Researchers find byproducts from gum disease incite deadly oral cancer growth

Researchers from Case Western Reserve University have discovered how byproducts in the form of small fatty acids from two bacteria prevalent in gum disease incite deadly oral cancer growth (the growth of deadly Kaposi’s sarcoma-related (KS) lesions and tumors in the mouth).

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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Johns Hopkins researchers find that normal bacterial colonies in human body linked to presence of cancer of the mouth and throat

In a sample study, researchers at Johns Hopkins say they have found an association between the makeup of an individual’s normal bacterial colonies and head and neck cancer, a finding that potentially advances the quest for faster and more accurate cancer diagnosis and therapy.

In a report on the research published on May 30 in Oncotarget, the scientists say that populations of the human microbiome — the collection of normal bacteria inhabiting peoples’ bodies (normal bacterial colonies) — can help discriminate between patients with head and neck cancer and healthy individuals.

“One of the goals of our research is to better understand how the microbiome may influence the immune response to cancer and how the immune response affects the microbiome in turn,” says Rafael Guerrero-Preston, Dr. P.H., assistant professor of otolaryngology–head and neck surgery at the Johns Hopkins University School of Medicine and a member of its Kimmel Cancer Center. “Our findings suggest that we may one day use the composition of the microbiome to test for disease.”

Normal bacterial colonies contain trillions of microbes colonize the adult body. Changes in this community have already been tied to the risk and presence of arthritis, multiple sclerosis, irritable bowel syndrome and cancer. With more information on how these microbes are connected with cancer and cancer risk factors, such as genetic predispositions, smoking and other environmental factors, researchers hope to create individualized screening and treatment plans for cancer patients and for those at an increased cancer risk.

For this study, Guerrero-Preston and his colleagues extracted bacterial DNA from the saliva of 42 patients. Seventeen samples were drawn from people with head and neck squamous cell carcinoma, seven of which were positive for HPV and 10 of which were HPV-negative. Twenty-five noncancerous samples were used as a control.

The bacterial DNA found in the saliva was sequenced and sorted into groups of highly related populations. Through further DNA analysis, researchers were then able to determine the category, or genus, of bacteria to which each group belonged.

The researchers found differences in the bacterial populations present in cancerous versus noncancerous samples. Samples from patients with tumors, for example, showed increased populations of Streptococcus, Dialister and Veillonella genera, as well as decreased populations of Neisseria, Aggregatibacter, Haemophilus and Leptotrichia genera with respect to controls. Tumor samples also showed an increased prevalence of the Lactobacillus genus, which was present in 9.1 percent of tumor samples and in only 0.1 percent of the healthy controls. In addition, the researchers found correlations between the types of bacteria present and the patients’ HPV statuses. HPV-positive samples had increased abundances of Gemellaceae, Leuconostoc and Veillonella genera when compared to HPV-negative samples. Veillonella, for example, was present in 15 percent of HPV-positive tumor samples but was only present in 9.4 percent of HPV-negative tumor samples.

“We see some specific bacterial populations that are increased or lost in the presence of cancer when compared to healthy controls,” says Guerrero-Preston. This may mean that either the tumor is affecting the environment in the mouth by killing bacteria that would fight cancer or that the patients may be predisposed to cancer because they originally lacked bacteria that prevent tumor development.

Guerrero-Preston cautions that these findings do not establish a direct cause-and-effect link between any of the bacteria and head and neck cancer, stressing the preliminary nature of these assays. In particular, he says that future research needs to distinguish between the detection of bacterial DNA and the effects of the bacteria themselves. In order to determine how bacteria affect the oral environment, Guerrero-Preston’s team intends to look at which genes bacteria have turned on in saliva samples.

If the differences in the microbiome between cancerous and noncancerous/HPV-positive and HPV-negative tumors are confirmed in further studies with more patients, doctors may be able to use the same sequencing tools as Guerrero-Preston to quickly and accurately screen and diagnose patients based on the bacteria present in their mouths.

Guerrero-Preston says other research on the human microbiome has found that bacteria only present in the gut influence immunotherapies that utilize the body’s immune system to combat cancer in other tissues. With a greater understanding of how bacteria interact with a patient’s immune system, doctors may be better able to determine if immunotherapy will be effective and what side effects the patient may experience as a result of the treatment.

Other scientists who contributed to the study include Jessica Bondy, Fahcina Lawson, Oluwasina Folawiyo, Christina Michailidi, Tal Hadar, Maartje G. Noordhuis, Wayne Koch and David Sidransky  of the Johns Hopkins University School of Medicine; Filipa Godoy-Vitorino, Arnold Rodriguez and Herminio Gonzalez of the Inter American University of Puerto Rico; Anne Jedlicka and Amanda Dziedzic of the Johns Hopkins Bloomberg School of Public Health; and Rajagowthamee Thangavel of the Icahn School of Medicine at Mount Sinai.

Funding for the study was provided by National Cancer Institute grants (U01CA84986, K01CA164092, CA121113), National Institute of Dental and Craniofacial Research grants (P50DE019032, RC2DE20957).