Newly discovered mechanisms that drive metastasis could be thwarted by existing drugs
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Antioxidants, once touted as a cancer preventive, may actually spur the disease’s spread. Now scientists have figured out how.
Whether taken as a dietary supplement or produced by the body, antioxidants appear to help lung cancer cells invade tissues beyond the chest cavity, two studies report online June 27 in Cell. Experiments in mice and human tissue revealed that antioxidants both safeguard tumors against cell-damaging molecules and prompt the accumulation of the protein Bach1. As Bach1 piles up, tumors burn through glucose at higher rates, thus fueling the cancer cells’ migration to new organs (SN: 1/9/16, p. 13).
“The results provide a new mechanism for how lung cancer cells can spread and may lead to new possibilities for treatment,” says Martin Bergö, a molecular biologist at the Karolinska Institutet in Stockholm who led one of the new studies.
Lung cancer, the leading cause of cancer-related deaths worldwide, claims about 1.6 million lives each year — more than colon, breast and prostate cancers combined. Most lung cancer deaths are related to metastasis. The new findings point to methods of slowing or stopping the spread before it’s too late.
In one study, Michele Pagano, a cancer biologist at the New York University School of Medicine, and his colleagues connected the dots between antioxidants and common mutations in lung cancer cells. Antioxidants neutralize free radicals, damaging molecules that can naturally build up during cell metabolism. About 30 percent of non–small cell lung cancers develop mutations in one of two key genes that regulate natural antioxidant production. The genetic tweaks either boost production or prevent the destruction of a protein called Nrf2, which activates a suite of antioxidant-producing genes. That lets tumors build up a line of defense against the free radicals let off by their fervent growth.
And these mutations come with an added perk.
Normally, oxidative stress — when free radicals run amok — releases free-floating heme, an oxygen-carrying pigment that generates even more damaging molecules. To protect themselves, healthy cells employ the enzyme heme oxygenase-1, or Ho1, to clear away excess heme. But in lung cancer cells, this safety measure gets hijacked. In mice with the tweaked genes, high levels of Nrf2 and antioxidants actually encourage Ho1 production and ultimately allow the cancer to spread.
That’s because it turns out heme has another function: It helps degrade the Bach1 protein, Pagano says. As a result, getting rid of heme lets Bach1 build up in cancer cells and activates genes that drive metastasis.
In human tissue, advanced-stage tumors and those that had metastasized also exhibited elevated levels of Bach1 and Ho1, Pagano and his colleagues found.
In the second study, Bergö’s team treated mutant mice and human lung cancer cells with antioxidants, mimicking the effects of taking a dietary supplement such as vitamin E. As in the NYU study, the compounds elevated Bach1 levels. Bach1 then switched on genes that accelerated glucose uptake and use, the team found. Stoking the cells with sugar drove aggressive metastasis.
Bergö and his colleagues had previously found that supplement doses of antioxidants accelerate primary tumor growth in mice, and clinical trials have unearthed similar results in humans. Now knowing how antioxidants exacerbate cancer, scientists may be able to undermine the mechanism with drugs that inhibit Ho1, block Bach1 production or prevent glycolysis, the glucose-guzzling process that fuels tumors. Ho1 inhibitors are already U.S. Food and Drug Administration–approved to treat inherited disorders called porphyrias, and could potentially be repurposed to fight cancer.
“Understanding why some cancers metastasize and some don’t is one of the biggest problems in lung cancer right now,” says Roy Herbst, a medical oncologist at Yale Cancer Center.
Recognizing this newfound pathway as a “potent promoter of metastasis” could help doctors develop new treatments, identify which tumors to treat aggressively and better advise patients about taking vitamin supplements, Herbst says. “This pathway could be explored in other tumor types — this will definitely have some impact on the field.”
L. Lignitto et al. Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1. Cell. Posted online June 27, 2019. doi: 10.1016/j.cell.2019.06.003.
C. Wiel et al. Bach1 stabilization by antioxidants stimulates lung cancer metastasis. Cell. Posted online June 27, 2019. doi: 10.1016/j.cell.2019.06.005.
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