Nerves, stress, cancer
The triad that needs to be broken down
Over the past three decades, scientists have discovered that one of the "partners" and assistants of a cancerous tumor are nerve fibers located in its immediate environment. One of the possible mechanisms explaining the relationship between the level of innervation and the progression of cancer is chronic stress, which causes the release of hormones that stimulate tumor growth. And although the results obtained so far have no immediate practical output, they open up the possibility of cancer therapy with the help of drug effects on the nervous system
Cancer cells are able to use the resources of the body and successfully interact with other, healthy cells. For example, they stimulate the growth of blood vessels, as a result of which the tumor receives more nutrients. By influencing the immune system, they become "invisible" to its killer cells, and today researchers are actively developing methods to counteract this influence. But the presence of small nerve bundles in tumors and in their vicinity could be established only after the appearance of accurate ways of labeling neurons. But even after that, there was relatively little interest in them.
The situation began to change after a link was established between chronic stress and the likelihood of developing cancer – the tumor grows faster in laboratory animals under stress due to limited mobility or social isolation. The main research was devoted to the sympathetic nervous system – the department of the autonomic (autonomic) nervous system, which, in particular, controls the reaction to the threat of "hit or run".
The key role in the work of this system is played by the hormones adrenaline and norepinephrine, which are released by the adrenal glands into the bloodstream, and sympathetic nerves – into nearby tissues. Many cells in the body, including cancer cells, contain b-adrenergic receptors to which these hormones bind, and the activation of these receptors seems to stimulate the growth of tumor cells. In 2006, it was shown that both chronic stress itself and an artificial activator of beta-adrenergic receptors accelerate the growth of mouse ovarian tumors, and their blockers slow down. And when, in 2013, researchers inoculated mice with human prostate tumor cells, and then removed all nearby nerves, they found a decrease in the growth rate and metastasis of the tumor.
The very fact of physical interaction between cancer cells and nerve fibers was noticed much earlier. So, back in the late 1990s, scientists in an experiment on the joint cultivation of mouse spinal nerves and human prostate cancer cells saw that the nerves themselves stretched out towards the cancer cells and grew into them. And in 2019, in studies on laboratory mice, it was found that cancer cells, with the help of certain signaling molecules, can not only "force" nerves to contact the tumor, but also encourage the body to grow new neurons from stem cells that will be directed to its location.
It also turned out, for example, that a person has a high density of nerve bundles inside and around a prostate tumor is directly related to the likelihood of recurrence after surgery. Similar correlations were found for tumors of other organs, including the mammary gland, large intestine and lungs. As a result, all peripheral nerves are now considered not just supporters, but active participants in oncogenesis, and the presence of cancer cells along the nerve fibers is a marker of high tumor aggressiveness.
But why do tumors need nerves? Perhaps the whole point is that nerve fibers themselves are able to grow and, consequently, produce molecular growth factors that promote the growth of cancer cells. Nerves can also encourage immune cells macrophages to destroy nearby tissues and secrete molecules that stimulate cell growth. On the other hand, cancer cells can monitor signals from sympathetic nerves, whose work changes under stress, and such monitoring helps them synchronize their activity with periods of weakening of the immune system.
The results obtained so far on the relationship between cancer and stress are interpreted in different ways. For example, they clarify that "stress" does not mean a negative psychological experience, because such experiences do not always coincide with the release of stress hormones. But they do not exclude that it is the chronic stay in the "fight or flight" mode that can explain the low success rate of treatment of cancer patients with low socio-economic status. However, it is still practically impossible to objectively measure the intensity of stress or determine which stressful experience influenced the development of the disease.
In any case, these results open up the possibility of cancer therapy by influencing the nervous system with drugs. Such as beta-blockers that "turn off" beta-adrenergic receptors, which have been used in cardiology since the 1960s to slow down the heart rate and, sometimes, to relieve short-term anxiety states.
Recently, studies have been initiated on the effect of taking beta-blockers together with anti-inflammatory drugs (inflammation also contributes to the development of cancer) on the level of metastasis after surgery to remove the tumor. In 2017, the results of clinical trials were published, in which 38 women with breast cancer participated, half of whom took the beta-blocker propranolol and the anti-inflammatory drug etodolac 5 days before surgery. It turned out that in the tumor tissues of patients receiving the drugs, the genes associated with metastasis were less active. Similar (as yet unpublished) data are available for a sample of 34 patients with colon cancer. Similar to these, but larger-scale studies are being conducted in Israeli medical centers, where scientists plan to monitor the condition of 210 people with pancreatic cancer for five years.
There are other potential drugs besides beta blockers. For example, antibodies that bind and "turn off" proteins that promote nerve growth. Or botulinum toxin, the injection of which in the experiment not only blocked nerves in one of the tumor sites, but also caused the death of more cancer cells. So this area is a real "untilled field" where scientists still have a lot of work to do.
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