The incidence of brain metastasis among lung cancer patients varies from 10-40%, with a poor survival prognosis of less than 6 months1. Cigarette smoking is reported to be a major risk factor associated with the development of lung cancer and correlates with a higher incidence of brain metastasis1,2. The main component associated with the consumption of cigarettes is nicotine. Addictive, but not carcinogenic, nicotine has however been reported by several studies to promote tumoral growth through its nicotinic acethylcholine receptor nACH3,4, center of nicotine dependence. Interestingly, this receptor is expressed in microglia, which forms the main active immune defense in the brain. Microglia cells play a key role in mediating brain tumor progression and, after an injury can be activated into a classic cytotoxic, phagocytic-driven phenotype (called M1) but also sequentially polarized into a cytoprotective, pro-tumoral phenotype (called M2). In a very recent study, Wu and colleagues5 focused on how nicotine could affect the development of brain metastasis and propose the compound parthenolide (PTL) as a potential solution to counteract these effects.
Continuous nicotine use is associated with brain metastasis in lung cancer
Results from the human cohort including 281 patients with advanced stage lung cancer showed that incidence of brain metastasis as well as the mortality rate correlated with the length of smoking history. Noticeably, higher levels of M2-like microglial cells were found in brain lesions of smokers as compared to non-smokers. Moving forward to mouse models of lung cancer, the authors found that nicotine, after crossing the blood brain barrier, increases the expression of its nACH receptor on microglia and deviates these cells from the classic M1-like phenotype to turn on the M2-like pro-tumoral phenotype, a process resulting in tumor growth in mice brains. By contrast, pharmacological depletion of microglia blocked the effect of nicotine in promoting tumoral growth and increased the survival of mice. In vitro and in vivo experiments showed that pro-tumoral factors were highly secreted by nicotine-treated microglia, promoting formation of cancer stem cells. Indeed, pro-tumoral factors as well as markers of cancer stemness were highly concentrated in serum and brain lesions respectively of both nicotine-treated mouse models of lung cancer and smokers involved in the study. Furthermore, the researchers discovered that nicotine suppresses the innate phagocytic function of microglia while increasing the anti-phagocytic markers on tumoral cells, allowing them to escape from death.
Parthenolide reverses the effects of nicotine in mouse models of lung cancer
Remarkably, the screening of a natural compound library to identify molecules that can block the polarization of the microglia to the M2-phenotype led to the identification of PTL, found in the extract of the medicinal herb Tanacetum Parthenium, (also called commonly Feverfew herb – see caption image) traditionally used for treating migraines6. In vivo experiments of mouse models showed that PTL acts as a suppressor of the various nicotine-driven effects on promoting brain metastasis. In this context, PTL reinstalls the innate immune function of microglia, converting M2-like microglial cells to the classical phagocytic M1-like cells.
Parthenolide could be used to prevent and treat metastatic growth
That nicotine has a promoting effect on tumoral growth was already documented by different reports in the past2,3,4. In terms of novelty, the study led by Wu and colleagues showed that continuous consumption of nicotine in patients with lung cancer is associated with a spread of cancer cells to the brain and reprograming of the brain tumor microenvironment via nACH receptor on M2-like microglial cells. According to those results, nicotine replacement therapies7, such as nicotine patches, gums, or novel nicotine–delivery products such as e-cigarettes may not be appropriate for patients with lung cancer brain metastasis. However, the discovery that PTL, a compound that can cross the blood-brain barrier, reverts the observed effects of nicotine in mouse models of lung cancer holds great promise from a medical perspective for the treatment of smokers with lung cancer diagnosis and prevention from metastatic growth.
- Schaal et al. (2014). Nicotine-mediated Cell Proliferation and Tumor Progression in Smoking-Related Cancers. Molecular Cancer Research 12(1):14-23
- Sasco et al. (2004). Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 45 Suppl 2:S3-9
- Davis et al. (2009). Nicotine Promotes Tumor Growth and Metastasis in Mouse Models of Lung Cancer. Plos One 4(10):e7524
- Sun et al. (2017). Alpha5 Nicotinic Acetylcholine Receptor Contributes to Nicotine-Induced Lung Cancer Development and Progression. Frontiers in Pharmacology8:573
- Wu et al. (2020). Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. Journal of Experimental Medicine 217(8):e20191131
- Pareek et al. (2011). Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacognosy Review 5(9): 103–110.
- Shields (2011). Long-term Nicotine Replacement Therapy: Cancer Risk in Context. Cancer Prev Research 4(11):1719-23
Take home message
Cigarette smoking is reported to be among the risk factors associated with the development of lung cancer and correlates with a high incidence of brain metastasis. Here, Wu and colleagues observed harmful effects of the main cigarette component, nicotine, on potentiating tumor growth and progression toward metastasis in late stage lung cancer and present ways to counteract these effects. The team discovered that a natural compound, parthenolide (PTL), traditionally used for migraines, is able to cross the blood brain barrier and remove the pro-tumoral effects of nicotine in mouse models of lung cancer brain metastasis, allowing the animals to be free of metastatic growth and live longer. The present report suggests that nicotine replacement therapies such as nicotine patches, gums, and novel nicotine–delivery products such as e-cigarettes may not be appropriate for consumers with lung cancer brain metastasis. However, the discovery of PTL holds promise for the prevention of metastatic growth in lung cancer smokers and the treatment of consumers with brain metastasis.