Nerve fibers within melanomas found to slow tumor growth

Nerve fibers within melanomas can slow the growth of these tumors, according to a study led by Weill Cornell Medicine investigators. The findings help clarify the emerging field of cancer neuroscience and may inform future therapeutic strategies.

In the study, published April 29 in Neuron, the researchers used mouse models of the skin cancer melanoma to examine the presence and the effects of peripheral nerves that grow into tumors. They found that nerves of the sympathetic nervous system are often abundant in such tumors, and can inhibit tumor growth by reducing local tumor-supportive macrophages-a type of immune cell.

The nervous system typically has been considered as a driver of cancer growth, but here we've found that it can be a brake on cancer growth in some contexts. Now the key will be to see how broadly relevant this is for human cancers, and how we can best step on that brake to help cancer patients."

Dr. David J. Simon, study senior author, assistant professor of biochemistry and biophysics at Weill Cornell Medicine

The peripheral nervous system is the tree-like system of nerves that extends outside the brain and spinal cord. It includes the sensory nerves that underlie feelings such as heat and cold, pain and itch; and nerves of the sympathetic nervous system, which transmit signals from the brain to influence the functions of various organs. In the skin, most sympathetic nerve fibers can release the stress hormone norepinephrine, affecting immune cells, sweat glands and other targets as part of the "fight-or-flight" response.

Peripheral nerves are commonly found in tumors, but it is only in recent years that researchers have begun examining the roles of these nerves in cancer outcomes. Most of these investigations have found that sensory and sympathetic nerves can enhance tumor growth, for example by releasing molecules that suppress antitumor immunity. In just the last few years, however, there have been hints that peripheral nerves in some cases may be able to slow tumor growth instead.

Dr. Simon and his team have expertise in studying the growth and survival of peripheral nerve fibers, especially those that grow into the skin. "We knew that these nerves entered melanoma, but studying their role in cancer growth was not our main goal," said Dr. Simon. "But we were fortunate to receive generous early-stage support from the Pershing Square Sohn Cancer Research Alliance that allowed us to take a risk and explore these nerve-tumor interactions in detail."

"We used a technique called whole mount immuno-labeling, in which an entire tissue sample is made optically transparent, to count, identify and trace the paths of the nerves in the tumors," said study first author Dr. Tingting Liu, a postdoctoral research associate in the Simon Lab.

These initial investigations revealed that pain-sensitive nerves and sympathetic nerves were prevalent in the melanomas, increasing in number as the tumors grew, particularly in slower-growing tumors. The pain-sensitive nerves, consistent with prior studies, appeared to have a pro-tumor effect-depleting them inhibited tumor growth-but the sympathetic nerves surprisingly exerted an anti-tumor effect.

The sympathetic nerves identified in the study release norepinephrine, which can activate receptors called adrenergic receptors on other cells in the vicinity. The researchers traced the anti-tumor effect in their models to a subset of adrenergic receptors called alpha adrenergic receptors, and identified immune cells called macrophages as the key cellular targets of this alpha adrenergic signaling. Tumors often turn macrophages into allies, for example by switching them into an immunosuppressive mode, but the alpha adrenergic signaling reduced the numbers of such pro-tumor macrophages, thereby slowing tumor growth.

The findings open up the prospect of future anti-cancer therapies that target sympathetic nerves within tumors, or even the alpha adrenergic receptors on tumor-associated macrophages. Drugs targeting these receptors are already in use as common blood pressure medicines. For now, Dr. Simon plans to continue with more fundamental research, for example to tease apart how these adrenergic receptors are activated and signal in actual cancers in humans.

"There's a lot still to do in terms of the basic biology here," he said.