How a common oral bacteria makes colon cancer more deadly

Findings may help predict aggressive colon cancer and identify new treatment targets

This article is alarming because it is identifying a second periodontal pathogen in connection to systemic health. Up to this point one bacteria that is found in aggressive forms of periodontal disease has been indicated in systemic disease, p. Gingivalis. These links to systemic health should be a huge wake up call to anyone with oral disease. If you suspect you or a loved one may have periodontal disease you could be saving a life by having it treated.

COLUMBIA UNIVERSITY IRVING MEDICAL CENTER

NEW YORK, NY (March 4, 2019)--Researchers at the Columbia University College of Dental Medicine have determined how F. nucleatum -- a common oral bacteria often implicated in tooth decay -- accelerates the growth of colon cancer. The study was published online in the journal EMBO Reports.

Why it matters

The findings could make it easier to identify and treat more aggressive colon cancers. It also helps explain why some cases advance far more quickly than others, thanks to the same bacteria found in dental plaque.

Background

Colon cancer is the second leading cause of cancer death in the U.S. Researchers have long known that the disease is caused by genetic mutations that typically accumulate over the course of a decade. "Mutations are just part of the story," says study leader Yiping W. Han, PhD, professor of microbial sciences at Columbia University's College of Dental Medicine and Vagelos College of Physicians & Surgeons. "Other factors, including microbes, can also play a role."

Scientists have also demonstrated that about a third of colorectal cancers are associated with a common oral bacterium called F. nucleatum. Those cases are often the most aggressive, but nobody knew why. In a prior study, Han's research team discovered that the bacterium makes a molecule called FadA adhesin, triggering a signaling pathway in colon cells that has been implicated in several cancers. They also found that FadA adhesin only stimulates the growth of cancerous cells, not healthy cells. "We needed to find out why F. nucleatum only seemed to interact with the cancerous cells," says Han.

What the study found

In the current study, the researchers found in cell cultures that noncancerous colon cells lack a protein, called Annexin A1, which stimulates cancer growth. They then confirmed both in vitro and later in mice that disabling Annexin A1 prevented F. nucleatum from binding to the cancer cells, slowing their growth.

The researchers also discovered that F. nucleatum increases production of Annexin A1, attracting more of the bacteria. "We identified a positive feedback loop that worsens the cancer's progression," says. Han. "We propose a two-hit model, where genetic mutations are the first hit. F. nucleatum serves as the second hit, accelerating the cancer signaling pathway and speeding tumor growth."

Clinical implications

The researchers then looked at an RNA-sequencing dataset, available through the National Center for Biotechnology Information of 466 patients with primary colon cancer. Patients with increased Annexin A1 expression had a worse prognosis, regardless of the cancer grade and stage, age, or sex.

Next steps

The researchers are currently looking for ways to develop Annexin A1 as a biomarker for more aggressive cancers and as a potential target for developing new treatments for colon and other types of cancer.

More details

Yiping Han, PhD, is a professor of microbial sciences in dental medicine at the Columbia University College of Dental Medicine and of microbiology and immunology at Columbia University Vagelos College of Physicians & Surgeons.

The study is titled, "Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/ß-catenin modulator Annexin A1."

The other contributors are Mara Roxana Rubinstein (Columbia), Jung Eun Baik (Columbia), Stephen M. Lagana (Columbia), Richard P. Han (The Horace Mann School, Bronx, NY), William J. Raab (Columbia), Debashis Sahoo (University of California San Diego, San Diego, CA), Piero Dalerba (Columbia), and Timothy C. Wang (Columbia).

The study was funded by grants from the National Institutes of Health (RO1CA192111, RO1DE014924, RO1DE023332, and P30 CA013696). Dr. Dalerba receives royalties and/or stocks from OncoMed Pharmaceuticals Inc., Quanticel Pharmaceuticals Inc. (now a fully owned subsidiary of Celgene) and Forty Seven Inc. as a coinventor of several patents and patent applications. The other authors declare no financial or other conflicts of interest.

About Columbia University College of Dental Medicine

Columbia University College of Dental Medicine (CDM), one of the nation's first dental schools, educates general dentists and specialists to practice dentistry as the oral health specialty of medicine. CDM provides comprehensive, precision care to over 30,000 patients each year through more than 130,000 visits, making CDM the largest source of oral healthcare to underserved upper Manhattan communities. A centerpiece of the school's offerings is the Center for Precision Dental Medicine, a clinic that will personalize care and education through big data and first-of-its-kind technology. Other programs bring oral healthcare to local schools, seniors, and community centers. For more information, visit dental.columbia.edu

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About Columbia University Irving Medical Center

Columbia University Irving Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Irving Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cuimc.columbia.edu or columbiadoctors.org.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

DENTAL DISEASE RESPONSIBLE FOR OVERALL HEALTH?

We continue to see more information streaming into the public area on the subject of  oral disease and it's  causative links to disease of the body. With this in mind, we'd like to share this following article from Medical News Today.

The unexpected dangers of gum disease

  Published Friday 22 February 2019

By Tim Newman

                Fact checked by Gianna D'Emilio

In this Spotlight, we will cover some of the surprising links between gum disease and disparate health issues.

Gums and the brain

Although spatially the gums are near the brain, one wouldn't normally associate dental complaints with neurological conditions.

Alzheimer's and P. gingivalis linked

However, some studies have found a link between periodontal disease and tooth loss and cognitive function. One study looking at cognitive performance followed 597 men for up to 32 years. The authors conclude:

"Risk of cognitive decline in older men increases as more teeth are lost. Periodontal disease and caries, major reasons for tooth loss, are also related to cognitive decline."

Researchers have also linked periodontal disease with an increased buildup of beta-amyloid in the brain — the neurological hallmark of Alzheimer's.Other experiments have produced evidence that one type of bacteria commonly found in cases of periodontitis — Porphyromonas gingivalis — can be found in the brains of individuals with Alzheimer's.

Following on from that discovery, in a more recent study, researchers showed that P. gingivalisinfection boosts the production of beta-amyloid in the brain.

In this study, the researchers paid particular attention to an enzyme produced by P. gingivalis called gingipain. They found that this protease was toxic to tau, another protein that plays a pivotal role in Alzheimer's.

It is worth noting that other researchers have concluded that beta-amyloid is produced in response to a pathogen. The way we view Alzheimer's is slowly changing.

In the future, scientists hope that targeting gingipain enzymes might help stop neurodegeneration in some people with Alzheimer's disease. They have already designed a gingipain inhibitor, which they are testing in humans.

The researchers hope that it will "slow or prevent further neurodegeneration and accumulation of pathology in [Alzheimer's disease] patients."

The heart of the matter

Although not everyone with heart disease has gum disease, and not everyone with gum disease has heart disease, there does appear to be a correlation.

Links between gum disease and the heart

Of course, individuals who smoke or drink large quantities of alcohol are more likely to have both oral and cardiovascular issues, but there appears to be more to the relationship than shared risk factors alone.

Whether gum disease is an independent risk factor for heart disease is still being discussed, but there are some theories as to how the two might be related.

Some think that the link could involve inflammation. Primarily, inflammation is a response to irritants or pathogens; it is a protective mechanism. However, if it continues for an extended period, it can damage tissues and organs.

It is possible that inflammation in the gums sets off a cascade that, ultimately, sparks inflammation in the cardiovascular system.

Alternatively, the link between heart and gum diseases may be due to bacteria.

Bacteria in the gums can enter the blood supply and be propelled to distant destinations, including the heart, where they can cause inflammation and damage. As evidence that this possible, researchers have shown that P. gingivalis is the most commonly found bacterial species in the coronary artery.

Cancer risk increase

Once again, gum disease and cancer do not, on the surface, appear to have much in common.

A study published in 2008 investigated tooth loss and cancer in 48,375 men. The authors concluded that there was, indeed, a link between gum disease and cancer. They write:

    "Periodontal disease was associated with a small, but significant, increase in overall cancer risk."

Another, more recent, study involving more than 68,000 adults found a strong association between gum disease and overall cancer risk; the link was also significant between gum disease and pancreatic cancer.

Why might this be the case? A paper published in Nature goes some way toward an explanation.

The researchers found that an enzyme produced by a type of bacteria commonly associated with gum disease — Treponema denticola — commonly appears in certain tumors of the gastrointestinal system.

The enzyme, known as T. denticola chymotrypsin-like proteinase, helps the bacteria invade tissue in gum disease. The researchers found that it also activated other enzymes that promote cancer cells as they advance into healthy tissue.

Erectile dysfunction

Gum disease could lead to trouble in the bedroom

An estimated 50 percent of men over the age of 40 experience erectile dysfunction. It is a complex condition that can result from both psychological and physiological factors.

Some well-known risk factors include smoking tobacco, drinking alcohol, and hypertension. According to some scientists, periodontal disease might also increase the risk of erectile dysfunction.

For instance, the authors of a literature review published in 2016 identify an association between erectile dysfunction and chronic periodontitis.

In fact, they suggest "that physicians should refer patients with [erectile dysfunction] to oral healthcare providers for a comprehensive oral evaluation and treatment."

Because erectile dysfunction and gum disease have shared risk factors, including smoking and diabetes, it has been difficult to ascertain whether gum disease is an independent risk factor for erectile dysfunction.

Although sexual dysfunction and gum health seem worlds apart, there are a number of potential ways in which they could influence each other.

Once again, inflammation might be the culprit. As mentioned earlier, inflammation in one part of the body — the mouth, in this instance — can spread via chemical messengers in the blood and impact other regions.

Erectile dysfunction is often due to malfunctioning blood vessels; specifically, the smooth muscles lining the walls of blood vessels lose their ability to relax. This is referred to as endothelial dysfunction, and it prevents vasodilation in the penis and, consequently, erections.

A so-called proinflammatory state may promote endothelial dysfunction and, therefore, increase the risk of erectile dysfunction.

However, the link has not been definitively proven. The authors of a review published in 2016 concluded that, although this link seems likely, more large-scale studies are needed.

Gums and lungs

Of course, the mouth is a shared gateway to the gums and the lungs, making a link between gum and lung diseases less surprising than some of the others that we have encountered.

A study published in February 2019 investigated the records of 1,380 men. The authors found a significant relationship between chronic periodontitis and a reduction in respiratory function.

This link remained significant, even after controlling for confounding variables, such as smoking.

Once again, inflammation may be the link between the two conditions. If the tubes in the lungs that carry air are inflamed, they become narrower and air flow is restricted.

Aside from the probable role of inflammation, bacteria present in the mouth might also be breathed into the lungs. Once in the lungs, the bacteria could trigger infections that directly lead to inflammation.

A recent meta-analysis investigated potential links between gum disease and lung cancer. The authors concluded that "patients with periodontal disease are at increased risk of developing lung cancer."

In their paper, they outline some potential ways in which gum disease might increase lung cancer risk. For instance, breathing in bacteria, such as P. gingivalis, from the mouth could cause infections.

Similarly, enzymes produced during the course of gum disease might pass into the lungs. Once there, they could help pathogens take root and colonize the lung tissue.

These changes spark inflammation; over the long term, inflammation causes changes in cells that raise the likelihood of cancer developing.

The take-home message

One could read this article as a worrying collection of conditions made all the more likely to occur, courtesy of gum disease.

If we adopt the opposite approach, though, the take-home message could be much more positive: Good dental hygiene may reduce our risk of developing a range of serious health problems.

As the authors of the lung cancer analysis, mentioned above, write, "periodontal disease is a preventable and treatable disease." Managing it at an early stage might reduce the risks of a multitude of ills.