Vincent Van Gogh, “A Skull with a Burning Cigarette” (c. 1885-1886)
Wikimedia commons
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Smoking and other uses of nicotine increase the risk of lung cancer metastases in the brain. Although nicotine itself is not a carcinogen, it reprograms the immune cells of the brain, preventing them from effectively fighting malignant neoplasms. As the researchers noted in an article for Journal of Experimental MedicineThe discovery shows that even substitution therapy such as nicotine patches and electronic cigarettes is deadly for patients with lung cancer.
40 percent of people suffering from lung cancer develop brain metastases. The average life expectancy of such patients is only six months. Unfortunately, it remains unclear exactly which factors stimulate the penetration of malignant cells into the brain. Many experts suspect that smoking may be the cause, however, although the relationship between this bad habit and the development of lung cancer has long been proven, its role in the formation of metastases has not been studied.
Investigators led by Konosuke Watabe of Wake Forest University School of Medicine decided to investigate this matter. At the first stage of work, they examined 281 patients with lung cancer, which metastasized to the brain. It turned out that among those who continued to smoke even after diagnosis, the risk of the disease entering the brain was much higher. In contrast, patients who never smoked or got rid of this habit were less likely to experience metastases.
As an analysis of the brain structure of smokers showed, instead of microglia of the standard M1 phenotype, the M2 variant dominated in the areas of metastasis. Such microglia suppressed inflammatory processes and thereby helped tumors survive and grow. In addition, cells of type M2 ceased to absorb malignant cells.
Researchers have suggested that a shift in the work of microglia was triggered by nicotine. To test this idea, they conducted an experiment with laboratory mice. The animals were transplanted with lung cancer cells, and then every three days a dose of nicotine was administered at the rate of one milligram per kilogram of body weight. As a result, individuals who received the injection were more likely to develop lung cancer metastases in the brain. As in humans, rodents in the affected areas of the brain were dominated by type M2 microglia. Interestingly, nicotine had no effect on the risk of bone metastasis.
Additional experiments with cell cultures confirmed that nicotine does not increase the growth rate of malignant cells, but changes the microglia phenotype from M1 to M2, affecting a number of its genes through nicotinic acetylcholine receptors. As a result, it loses its ability to inhibit cancer metastasis.
Then the team members tried to find a compound that could neutralize the effect of nicotine. After looking at a library of natural compounds, they selected 103 candidate molecules that could cross the blood-brain barrier. The most promising of them turned out to be a substance called parthenolide, sesquiterpene lactone from the medicinal plants of tansy of a girl (Tanacetum parthenium) In experiments with cell cultures and mice, parthenolide not only reversed the conversion of M1 to M2 microglia, but also helped to reduce metastases. Researchers hope that this molecule will form the basis of new drugs for the treatment of advanced lung cancer.
The results obtained not only open up new prospects for cancer therapy. As the authors emphasize, they once again recall the dangers of nicotine for patients with lung cancer. And the threat is not only smoking, but also the use of substitutes, such as nicotine patches and electronic cigarettes.
Smoking not only increases the risk of malignant neoplasms in the brain, but also harms mental health. A study by British geneticists has shown that there is a causal relationship between smoking and the risk of developing schizophrenia and depression. Smokers suffer from schizophrenia 2.27 times more often, and depression – 1.99 times more often.
Sergey Kolenov
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