At a recent conference, an outstanding lecture by Dr. Scott Lester of the Mayo Clinic, Rochester, provided insight into the question of why tumors exhibit “perineural invasion” – the behavior of tumors wrapping around and travelling along nerves. The answer is another example of how nature and biology never cease to surprise.
In medical school, one of my favorite professors loved to say, “50% of what you are going to learn during these four years will ultimately be proved wrong.” As I sat in my hard wooden chair taking notes on apparently error-ridden knowledge, I hoped that the 50% that was misinformation was at least not the half that mattered.
As it turns out, one of the pieces of misinformation apparently concerned perineural invasion. In medical school, I was taught that some tumors track along nerves because nerves are convenient highways to other parts of the body. This was the “path of least resistance idea.” Professors also posited that some of the vessels and lymphatics running along with the nerve are an additional reason for tumor growth along nerves – essentially the idea that tumors spreading along nerves is really just tumors spreading along the surrounding lymphatics and blood vessels – “business as usual.”
Several recent studies presented by Dr. Lester have provided data that sheds new light on this subject:
In one experiment, scientists placed a nerve next to but well apart from a tumor growing in a petri dish. The tumor extended a strand of cells in the direction of the nerve and grew toward the nerve. This challenges the idea that perineural tumor growth in patients is simply cancer extension along nerves already touching a tumor. Then, the scientists tested proteins found in the nerve and found that the entire nerve did not have to be present in the dish to attract tumor growth. When scientists put a small amount of a nerve protein called GDNF (glial derived neurotrophic factor) in the dish, the tumor grew towards the GDNF. Apparently, proteins in the nerve attract tumor growth. So nerves are not just highways: some tumors seek out nerves by growing towards proteins that nerves produce.
In another experiment, scientists placed pancreatic cancer cells next to the sciatic nerve inside of a live rat. Predictably, the cancer grew and invaded the sciatic nerve. The muscles relying on the sciatic nerve were unable to function which caused partial paralysis. However, when the scientists delivered radiation to the rat’s sciatic nerve BEFORE implanting the pancreatic cancer, the tumor grew but paralysis did not occur upon tumor implantation against the nerve. Nerves that had received radiation produced less GDNF.
We have long thought of radiation as primarily working by killing cancerous cells because radiation is known to cause breaks in cancer cell DNA resulting in cell death. But these studies led Dr. Lester, a radiation oncologist, to ask if radiation therapy’s effect on healthy tissue is just as important to its success as its effect on cancer cells themselves. Perhaps in some cases, radiation’s effect on growth factors in healthy nerve tissue is critical to preventing cancer recurrence.
As many questions as answers are raised by these studies. Will we one day have medicines that treat perineural tumors by inhibiting neurotrophic factors? For tumors that do not track along nerves but that invade muscle, bone or other tissue, will medicines increasingly target growth factors in these tissues to prevent spread? Already, medicine that targets “vascular endothelial growth factor” is being used to treat certain cancers. Perhaps one day a local injection of a medicine that blocks neurotrophic factors will be used to help treat perineural tumors.
As a Mohs surgeon, I took interest in these studies because many skin cancers track along nerves and because identifying perineural invasion under the microscope is an important part of my job. When I find significant perineural invasion, radiation therapy after surgery is an option I discuss. I hope that I might one day be able to offer a targeted pill or injection as an alternative to radiation.
However, I thought that these studies are of broad general interest because they are an intriguing example of how the obvious or intuitive answer so often is not the correct answer when biology is involved. Tumor growing along nerves is not just a case of taking the path of least resistance. So much of what we assume or are taught does not turn out to be the whole story. Nature is always more complex than we imagine, and new discoveries provide opportunities for medical advancement.
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