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Does Nicotine Promote Brain Metastasis of Lung Cancer?

By: Julia Fiederlein
Posted: Friday, August 21, 2020

Nicotine appears to induce brain metastasis of lung cancer by altering the polarity of microglia, according to a recent study published in the Journal of Experimental Medicine. However, Kounosuke Watabe, PhD, of the Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, and colleagues suggest treatment with the natural compound parthenolide may suppress this effect.

“Nicotine replacement therapies [are commonly used] to help these patients cease smoking,” Dr. Watabe explained in a Rockefeller University press release. “However, our results clearly show that nicotine has profound and long-term effects on brain metastasis progression, suggesting that cancer patients should be cautious in their use of nicotine for smoking cessation.”

Of the 281 enrolled patients with stage IV non–small cell lung cancer, 79 had brain metastasis. A total of 59 patients were current smokers, 181 were former smokers, and 41 had never smoked. The investigators conducted experiments using 5-to-6-week-old female nude BALB/c and C57BL/6 mice, cell culture using the H2030BrM and PC9BrM cell lines, and several laboratory assessments to analyze the association between nicotine use and the development of brain metastasis.

The incidence rates of brain metastasis in never, former, and current smokers were 22%, 25%, and 42%, respectively. Expression of α4β2, a nicotine receptor in the brain, was significantly higher in microglia than in macrophages both before (P < .05) and after (P < .001) nicotine treatment. Nicotine-mediated brain metastasis was significantly suppressed by PLX3397, an inhibitor of the colony-stimulating factor 1 receptor, in mouse models.

Immunohistochemical analyses of microglia in the metastatic brain lesions of mice showed an increased number of M2 microglia after nicotine treatment, indicating microglial polarization. Western blotting revealed an upregulation of signal-regulatory protein α in human microglia after nicotine treatment; thus, microglial phagocytotic activity appeared to be restricted. At a dosage of less than 1 µM, parthenolide reduced nicotine-mediated microglial polarization to the M2 phenotype.

Disclosure: For full disclosures of the study authors, visit rupress.org.



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