Nav: Home

Too many antioxidants may cause lung cancer spread

June 27, 2019

A new study explains why lung cancer spreads faster in patients with certain genetic changes, and suggests that taking vitamin E, long thought of as preventive, may cause the same spread.

Led by researchers at NYU School of Medicine and Perlmutter Cancer Center, experiments in mice and human tissue revealed how mechanisms that protect cancer cells from the byproducts of their own aggressive growth are connected by the protein BACH1 to cancer cell migration and tissue invasion.

Published online on June 27 in the journal Cell, the study results reflect the nature of cancer cells, which arise in one place, but often spread (metastasize) and take root elsewhere. Lung cancer metastasis is the leading cause of cancer death in the United States.

About 40 percent of lung cancers are adenocarcinomas, which form from mucous-producing cells, and which have already spread beyond lung tissue in 22 percent of cases by the time they are diagnosed.

"Our results finally clarify the web of mechanisms surrounding the BACH 1 signal, and suggest that an already approved drug class may counter cancer spread in about 30 percent of lung adenocarcinoma patients," says senior study author Michele Pagano, MD, chair of the Department of Biochemistry and Molecular Pharmacology at NYU School of Medicine.

The Price of Fuel

The newly published work revolves around random changes, called mutations, which occur continually throughout the DNA code. While many are weeded out, some persist to either make no difference, cause disease, or help cells to better survive changing conditions as part of evolution.

Such changes are known to, for instance, help lung adenocarcinoma cells survive oxidative stress, a process where highly-reactive, cell-damaging molecules (oxidants) are made as a side effect of "burning" fuel to make energy. Cancer cells need extra fuel to support aggressive growth, produce more oxidants, and depend more on naturally occurring antioxidants to neutralize them.

Along these lines, past studies have shown that about 30 percent of non-small cell lung cancers (which include adenocarcinomas) thrive by acquiring mutations that ether increase levels of the protein NRF2 - known to turn on genes that increase antioxidant production - or that disable KEAP1, which targets NRF2 for destruction.

Complicating matters, oxidative stress is known to cause the release a chemical compound called heme. Best known for its role in hemoglobin - the oxygen-carrying red blood cell pigment - heme, in its free form, also amplifies oxidative stress. Cells protect themselves from the heme-driven wave of oxidants by making more of the enzyme heme oxygenase-1 (HO1), which neutralizes heme.

By engineering mice with lung adenocarcinoma cells that lacked Keap1 gene (and thereby increasing levels of NRF2), the study authors were able to show that too high NRF2 levels, and the related overproduction of antioxidants, encourages HO1 production. More HO1 activity means lower amounts of active heme.

This became even more important when the researchers discovered that heme partners with the protein FBOX22 to cause the breakdown of BACH1, explaining how increased NRF2 activity increases BACH1 levels.

Normally, say the authors, NRF2-driven, antioxidant-dependent increases in BACH1 levels are short-lived, activated only during brief blasts of oxidative stress, and possibly not rising to levels that trigger cell migration through BACH1. But the new data suggest that big enough increases override mechanisms that would otherwise limit BACH1 levels.

Furthermore, analyses of human tumor tissue revealed that HO1 and BACH1 are found in significantly higher levels in human lung cancer cells that have spread, and in lung cancers of advanced stage and grade. One theory holds that oxidative stress defenses and migration evolved to overlap so that cells faced with extreme stress locally could migrate in search of a better home.

Moving forward, the team seeks to explore whether HO1 inhibitors - already FDA approved the treatment of inherited disorders called porphyrias - could be tested in a clinical trial to slow or prevent lung cancer spread.

Importantly, a second paper publishing in the same edition of Cell, and led by Martin Bergo of the Department of Biosciences and Nutrition at Karolinska Institutet in Sweden, suggests that vitamin E taken as part of a dietary supplement also increases the chances of lung cancer spread through its effect on BACH1.

"For lung cancer patients, taking vitamin E may cause the same increases in cancer's ability to spread as the NRF2 and KEAP1 mutations that our team has linked to shorter survival," says study author Thales Papagiannakopoulos, PhD, assistant professor in the Department of Pathology at NYU School of Medicine. "We hope these findings help to dispel the myth that antioxidants like vitamin E help to prevent every type of cancer."
-end-
Along with Pagano and Papagiannakopoulos, study authors from the department of Pathology, and Biochemistry and Molecular Pharmacology, at NYU School of Medicine; as well as the Perlmutter Cancer Center at NYU Langone Health; were Luca Lignitto, Sarah LeBoeuf, Harrison Homer, Shaowen Jiang, Manor Askenazi, Triantafyllia Karakousi, Harvey Pass, Aristotelis Tsirigos, Beatrix Ueberheide and Volkan Sayin. Also a study author was Arjun Bhutkar of the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology. Pagano is an investigator with the Howard Hughes Medical Institute.

The work was supported by Perlmutter Cancer Center grant P30CA016087; National Institutes of Health grants T32HL007151, NMSF S10OD010582, NCBRD S10OD01058, S10OD018338, K22CA201088. R37CA222504, and R01CA227649; and by American Cancer Society Research Scholar Grant RSG-17-200-01-TBE. The study was also supported by the Italian Cancer Foundation (AICF) and by Associazione Italiana per la Ricerca sul Cancro, which is co-funded by the European Union (AIRC/Marie Curie).

NYU Langone Health / NYU School of Medicine

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
More Cancer News and Cancer Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab