Cutting both branches of the vagus nerve to the stomach or blocking its chemical signal with botulinum toxin (Botox) injections prevents the development and progression of gastric cancer in mouse models, new research shows.
The advantage of botulinum toxin is that "it can be used locally and it targets cancer stem cells," study investigator Duan Chen, MD, PhD, from the Norwegian University of Science and Technology in Trondheim, said in a press release. It "can also be injected through gastroscopy, and it only requires the patient to stay in the hospital for a few hours."
The study was published online August 20 in Science Translational Medicine.
When studying gastric cancer, "one of the things we observed was that there was a significant accumulation of nerves within the [tumor] microenvironment," explained Timothy Wang, MD, from the Columbia University Medical Center in New York City, who is another of the study investigators. "The density of the nerves seemed to correlate with prognosis, suggesting that in the same way that blood vessels and angiogenesis might be important to tumor growth, what we call 'neurogenesis' might be important to cancer growth," he told Medscape Medical News.The vagus nerve branches into 2 separate trunks in the stomach, each innervating half of it, Dr. Wang explained. In a series of experiments, the investigators performed unilateral or bilateral vagotomy in several different mouse models of gastric cancer. The mice evaluated were in the preneoplastic stages of gastric cancer or had established neoplastic changes.
"We found that cutting both branches of the vagus nerve really blocked the development of gastric cancer in our mouse models, whereas cutting only one branch prevented tumor growth on one side of the stomach but not the other— indicating that this was a very local effect," Dr. Wang noted.
Subsequent experiments confirmed that denervation of the stomach consistently suppressed gastric tumorigenesis in all mouse models.
The investigators found that denervation of the vagus nerve with localized botulinum toxin injections was as effective as vagotomy for blocking the development and progression of early and later stages of gastric cancer. Botulinum toxin blocks the release of all neurotransmitters, including acetylcholine, so that nerve endings can no longer communicate with other nerves or, in this case, the cancer stems cells that are driving cancerous growth, Dr. Wang explained.
The team determined that acetylcholine jumpstarts a number of the signaling pathways implicated in gastric cancer, and stimulates cancer stem cells to divide.
"This gave us a complete pathway by which the release of this neurotransmitter is feeding the growth of stomach cancer cells," Dr. Wang elaborated. "And this could be blocked using a variety of techniques."
Subsequent experiments in the same mouse models showed that denervation with botulinum toxin injections could enhance the effect of systemic chemotherapy, and could enhance survival even in mice with advanced tumors.
"For most patients, we are suggesting that denervation works best in combination with traditional chemotherapy. Loss of nervous input appears to make cancer cells more vulnerable to chemotherapy, which makes chemotherapy more efficient," Dr. Wang stated in a press release.
This research could have applications in other tumor types. "The nerve–tumor growth connection is likely to be true in other solid tumors, such as in prostate cancer, but the precise nerves that are involved likely vary from organ to organ and tumor to tumor. Further studies are needed," Drs. Chen and Wang note.
Results in animal models have been so positive that a phase 2 clinical trial is underway in Norway, where patients with inoperable stomach cancer will receive injections of botulinum toxin in an effort to denervate the stomach and stop tumor progression.
This research was supported by grants from the Research Council of Norway, the Joint Programme of the Norwegian University of Science and Technology Medical Faculty and St. Olavs University Hospital, and the US National Institutes of Health. The authors have disclosed no relevant financial relationships.
Sci Transl Med. Published online August 20, 2014. Abstract
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