Researchers find byproducts from gum disease incite deadly oral cancer growth

The discovery could lead to early saliva testing for the bacteria, which, if found, could be treated and monitored for signs of cancer before it develops into a malignancy, researchers say.

“These new findings provide one of the first looks at how the periodontal bacteria create a unique microenvironment in the oral cavity that contributes to the replication the Kaposi’s sarcoma Herpesvirus (KSHV) and development of KS,” said Fengchun Ye, the study’s lead investigator from Case Western Reserve School of Dental Medicine’s Department of Biological Sciences.

The discovery is described in The Journal of Virology article, “Short Chain Fatty Acids from Periodontal Pathogens Suppress HDACs, EZH2, and SUV39H1 to Promote Kaposi’s Sarcoma-Associated Herpesvirus Replication.”

The research focuses on how the bacteria, Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn), which are associated with gum disease, contribute to cancer formation.

Ye said high levels of these bacteria are found in the saliva of people with periodontal disease, and at lower levels in those with good oral health—further evidence of the link between oral and overall physical health.

The deadly oral cancer growth KS impacts a significant number of people with HIV, whose immune systems lack the ability to fight off the herpesvirus and other infections, he said.

“These individuals are susceptible to the cancer,” Ye said.

Deadly oral cancer growth KS first appears as lesions on the surface of the mouth that, if not removed, can grow into malignant tumors. Survival rates are higher when detected and treated early in the lesion state than when a malignancy develops.

Also at risk are people with compromised immune systems: those on medications to suppress rejection of transplants, cancer patients on chemotherapies and the elderly population whose immune systems naturally weaken with age.

The researchers wanted to learn why most people never develop this form of cancer and what it is that protects them.

The researchers recruited 21 patients, dividing them into two groups. All participants were given standard gum-disease tests.

The first group of 11 participants had an average age of 50 and had severe chronic gum disease. The second group of 10 participants, whose average age was about 26, had healthy gums, practiced good oral health and showed no signs of bleeding or tooth loss from periodontal disease.

The researchers also studied a saliva sample from each. Part of the saliva sample was separated into its components using a spinning centrifuge. The remaining saliva was used for DNA testing to track and identify bacteria present, and at what levels.

The researchers were interested in Pg’s and Fn’s byproducts of lipopolysaccharide, fimbriae, proteinases and at least five different short-chain fatty acids (SCFA): butyric acid, isobutryic acid, isovaleric acid, propionic acid and acetic acid.

After initially testing the byproducts, the researchers suspected that the fatty acids were involved in replicating KSHV. The researchers cleansed the fatty acids and then introduced them to cells with quiescent KSHV virus in a petri dish for monitoring the virus’s reaction.

After introducing SCFA, the virus began to replicate. But the researchers saw that, while the fatty acids allowed the virus to multiple, the process also set in motion a cascade of actions that also inhibited molecules in the body’s immune system from stopping the growth of KSHV.

“The most important thing to come out of this study is that we believe periodontal disease is a risk factor for Kaposi sarcoma tumor in HIV patients,” Ye said.

With that knowledge, Ye said those with HIV must be informed about the importance of good oral health and the possible consequences of overlooking that area.

The research was supported by a career development grant at Center for AIDS Research at Case Western Reserve University, and a National Institute of Dental and Craniofacial Research grant.

Contributing to the study were Case Western Reserve University researchers Abdel-Malek Shahir and Nabil Bissada, from the Department of Periodontics; Xiaolan Yu, Jingfeng Sha, Zhimin Feng, Betty Eapen, Stanley Nithianantham, and Aaron Weinberg, from the dental school’s Department of Biological Sciences; and Biswajit Das and Jonathan Karn, from the Department of Molecular Biology & Microbiology at the School of Medicine.

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Identification of gum disease genes may speed quest for compounds to treat severe periodontitis

Identification of the genes represents a vital step toward developing compounds that can be used in targeted, individualized treatment of severe periodontitis, before loss of teeth and supportive bone occurs.

Findings of the study were published recently in the Journal of Dental Research.

In gene expression studies, investigators find those genes that are most commonly expressed in either healthy or diseased tissue. But such studies cannot identify a causal link between these genes and the disease, and often miss genes that affect a larger number of genetic pathways, which may have a large impact on the disease process.

In this study, a team led by Panos N. Papapanou, DDS, PhD, professor and chair of oral, diagnostic and rehabilitation sciences at the College of Dental Medicine at CUMC, “reverse-engineered” the gene expression data to build a map of the genetic interactions that lead to periodontitis and identify individual genes that appear to have the most influence on the disease. “Our approach narrows down the list of potentially interesting regulatory genes involved in periodontitis,” says Dr. Papapanou. “This allows us to focus on the handful of genes that represent the most important players in the process rather than the whole transcriptome.”

To identify the genes, Dr. Papapanou partnered with CUMC investigators including Ryan Demmer, PhD, assistant professor of epidemiology, at the Mailman School of Public Health, and researchers in Systems Biology who had previously developed algorithms to identify regulatory genes that fuel cancer growth. The researchers examined RNA from healthy and diseased gum tissues of 120 patients with periodontitis. They applied one algorithm to study the interactions among the genes and used another algorithm to identify genes that disrupt healthy tissue and drive the disease process.

Many of the genes identified by Dr. Papapanou and his team are implicated in immune and inflammatory pathways, confirming laboratory and clinical observations of the development of periodontal disease.

Identification of the master regulator genes will allow investigators to test compounds that interrupt their action, creating treatments that stop periodontal disease at its source. “Now it’s important to do the downstream work of validating these master regulators in the lab before we can test these genes in experimental models,” says Dr. Papapanou.