Nicotine promotes metastasis of lung cancer to the brain

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Among people who have the most common type of lung cancer, up to 40% develop metastatic brain tumours, with an average survival time of less than six months. But why non-small-cell lung cancer so often spreads to the brain has been poorly understood. Now scientists at Wake Forest School of Medicine found that nicotine, a non-carcinogenic chemical found in tobacco, promotes the metastasis of lung cancer cells into the brain.

“Based on our findings, we don’t think that nicotine replacement products are the safest way for people with lung cancer to stop smoking,” said Dr Kounosuke Watabe, professor of cancer biology at Wake Forest School of Medicine and lead author of the study.

In the study, Watabe’s team first examined 281 lung cancer patients and found that cigarette smokers exhibited a significantly higher incidence of brain cancer. Then, using a mouse model, the researchers discovered that nicotine enhanced brain metastasis by crossing the blood-brain barrier to change the microglia – a type of immune cell in the brain – from being protective to supporting tumour growth.

Next Watabe and colleagues looked for drugs that might reverse the effects of nicotine and identified parthenolide, a naturally occurring substance in the medicinal herb feverfew, which blocked nicotine-induced brain metastasis in the mice. Because feverfew has been used for years and is considered safe, Watabe believes parthenolide may provide a new approach to fight brain metastasis, particularly for patients who have smoked or still smoke.

“Currently, the only treatment for this devastating illness is radiation therapy,” Watabe said. “Traditional chemotherapy drugs can’t cross the blood-brain barrier, but parthenolide can, and thus holds promise as a treatment or possibly even a way to prevent brain metastasis.”

Watabe said he hopes to work with oncologists at Wake Forest School of Medicine, part of Wake Forest Baptist Health, to develop a clinical trial to test parthenolide in the near future.

Abstract
Up to 40% of lung cancer patients develop brain metastasis, and the median survival of these patients remains less than 6 months. Smoking is associated with lung cancer. However, how smoking impacts the development of brain metastasis remains elusive. We examined 281 lung cancer patients with distant metastasis and found that smokers exhibited a significantly high incidence of brain metastasis. We found that nicotine enhanced brain metastasis, while a depletion of microglia suppressed this effect in vivo. Nicotine skewed the polarity of microglia to the M2 phenotype, thereby increasing the secretion of IGF-1 and CCL20, which promoted tumor progression and stemness. Importantly, nicotine enhanced the expression of SIRPα in microglia and restricted their phagocytic ability. We also identified a compound, parthenolide, that suppressed brain metastasis by blocking M2 polarization. Our results indicate that nicotine promotes brain metastasis by skewing the polarity of M2 microglia, which enhances metastatic tumor growth. Our results also highlight a potential risk of using nicotine for tobacco cessation.

Authors
Kounosuke Watabe, Andrew Dothard, Thomas W Lycan, Jimmy Ruiz, Michael Chan, Wei Zhang, Tamjeed Ahmed, Yusuke Shiozawa, Ravindra Pramod Deshpande, Dan Zhao, Yin Liu, Abhishek Tyagi, Kerui Wu, Sambad Sharma, Fei Xing, Shih-Ying Wu

 

Wake Forest Baptist Medical Centre material

 

Journal of Experimental Medicine abstract

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