In a preliminary study using a mouse model, researchers found that vagal denervation using Botox or other methods could help slow gastric cancer’s growth.
In a preliminary study using a mouse model, researchers have shown that vagal innervation plays a big role in gastric tumorigenesis, and that denervation using Botox injections or other methods could help slow the cancer’s growth.
In previous work, “it has been demonstrated that vagotomy decreases gastric mucosal thickness and cellular proliferation,” wrote researchers led by Duan Chen, MD, PhD, of the Norwegian University of Science and Technology in Trondheim. “An epidemiological study showed that the risk of gastric cancer after vagotomy was not reduced during the first 10-year period, but was reduced by 50% during the second 10-year follow-up.”
To test that influence of innervation on gastric tumorigenesis, Chen’s group tried various methods of denervation on mice; results were published in August in Science Translational Medicine. Surgical denervation with vagotomy yielded striking results: 6 months after the surgery, tumor incidence was 17% in mice who underwent vagotomy and 86% in the mice that underwent pyloroplasty alone. They confirmed these results in two other gastric cancer mouse models.
To prove the primarily local effects of this denervation, they then tested injections of botulinum toxin A (Botox) into the gastric wall. Six months after injections, “tumor size, score for dysplasia, and number of proliferating cells were markedly reduced,” the authors wrote. The changes were further associated with attenuated scores for inflammation, epithelial defects, and others connected with tumorigenesis. The protective effect of both surgery and Botox was seen further along in the mouse lifespan as well, suggesting cancer progression could be slowed even later on in life.
Though the mouse model is clearly preliminary, there were positive signs of how the idea of denervation might be used in humans eventually. In mice that had undergone denervation, the effects of systemic chemotherapy with 5-FU and oxaliplatin were significantly enhanced. Survival was better in denervated mice than in those that received the chemotherapy alone. “Together, these findings suggest that the combination of denervation and chemotherapy has an enhanced effect on tumor growth and survival,” the authors wrote.
The mechanisms behind the effects of denervation appear to involve gastric Wnt signaling, a pathway that helps regulate gastrointestinal stem cells and tumorigenesis. The investigators evaluated three cohorts of human gastric cancer patients and found that Wnt signaling was activated in cancerous tissue when compared to adjacent noncancerous tissue.
“Our finding that nerves play an important role in cancer initiation and progression highlights a component of the tumor microenvironment contributing the cancer stem cell niche,” the authors concluded. “The data strongly support the notion that denervation and cholinergic antagonism, in combination with other therapies, could represent a viable approach for the treatment of gastric cancer and possibly other solid malignancies.”