About 40 percent of patients with small cell lung cancer develop metastases in the brain. This significantly worsens the prognosis of these people, whose average survival does not exceed 6 months. But what favors the spread of cancer cells? Now, a study published by the Journal of Experimental Medicine points to nicotine as a determining factor.

Kounosuke Watabe and his team, from Wake Forest Baptist Medical Center in North Carolina, reached this conclusion after examining 281 subjects with metastatic lung cancer and noting that brain metastasis appeared more frequently among smokers. Tobacco smoke contains a mixture of more than 7,000 toxic chemical compounds, including nicotine, which, despite not being carcinogenic, seems to promote tumor growth.

In the brain, nicotinic receptors, and especially alpha4-beta2, play a key role in nicotine dependence. In addition to neurons and astrocytes, microglial cells, known as the immune system of the central nervous system, also express these receptors on their membranes. The microglial cells react to any alteration in brain tissue in order to restore balance. However, depending on the stimulus, they may adopt a proinflammatory state, which inhibits tumor growth through the secretion of cytokines or phagocytosis, or an immunomodulator, which favors the development of cancer. Interestingly, the researchers detected a marked increase in this second type of microglia in samples from smoker patients with metastases.

Experiments performed on an animal model of lung carcinoma confirmed that nicotine administration polarizes microglial cells to an immunomodulatory state; fact that increases the release of insulin growth factor 1 and CCL20 chemokine. Both molecules promote tumor progression, as well as brain metastasis. Likewise, nicotine suppressed the ability of microglia to engulf, that is, to “capture” and digest, cancer cells.

Thus, the scientists postulated that treatment with a compound capable of inhibiting the change of state of the microglial cells could prevent the appearance of metastasis. In order to test their hypothesis, they chose a molecule synthesized by the medicinal plant feverfew (Tanacetum parthenium), whose injection in mice blocked the reproduction of lung cancer in the brain, induced by nicotine.

Watabe and his collaborators conclude their work with the recommendation to use nicotine replacement therapies, such as patches or chewing gums, with caution in the case of patients with lung cancer who wish to quit smoking.

Marta Pulido Salgado

Reference: S. Y. Wu et al., “Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function”, in Journal of Experimental Medicine; 217 (8): e20191131, published June 4, 2020.