Chronic inflammation can trigger cancers via newly discovered mechanism

August 23, 2018 by Nicholas Weiler, University of California, San Francisco
Chronic inflammation can trigger cancers via newly discovered mechanism
A microscopic view of an invasive squamous cell cancer that stemmed from a rare skin disorder called recessive dystrophic epidermolysis bullosa (RDEB), or Butterfly Syndrome. Credit: Andrew South

It is well known that extended exposure to the sun's UV rays can cause DNA mutations that lead to skin cancer. Now new research reveals that inflammation from chronic skin injury can trigger cancer-causing mutations as well by a totally distinct mechanism.

The researchers – led by scientists at UC San Francisco and Thomas Jefferson University in Philadelphia, in collaboration with Santa Cruz-based Nantomics LLC – say that better understanding this previously invisible driver of tumor formation could lead to a new class of therapies for a variety of cancers.

"We're describing for the first time a mechanism that instigates tissue damage-driven cancers," said study senior author Andrew South, Ph.D., an associate professor in the Department of Dermatology and Cutaneous Biology at Jefferson.

Previous studies of patients with head and neck cancers have suggested a link between tissue inflammation and cancer, but the specific mechanism behind this connection has remained elusive.

In their new study, published August 22, 2018, in Science Translational Medicine, South and UCSF Health dermatologist and geneticist Raymond Cho, MD, Ph.D., the study's first author, studied the cells of children with a rare skin disorder called recessive dystrophic epidermolysis bullosa (RDEB). Patients with RDEB, sometimes called "butterfly children" because their skin's extreme fragility calls to mind a butterfly's wings, lack the connective protein collagen, which makes their skin prone to blistering and scarring at the slightest touch. In addition to severe pain and potential disfigurement, patients also frequently develop aggressive early in life in frequently injured areas.

"RDEB is a terribly painful condition, but cancer is what causes premature mortality in these patients," said Cho, who is an associate professor of dermatology at UCSF and member of the UCSF Helen Diller Comprehensive Cancer Center. "The reason these patients get cancer is not well understood, but we realized that it had to be directly linked to chronic tissue damage, because the fragility of the skin is at the root of everything in this disease."

Because RDEB is so rare – about five cases occur in every ten million live births in the U.S. – Cho and South needed to assemble a consortium of researchers from around the world to collect a sufficient number of tissue samples from children with the disease for the new study, including samples of cancerous, inflamed and normal tissue. Rather than focus on a few cancer-linked genes, the researchers sequenced the entire protein-coding part of the genome in these samples, which enabled them to detect subtle patterns of DNA mutation across the genome in inflamed and cancerous tissue that were clearly distinct from the types of mutational signatures caused by UV radiation.

The researchers showed that this pattern of mutation is caused by a protein called APOBEC, which normally plays a role in adding diversity to cellular proteins and is also thought to help defend against viruses. In RDEB patients, APOBEC appears to become overly active as a consequence of chronic , causing it to introduce mutations across the genome, some of which eventually lead to cancer.

Using a computational approach developed in the Cho lab at UCSF, the researchers ruled out problems with DNA repair, which is a common driver of increased levels of mutation in many cancers. Patterns of mutation density throughout the genome of RDEB tissue samples indicated that normal DNA repair mechanisms were functioning properly, confirming that the cancer-causing seen in RDEB patients were a result of inflammation and dysfunctional APOBEC alone.

The notion that inflammation and cancer are somehow linked has been gaining traction both in the medical world and in the general public, according to Cho, who hopes the new findings will help make further investigations of this relationship – in skin cancers, head and neck cancers and other conditions – more concrete.

"In many ways, cancers are akin to wounds that never heal," Cho said. "Here we're showing a new mechanism for how inflammation from chronic damage can actually lead to . This could present the medical community with new opportunities to develop preventive measures against inflammation-driven cancers, as we have done successfully with cancers caused by UV exposure."

Explore further: Collagen's role in skin cancer

More information: Raymond J. Cho et al. APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa, Science Translational Medicine (2018). DOI: 10.1126/scitranslmed.aas9668

Related Stories

Collagen's role in skin cancer

October 23, 2015
Type VII collagen is an important protein that helps hold the skin together. Patients with a severe skin condition known as recessive dystrophic epidermolysis bullosa (RDEB) have genetic mutations that lead to reductions ...

Researchers have revealed how a rare genetic skin condition causes aggressive skin tumours

March 11, 2016
Fragile skin that blisters easily: 90 percent of the patients that suffer from the skin condition recessive dystrophic epidermolysis bullosa (RDEB) develop rapidly progressing cutaneous squamous cell carcinomas, a type of ...

Common skin cancer can signal increased risk of other cancers, researchers say

August 9, 2018
People who develop abnormally frequent cases of a skin cancer known as basal cell carcinoma appear to be at significantly increased risk for the development of other cancers, including blood, breast, colon and prostate cancers, ...

From 'sea of mutations,' two possible cancer links rise to the surface

August 9, 2018
By analyzing data from thousands of patients, Princeton researchers have identified genetic mutations that frequently occur in people with uterine cancer, colorectal cancer or skin cancer—an important step toward using ...

Two-faced gene: SIRT6 prevents some cancers but promotes sun-induced skin cancer

October 15, 2014
A new study published in Cancer Research shows SIRT6—a protein known to inhibit the growth of liver and colon cancers—can promote the development of skin cancers by turning on an enzyme that increases inflammation, proliferation ...

Stem cell therapy for inherited skin blistering

May 26, 2015
Promising results from a trial of a new stem-cell based therapy for a rare and debilitating skin condition have been published in the Journal of Investigative Dermatology. The therapy, involving infusions of stem cells, was ...

Recommended for you

Obesity both feeds tumors and helps immunotherapy kill cancer

November 12, 2018
A groundbreaking new study by UC Davis researchers has uncovered why obesity both fuels cancer growth and allows blockbuster new immunotherapies to work better against those same tumors.

Spread of deadly eye cancer halted in cells and animals

November 12, 2018
By comparing genetic sequences in the eye tumors of children whose cancers spread with tumors that didn't spread, Johns Hopkins Medicine researchers report new evidence that a domino effect in cells is responsible for the ...

Cancer stem cells get energy from protein, and it's proving to be their Achilles' heel

November 12, 2018
Think of energy metabolism like a party popper: Ripping something apart releases a bang. Most of your cells rip apart sugar to release the "bang" of energy. Sometimes they rip apart fats, and in a pinch, cells can even metabolize ...

Scientists shine new light on link between obesity and cancer

November 12, 2018
Scientists have made a major discovery that shines a new, explanatory light on the link between obesity and cancer. Their research confirms why the body's immune surveillance systems—led by cancer-fighting Natural Killer ...

Two-pronged device enables maverick immune cells to identify and kill cancers

November 12, 2018
Immune cells called Gamma Delta T cells can act independently to identify and kill cancer cells, defying the conventional view of the immune system, reveals new research from the Francis Crick Institute and King's College ...

Research brings personalized medicine to treat leukemia one step closer

November 12, 2018
Scientists at the University of Birmingham have revealed the roles that different types of gene mutations play in causing blood cancers in a study that was the culmination of a decade's research.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.