Beta-catenin alters T cells in lasting and harmful ways

February 26, 2014

Activation of beta-catenin, the primary mediator of the ubiquitous Wnt signaling pathway, alters the immune system in lasting and harmful ways, a team of Chicago-based researchers demonstrate in the February 26, 2014, issue of Science Translational Medicine.

An increase in beta-catenin in certain types of T —a class of —causes chronic inflammation in the intestine and colon, eventually leading to cancer. The same mechanism is used by colon cancer to propagate itself. The researchers combine data from patients suffering from colitis or colon cancer with studies in mouse models of the disease to unravel the mechanism of this transition.

"We initially focused on this process in mouse models of hereditary colon cancer (polyposis), but the breakthrough came when we went to see patients," said the study's principal investigator, Fotini Gounari, PhD, associate professor of medicine at the Gwen Knapp Center for Lupus and Immunology Research at the University of Chicago. "Biopsied tissues from colitis patients contained T cells with high levels of beta-catenin. When we examined blood from colon-cancer patients, we found the same pathway activated in both conventional T cells and regulatory T cells."

Previous work by the team showed that a subset of protective T cells known as regulatory T cells, or Tregs—which normally stifle inflammation—switches functions in colon cancer patients to promote inflammation and enhance tumor growth.

The current study points to beta-catenin as the primary culprit. The researchers found mounting levels of this protein in T cells from patients with long-lasting ulcerative colitis and colon cancer. When Gounari and colleagues genetically engineered mice so that their T cells expressed high levels of beta-catenin, those mice were highly susceptible to colon cancer.

The finding "was a revelation," Gounari said. Activation of this signaling pathway appears to be an initiating event for colon cancer, which is then fed by uncontrolled inflammation in the tumor environment.

Normally, inflammation in the gut is elevated through the action of T-helper 17 (TH17) cells and suppressed by Tregs. This balance is important for keeping microbes in the gut at bay and for stimulating growth of cells during tissue repair. However, in colon cancer, a distinct set of regulatory T cells that have pro-inflammatory properties, expands rapidly and upsets the balance.

"We now have evidence that beta-catenin is a key molecule for expansion of both TH17 cells and pro-inflammatory Tregs," Gounari said.

With their unique mouse models, Gounari and colleagues were able to tease apart some of the mechanisms that generated pro-inflammatory T cells. They found that beta-catenin signaling initiated a cascade of events in both conventional T cells and Tregs that altered the chromatin organization and the type of genes expressed by T cells. These changes activate a protein called RORγT that was previously known to direct the differentiation of TH17 cells.

"It's like a tsunami," said collaborating partner, Khashayarsha Khazaie, PhD, professor of immunology at the Mayo Clinic. "If you make both your conventional T cells and Tregs pro-inflammatory, then you've done it. You've lost control in a bad way."

Understanding the process will provide ways to intervene in many diseases, the authors suggest.

"We want to disrupt the signals," Gounari said. "There are inhibitors under development that block RORγt or selectively interrupt the Wnt pathway in T cells. If you could block the pathway enough to tip the balance back to normal, that could potentially stop inflammatory bowel diseases and help control ."

"Activation of beta-catenin in T cells is unlikely to be restricted to these diseases, and is likely to happen in other autoimmune diseases and cancers, so there may be broad prospects for therapy of a range of chronic and often lethal diseases," she adds.

There is still work to be done, the researchers emphasize. They hope to learn more about how beta-catenin produces chromatin changes that disturb normal immune function, how this system interacts with the microbiome, and to determine the best targets for therapy.

But they have taken an important step. "Elucidating the molecular mechanisms that shift the lymphocyte balance from anti-inflammatory to proinflammatory," they wrote, "is expected to improve diagnosis and treatment of autoimmune diseases and cancer."

Explore further: 'Two-faced' cells discovered in colon cancer: Immune cells can suppress or promote tumor growth

Related Stories

'Two-faced' cells discovered in colon cancer: Immune cells can suppress or promote tumor growth

December 13, 2012
Northwestern Medicine researchers have discovered a "two-faced" group of cells at work in human colon cancer, with opposing functions that can suppress or promote tumor growth. These cells are a subset of T-regulatory (Treg) ...

Outwitting a brainy gene

May 1, 2012
(Medical Xpress) -- The very first in the series of mutations causing colon cancer occurs in the beta-catenin gene; this gene is abnormally activated in about 90 percent of colorectal cancer patients, and in a much smaller ...

Balancing T cell populations

November 25, 2013
Depending on the signals received, naïve T cells are able to differentiate into mature T cell populations, which play different roles in the immune system. For example, regulatory T cells (Tregs) are important for tamping ...

Potential new treatment for gastrointestinal cancers discovered

January 17, 2013
(Medical Xpress)—Researchers have identified a complex of proteins that promotes the growth of some types of colon and gastric cancers, and shown that medications that block the function of this complex have the potential ...

Battling defiant leukemia cells

October 7, 2013
Two gene alterations pair up to promote the growth of leukemia cells and their escape from anti-cancer drugs, according to a study in The Journal of Experimental Medicine.

Findings bolster fiber's role in colon health

January 16, 2014
Scientists have more reasons for you to eat fiber and not abuse antibiotics.

Recommended for you

Study provides insight into link between two rare tumor syndromes

August 22, 2017
UCLA researchers have discovered that timing is everything when it comes to preventing a specific gene mutation in mice from developing rare and fast-growing cancerous tumors, which also affects young children. This mutation ...

Retaining one normal BRCA gene in breast, ovarian cancers influences patient survival

August 22, 2017
Determining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little ...

Study identifies miR122 target sites in liver cancer and links a gene to patient survival

August 22, 2017
A new study of a molecule that regulates liver-cell metabolism and suppresses liver-cancer development shows that the molecule interacts with thousands of genes in liver cells, and that when levels of the molecule go down, ...

Zebrafish larvae could be used as 'avatars' to optimize personalized treatment of cancer

August 21, 2017
Portuguese scientists have for the first time shown that the larvae of a tiny fish could one day become the preferred model for predicting, in advance, the response of human malignant tumors to the various therapeutic drugs ...

Scientists discover vitamin C regulates stem cell function, curbs leukemia development

August 21, 2017
Not much is known about stem cell metabolism, but a new study from the Children's Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then ...

Searching for the 'signature' causes of BRCAness in breast cancer

August 21, 2017
Breast cancer cells with defects in the DNA damage repair-genes BRCA1 and BRCA2 have a mutational signature (a pattern of base swaps—e.g., Ts for Gs, Cs for As—throughout a genome) known in cancer genomics as "Signature ...


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.