Preclinical findings from Columbia University Medical Center are the latest evidence that nerves help drive tumor growth. A coauthor tells Cancer Therapy Advisor that nerves may be more important than angiogenesis and blood flow for tumor growth, providing researchers with an important new investigational target for treatment.
Vagus nerves may play a key role in driving gastric tumor growth, and blocking nerve signals surgically or with Botox® (onabotulinumtoxinA) injections appears to slow tumor growth, according to preclinical research published in Science Translational Medicine.1
“Our work in stomach cancer suggests that nerves are involved at the earliest stages of tumor development, through interactions with cancer-initiating cells, and are clearly required for later tumor growth,” said coauthor Timothy C. Wang, MD, of the Columbia University College of Physicians and Surgeons in New York, New York.
“We believe that nerves are a key part of the [tumor] microenvironment, and may be more important than angiogenesis or blood flow for tumor growth,” Dr. Wang told Cancer Therapy Advisor. “Early in tumor development, there appears to be a ‘cross-talk’ between the cancer cells and the nerves, with signals going back and forth. Cancer cells induce the outgrowth of neuritis toward the tumor, while nerves provide growth signals to the tumor cells.”
The team performed vagotomies (surgical innervations) using three mouse models of stomach cancer, noting that cutting nerves on only one side of the stomach was followed by continued growth of tumors on the side with intact nerves, while growth slowed significantly in tumors near the severed nerves.1 The team also saw similar results when they used Botox, a bacterial neurotoxin, to block nerve release of acetylcholine, a neurotransmitter that stimulates cell division.
Dr. Wang’s team also reported that in 12 of 13 human patients who underwent vagotomy after gastric cancer recurrence, gastric tumors did not recur or develop near severed nerves in a region where tumors did recur among 24 patients who did not undergo vagotomy.
“We suspect that nerves play a role in the growth of most solid tumors,” Dr. Wang said, citing another team’s study of nerve involvement in prostate cancer, which was published last year in Science.2
His own team’s unpublished data suggests that nerves are also “likely very important” in pancreatic cancer, and there is also evidence that nerves are involved in lung cancer, he says. “We believe this is a common principle, although with some variation [between cancer types] in the role of different neurotransmitters.”
Posttreatment tumor recurrence rate data are not yet available, Dr. Wang said.
It is also not yet clear whether more advanced cancers will respond differently than early-stage tumors to nerve-targeting treatments—or whether nerves are involved in metastasis, he is quick to acknowledge.
“In general, more advanced cancers tend to be a bit less responsive to most forms of therapy for a variety of reasons,” he noted. “Our best guess, based on the history of therapy in cancer, is that denervation therapy will have some efficacy in advanced tumors but will be insufficient as a standalone therapy. We would suggest it would work best in combination with chemotherapy or other therapies. However, the major challenge in advanced or invasive tumors is that it is more difficult to target Botox or surgical denervation approaches if the tumor becomes more diffuse and widespread in its location.”
Dr. Wang and his colleagues are now looking at nerve/tumor communication in the stomach and the pancreas. “We are encouraging our colleagues who are clinical investigators to follow-up with phase 1 studies in patients,” he said. “In addition, we are following up on our observation that in stomach cancer the M3 cholinergic receptor is most important and whether there may be antagonists that are effective and which can be tolerated by patients for extended periods of time.”
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Yanghee Woo, MD, of the Columbia University Medical Center’s Gastric Cancer Center in New York, New York, is now heading up a phase 1 clinical study of vagotomy combined with gastric resection for early-stage gastric cancer.
Duan Chen, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, Norway, is conducting a phase 2 clinical trial of Botox for advanced gastric cancer that is unresponsive to first- and second-line chemotherapy.
“More studies are needed,” Dr. Wang concluded.
- Zhao CM, Hayakawa Y, Kodama Y, et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med. 2014;6(250):250ra115.
- Magnon C, Hall SJ, Lin J, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341(6142):1236361.