Nicotine promotes spread of lung cancer to the brain

Nicotine promotes spread of lung cancer to the brain

Among people who have the most common type of lung cancer, up to 40% develop metastatic brain tumors, 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 have found that nicotine, a non-carcinogenic chemical found in tobacco, actually promotes the spread, or 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 the lead author of the study.

In the study, published in the Journal of Experimental Medicine, the 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 tumor growth.

The authors showed that the 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. 

The authors then 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.Parthenolide suppressed brain metastasis by blocking M2 polarization.

Because feverfew has been used for years and is considered safe, the senior author 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," the senior author 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."