JEM: Cracking the mystery of smoking promotes lung cancer cells to get into the brain! Scientists have found that nicotine can alter the properties of small glial cells, making the brain suitable for cancer cells to grow.

The incidence rate of lung cancer is one of the highest incidence cancers, and it is easy to metastasize. According to statistics, brain metastasis occurs in 10%-36% lung cancer patients, and this figure may still be underestimated [1].after brain metastases, the median survival time of patients is usually less than 6, mainly because of the complex and special brain structure, difficult drug delivery and high surgical risk. Although new radiotherapy has been found to help control brain metastases in recent years, the effect is still not very good, and radiotherapy can kill normal nerve cells, which has an impact on patients' life.therefore, finding out the cause of brain metastasis and preventing it is a direction of many researchers' efforts.in the recent journal of Experimental Medicine [2], researchers from the Baptist Medical Center at Wake Forest University have shown that smoking is a cause of lung cancer metastasis to the brain! Picture from pexel.com Their experiments found that nicotine in cigarette smoke can cross the blood-brain barrier and reach the brain, prompting macrophages microglia in the brain to change their phenotypes, increase the secretion of growth promoting factors and chemokines, and promote the formation and development of metastatic foci.not only that, nicotine also inhibits the phagocytosis of microglia and prevents them from processing tumor cells.however, the researchers identified a compound, chrysolide, extracted from Chrysanthemum morifolium, which can prevent nicotine from changing the phenotype of microglia, thereby inhibiting brain metastasis.smoking has been proved to be one of the main risk factors of lung cancer by many studies, while previous studies have found that smoking is related to the rapid development of brain metastasis of lung cancer [3].this time, the researchers also analyzed the relationship between brain metastasis and smoking in 281 patients with advanced lung cancer. Compared with those without smoking habit and those who had quit smoking, the incidence of brain metastasis in patients with smoking habit was significantly higher, and smoking was associated with lower survival rate and overall survival rate without brain metastasis.A: the incidence of brain metastasis (black) in non-smoking, quitting smoking and always smoking patients B, C: progression free survival and overall survival of smokers (red) and non-smokers (blue). In the brain metastases of smoking patients, the number of microglia increased significantly, and most of them were M2 type.in view of the fact that the activation of microglia is related to the progress of brain tumors [4], nicotine, one of the main components of cigarette smoke, can bind to nicotinic acetylcholine (nach) receptor, which is also widely expressed in microglia [5].therefore, the researchers speculate that smoking patients with lung cancer are more likely to have brain metastases, which may be due to nicotine and microglia.there are two types of microglia after activation, one is classical type (M1), the other is replacement type (M2).M1 microglia can secrete proinflammatory factors such as tumor necrosis factor - α (TNF - α) and interleukin-1 β (IL-1 β) to initiate inflammatory reaction and induce cell apoptosis, while M2 type microglia mainly secrete vascular endothelial growth factor (VEGF) and transforming growth factor - β (TGF - β) to promote angiogenesis and inflammatory repair.under normal conditions, the two types of microglia maintain dynamic balance.but for now, the presence of nicotine seems to have upset their balance.the researchers found that microglia express high levels of nach receptor α 4 β 2, which is the most sensitive receptor for nicotine in the brain.in the two lung cancer mouse models, the researchers injected them with nicotine, the incidence of brain metastasis in both lung cancer mice was significantly increased, and the growth of metastatic foci was faster. However, there was no significant difference in bone metastasis, which is also prone to lung cancer. in the control group (left) and nicotine group (right), immunohistochemical analysis showed that there were high levels of activated microglia in the metastatic foci of nicotine group, and most of them were M2 type, which was much less than M1 type. the researchers injected the mouse brain with the csf1 receptor inhibitor plx3397, which can eliminate about 99% of the brain microglia. Sure enough, the brain metastasis of lung cancer mice was significantly inhibited, and the survival time without brain metastasis was significantly prolonged. sequencing results showed that nicotine increased the expression of arginase-1, arginase-2 and cd204 genes, as well as the activity of JAK / STAT3 signaling pathway, which were the characteristics of microglia polarization toward M2 type. after polarization, M2 microglia induced the increase of Sox2 and Nanog Gene Expression in brain metastatic tumor cells. These two genes are important genes in stem cells, which maintain the stem cells' high self-renewal ability and differentiation ability. moreover, M2 increases the secretion of insulin-like growth factor 1 (IGF1) and chemokine CCL20, one promoting growth and the other promoting aggregation. Therefore, excessive M2 leads to the rapid formation of brain metastases. not only that, nicotine also inhibited the phagocytosis of microglia and increased the expression of CD47 on tumor cells. CD47 is the "gold medal" of tumor cells. They mimic normal cells to express CD47 and transmit "don't eat me" signal to immune cells to disguise as normal cells to escape the sanction of immune cells. from pictures pexel.com So nicotine not only acts on microglia, suppresses phagocytosis, and activates them toward growth promoting phenotypes, but also acts on tumor cells to help them avoid immune cells. based on these results, the researchers thought that avoiding M2 polarization of microglia might be a potential therapy to block brain metastases from lung cancer. they screened the natural compound library and found three compounds from 103 known compounds that can cross the blood-brain barrier, which can effectively inhibit nicotine induced M2 microglia related gene promoter activation at a low concentration of 1 μ M. among them, chrysanthelide has the strongest inhibitory effect, and the promoter activity is reduced by more than 20 times. inulin is extracted from a kind of Tanacetum Parthenium and is used to treat inflammation and headache in Europe [6]. and previous studies have found that it can regulate JAK / STAT3 signal transduction [6]. this experiment also confirmed that parthenolide inhibited JAK / STAT3 signal, reduced M2 microglia, and restored the phagocytic capacity of microglia, and the survival time without brain metastasis of mice was doubled! The weight of the mice was not affected and no liver toxicity was detected. the survival rate of mice in control group (green), nicotine group (red) and after nicotine treatment of parthenolide group (black) changes, the researchers believe that this may represent a new treatment for brain metastasis of lung cancer, especially for smoking lung cancer patients. most importantly, unlike chemotherapy drugs, it can cross the blood-brain barrier and is not highly toxic. research co-author Dr. kounosuke Watabe said that in the near future, he hopes to work with clinical oncologists to verify the effect of parthenolide on brain metastasis of lung cancer in clinical trials. although ASCO in 2020 is over, its impact on cancer treatment in the next few years is just beginning. in order to help you quickly grasp the key points of this year's ASCO and effectively obtain a panoramic understanding of the frontier progress, we have also made full efforts to create the "asco2020 trend interpretation". it comprehensively combs the 9 major cancer species and the key academic research in 300 oral reports, so as to give you a comprehensive overview of the progress of ASCO in 90 minutes.