Study Sniffs Out New Glioma Mechanism

Noses twitching, mice sniff the air for the telltale scents of food, mates, and predators. But for some of them, this normal behavior has a surprising downside—promoting the growth of gliomas—a study has found (Nature 2022;606:550–6). The work is the first to suggest that olfaction plays a role in cancer.

The nervous system often abets tumors. In prostate cancer, for instance, nerves promote angiogenesis and metastasis. And one study determined that optic nerve activity boosts the formation and growth of gliomas in mice with a mutated Nf1 tumor suppressor gene, suggesting that “visual experience” might foster cancer (Nature 2021;594:277–82).

Chong Liu, PhD, of Zhejiang University in China, and colleagues wanted to determine why gliomas often occur in the olfactory bulb. They suspected that sensory neuron activity was to blame.

To test their hypothesis, the scientists turned to mice lacking Nf1 and the tumor suppressor Trp53 in oligodendrocyte precursor cells, the cells from which gliomas often arise. Such rodents are prone to gliomas in the olfactory bulb, which first receives impulses from olfactory neurons. The scientists also genetically modified the animals so that their olfactory neurons carried either of two types of receptors sensitive to the drug clozapine: One receptor variety stimulates the neurons, and the other inhibits them.

The team first tested whether prodding the inhibitory receptor—and thus blunting the sense of smell—curtailed tumor growth. They gave clozapine to animals with this receptor. After about 6 months, the mice harbored olfactory bulb tumors about half the size of tumors that formed in controls lacking the receptor, the researchers found.

To determine the effect of amplifying the sense of smell, Liu and colleagues dosed rodents that carried the stimulatory receptor with clozapine. When the researchers measured the resulting gliomas after about 6 months, the tumors were larger in the mice with the receptor than in controls without it.

Next, the team plugged one of glioma-prone rodents’ nostrils with a sliver of silica gel. The mice could still breathe and smell through the other nostril. Animals with a blocked right nostril grew larger tumors on the left side of olfactory bulb, which receives signals from the olfactory receptors in the left side of the nose. Similarly, right-side tumors were larger in mice that couldn't breathe through their left nostril.

“We provide causal evidence that sensory experience can directly affect tumorigenesis via the corresponding neuronal circuits,” says Liu.

Other research has shown that neurotransmitters released by neurons stoke tumor growth. However, olfactory neurons probably don't directly stimulate tumors, Liu and colleagues found. Instead, the neurons nudge other cells in the olfactory bulb to release IGF1, a growth factor that spurs division of oligodendrocyte precursor cells with cancer-promoting mutations.

“This is a beautiful paper,” says Ali Zahalka, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, NY, who wasn't connected to the research. “It provides very convincing evidence that there is an interaction between our environment and our senses that can lead to cancer.”

So far, there's no evidence that a similar mechanism occurs in humans, notes Moran Amit, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who also wasn't involved in the research. “It's simplistic to say that smell causes cancer,” he explains, because the mice had been genetically engineered to develop gliomas. However, olfactory stimulation may provide the final “hit” that triggers cancer development if mice—and possibly people—already have a genetic predisposition, he says. –Mitch Leslie

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