My BEST Dentists Journal


NYU study shows oral cancer pain may predict likelihood of cancer spreading

An oral cancer patient's pain intensity score could predict cancer metastasis, helping with future testing options and surgical decision-making, according to a study from the New York University College of Dentistry.

The authors of "Oncogenes Overexpressed in Metastatic Oral Cancers from Patients with Pain: Potential Pain Mediators Released in Exosomes," published in September by Scientific Reports, an open-access journal from Nature Research, used a questionnaire to document the pain experienced by 72 oral cancer patients before oral cancer surgery.

While most patients reported some pain, those with the most pain were more likely to have cancer that had spread to lymph nodes in the neck, suggesting patients with less pain were at lower risk of metastasis, according to the study. "While we need to undertake a follow-up study, our current data reveal that a patient's pain intensity score works as well as the current method — depth of invasion, or how deeply a tumor has invaded nearby tissue — as an index to predict metastasis," lead author Aditi Bhattacharya, Ph.D., said in an NYU news release about the study.

To help understand why metastatic cancers are more painful, the researchers looked for differences in gene expression in metastatic cancers from patients with high levels of pain and nonmetastatic cancers from patients not experiencing pain and identified 40 genes that were more highly expressed in painful metastatic cancers, suggesting those genes are associated with oral cancer metastasis and mediate cancer pain, according to the study.

One cause of cancer pain is attributable to the release of mediators from cancers that sensitize nerves near the tumor. Many of the 40 genes identified in this study code for proteins found in exosomes, small vesicles that break away from a cell and can be taken up by other cells. This is a potential mechanism for how oral cancer cells affect nerves, according to the study.

When the researchers injected the paws of mice with the extracellular fluid of oral cancer cells grown in culture, only those animals injected with the fluid containing exosomes experienced pain. This suggests exosomes from cancer may be responsible for oral cancer pain, according to the study."The identified genes are targets for therapy aimed at stopping pain and cancer. In addition, exosomes shed from cancers can be detected in saliva, blood and urine, offering the potential for an objective molecular test to diagnose risk of metastasis," said Donna Albertson, Ph.D., professor in the department of oral and maxillofacial surgery at the NYU College of Dentistry, an investigator at the NYU Bluestone Center for Clinical Research and the study's corresponding author.

When oral cancer spreads to lymph nodes in the neck, a patient's chance of survival is cut by half, according to the release. Because it's often unclear through imaging and physical assessment if oral cancer has spread, most oral cancer surgeries include preemptively removing lymph nodes, even though research shows as many as 70% of these prophylactic neck dissections are unnecessary, the release stated.

"Clinicians and researchers are keen to define a biomarker that accurately predicts metastasis," said Dr. Bhattacharya, who is also an assistant professor in the department of oral and maxillofacial surgery at the NYU College of Dentistry and an investigator at the NYU Bluestone Center for Clinical Research.

"Given that patients with metastatic oral cancer experience more pain, we thought that a patient’s level of pain might help predict metastasis. A surgeon could then use this knowledge to only remove lymph nodes in patients with cancers that are most likely to metastasize."

The study was supported by grants from the National Institutes of Health.

by NYU

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Too much fluoride causes defects in tooth enamel

Exposing teeth to excessive fluoride alters calcium signaling, mitochondrial function, and gene expression in the cells forming tooth enamel -- a novel explanation for how dental fluorosis, a condition caused by overexposure to fluoride during childhood, arises. The study, led by researchers at NYU College of Dentistry, is published in Science Signaling.

Fluoride is a naturally occurring mineral that helps to prevent cavities by promoting mineralization and making tooth enamel more resistant to acid. It is added to drinking water around the world -- the U.S. Department of Health and Human Services recommends a level of 0.7 parts per million -- and all toothpastes backed by the American Dental Association's Seal of Acceptance contain fluoride. The Centers for Disease Control and Prevention (CDC) named water fluoridation one of 10 great public health achievements of the 20th century for its role in reducing tooth decay.

While low levels of fluoride help strengthen and protect tooth enamel, too much fluoride can cause dental fluorosis -- a discoloration of teeth, usually with opaque white marks, lines, or mottled enamel and poor mineralization. Dental fluorosis occurs when children between birth and around nine years of age are exposed to high levels fluoride during this critical window when their teeth are forming, and can actually increase their risk of tooth decay. A survey by the CDC found that roughly 25 percent of the U.S. population examined (ages 6 to 49) show some degree of dental fluorosis.

"The benefits of fluoride for oral health considerably outweigh the risks. But given how common dental fluorosis is and how poorly understood the cellular mechanisms responsible for this disease are, it is important to study this problem," said Rodrigo Lacruz, PhD, associate professor of basic science and craniofacial biology at NYU College of Dentistry and the study's senior author.

To investigate the molecular bases of dental fluorosis, the researchers analyzed the effects of exposing tooth enamel cells to fluoride -- levels on the higher end of what you would find in drinking water and consistent with what is found in areas where people commonly have fluorosis. They then assessed fluoride's impact on calcium signaling within the cells, given calcium's role in mineralizing tooth enamel.

The researchers found that exposing enamel cells from rodents to fluoride resulted in calcium dysregulation, with decreases in calcium entering and stored in the endoplasmic reticulum, a compartment within cells with many functions, including storing calcium. In addition, fluoride disrupted the function of mitochondria (the cells' power generators), and therefore energy production was altered. Finally, RNA sequencing -- which queries the genomes of cells -- revealed that, in enamel cells exposed to fluoride, there was an increased expression of genes encoding endoplasmic reticulum stress response proteins and those encoding mitochondrial proteins, which are involved in producing the cell's energy.

"This gives us a very promising mechanistic view of how fluorosis arises," Lacruz said. "If your cells have to make enamel, which is heavily calcified, and due to exposure to too much fluoride the cells undergo continued stress in their capacity to handle calcium, that will be reflected in the enamel crystals as they are formed and will impact mineralization."

The researchers then repeated the experiment using early-stage kidney cells from humans, but they did not observe the same effects when the kidney cells were exposed to fluoride -- suggesting that enamel cells are different from cells forming tissue in other parts of the body.

"You would think that if you expose the enamel cells and kidney cells to the same stressor -- treating them with the same amount of fluoride for the same period of time -- that you'd have more or less similar responses. But that was not the case," said Lacruz. "Under the same circumstances, enamel cells react to coping with stress in vastly different ways than kidney cells. We are unraveling a mechanism that highlights the uniqueness of enamel cells and explains why fluorosis is more of a problem in the teeth than anywhere else in the body."

by New York University

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