much more research, including in animals and cell culture, into how the bacteria might raise the risk of CRC. “Mechanistic studies of these bacteria and colon cancer have been happening for years now and a few things have emerged,” says Robert Holt, a genomic scientist and immunogeneticist at the BC Cancer Research Center in Vancouver.
One important mechanism seems to be how F. nucleatum can attach itself to a sugar molecule called Gal-GalNAc that is overexpressed on the surface of many cancer cells.
Slade says, “the bacteria are not necessarily picking specific cancers. But if cancers are expressing the sugar on the surface, then they are able to bind to it.” In addition to colon tumors, studies show that F. nucleatum can also bind breast cancer cells in this way.
Once bound, the bacteria could aid cancer progression in several ways. F. nucleatum could act as a bridgehead to allow other bacteria to colonize tumors, helping to generate biofilms within which microorganisms aggregate and interact.
“There are lots of other different bacteria, especially in the oral environment. So, does it have a partner that we’re missing, or is it able to do this alone?” Slade adds. “I think that’s an area that is really going to explode in the near future.”
There is evidence that proteins expressed by F. nucleatum interfere with cell signaling processes, which can influence the progression of tumors. Some studies show the bacteria rev up cancer cell proliferation and can decrease levels of DNA repair proteins.
Inflammation could play a role as well. F. nucleatum is known to trigger a powerful inflammatory immune response. And chronic inflammation is associated with both the onset and progression of cancer at various sites in the body. A study published in September of this year that analyzed human colorectal tumors suggested that F. nucleatum might even help cancer spread from site to site through the body.
Uncertainty around causality shouldn’t delay work on possible clinical implications of a link from the bacteria and tumors in the mouth or elsewhere, says Holt. “It doesn’t hurt at this stage to be exploring approaches to intervene,” he says. “It’s unlikely that removing these bacteria would be negative. There is nothing good that this bug appears to be doing. But it does do a lot of bad.”
Antibiotics are the most obvious way to attack bacteria, but are a nonstarter for cancer, Slade says.
“One problem with that is it is very difficult to create a specific antibiotic,” he says. “With broad spectrum antibiotics you will be wiping out potentially good parts of our microbiome.” Research suggests that patients with a healthy microbiome respond better to cancer chemotherapy. “It could be that while you are trying to eliminate this bacterium to prevent or treat cancer, you also remove a good subset of bacteria that actually allows cancer treatment to perform better,” Slade says.
Hernandez-Kapila is looking instead to combat F. nucleatum with nisin, an antimicrobial peptide produced by the bacteria Lactococcus lactis. Nisin is a tested and approved preservative in the food industry, and encouraging reports of its anticancer effects in animal studies have led to some cancer patients taking it. Hernandez-Kapila is now trying to raise funds to carry out a proper clinical trial.
Another promising strategy is to develop a vaccine, Holt says. His group is trying to identify possible antigen targets for a vaccine against F. nucleatum that could be given to cancer patients who have responded well to treatment but who have a high genetic risk of tumor reoccurrence. “That would be a good scenario where we could potentially see good vaccine efficacy,” he says. “It would truly be experimental at this stage, but there are some good reasons to be pursuing this.”
If F. nucleatum does promote the development of tumors across the body, from the gut to the head and neck, then such a vaccine could address many cancer types. “The pharma industry has adapted well to now considering very precise indications and more personalized indications. So in a sense we would be taking things in the other direction, of potentially a broader application,” Holt says.
Hernandez-Kapila says a growing number of scientists are realizing that solid results from lab and animal studies suggest that targeting pathogenic bacteria like F. nucleatum could offer a new route to addressing cancer in the head and neck and elsewhere. “I’ve spent my whole career on this, and people used to tell me it was nonsense,” she says. “But radiation and chemo are very difficult for patients to take, and if you can find something like a probiotic that is very selective and doesn’t cause as many off-target effects, then that would be very helpful.”