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Neurons play role in oral cancer

Mouse sensory neurons sprout projections called neurites (red) after receiving growth signals from nearby oral cancer cells. Moran Amit, MD Anderson Cancer Center

More than 53,000 Americans this year are predicted to be diagnosed with head and neck cancers, some of which arise in the oral cavity. Advanced stages of the disease are hard to treat. Effective therapies must target both the tumor and its microenvironment—the supportive network of connective tissue, blood vessels, cells, and molecules that surround the tumor.

Nerves infiltrate this cancerous environment early in tumor development. Recent studies suggest that these nerves play a role in tumor growth and progression. Scientists are trying to understand the tumor-nerve relationship in hope that it could lead to better therapies for head and neck cancer.

A research team led by Drs. Moran Amit, George A. Calin, and Jeffrey N. Myers from the University of Texas MD Anderson Cancer Center began their study into this relationship by analyzing human data from the Cancer Genome Atlas. Their work was funded in part by NIH’s National Institute of Dental and Craniofacial Research (NIDCR) and other NIH components. The findings were published on February 20, 2020, in Nature.

The team found that high nerve density and TP53 mutations in oral cancer tissue were associated with earlier death. TP53 is the most commonly mutated gene in head and neck cancer. Its protein product, p53, is a tumor suppressor that acts as a brake on cancer growth. This function is lost when the gene is mutated, enabling tumors to grow unrestrained.

Using mouse models of oral cancer and laboratory cell cultures, the scientists confirmed the connection between p53 and nerve density. Sensory neurons (a type of nerve cell) in culture that were exposed to p53-deficient oral cancer cells sprouted projections called neurites. Sensory nerves are highly abundant in the oral cavity and convey touch, texture, and taste. These results suggest that loss of p53 in oral cancer enhances nerve growth and density in the tumor microenvironment.

Further experiments showed that growth cues come from tumors to neurons in the form of signaling molecules called microRNAs. These tiny snippets of RNA can alter growth, identity, and other functions of targeted cells. The scientists found that spherical delivery vehicles called extracellular vesicles were transferring the microRNAs from tumors to nerve cells in the microenvironment. These microRNAs nudge sensory neurons to reduce their normal gene activity and adopt genetic characteristics of a different class of nerve cells, known as adrenergic neurons, that are usually rare in the oral cavity.

Signals from adrenergic nerves trigger the body’s “fight-or-flight” response. Past studies showed that these signals can also promote tumor progression in other cancers. To confirm that the adrenergic neurons were promoting tumors, the scientists blunted adrenergic signaling in mice—either by disabling sensory nerves or giving adrenergic-blocking drugs. The resulting tumors were slower growing, smaller, and surrounded by fewer adrenergic-like neurons.

“We wanted to understand the reciprocal tumor-nerve signals that drive cancer progression,” Amit says. “This information could help scientists develop the means to target this crosstalk.”

—by Catherine Evans, Ph.D.