Featured Research

from universities, journals, and other organizations

Beta-catenin alters T cells in lasting, harmful ways

Date:
February 26, 2014
Source:
University of Chicago Medical Center
Summary:
Activation of beta-catenin, the primary mediator of the ubiquitous Wnt signaling pathway, alters the immune system in lasting and harmful ways, causing chronic inflammation in the intestine and colon, eventually leading to cancer. Researchers have unraveled the mechanism of this transition, and call it "a revelation." 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..

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 cells -- a class of white blood cells -- 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 colon cancer."

"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."


Story Source:

The above story is based on materials provided by University of Chicago Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. S. Keerthivasan, K. Aghajani, M. Dose, L. Molinero, M. W. Khan, V. Venkateswaran, C. Weber, A. O. Emmanuel, T. Sun, D. J. Bentrem, M. Mulcahy, A. Keshavarzian, E. M. Ramos, N. Blatner, K. Khazaie, F. Gounari. Beta-Catenin Promotes Colitis and Colon Cancer Through Imprinting of Proinflammatory Properties in T Cells. Science Translational Medicine, 2014; 6 (225): 225ra28 DOI: 10.1126/scitranslmed.3007607

Cite This Page:

University of Chicago Medical Center. "Beta-catenin alters T cells in lasting, harmful ways." ScienceDaily. ScienceDaily, 26 February 2014. <www.sciencedaily.com/releases/2014/02/140226144505.htm>.
University of Chicago Medical Center. (2014, February 26). Beta-catenin alters T cells in lasting, harmful ways. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2014/02/140226144505.htm
University of Chicago Medical Center. "Beta-catenin alters T cells in lasting, harmful ways." ScienceDaily. www.sciencedaily.com/releases/2014/02/140226144505.htm (accessed July 29, 2014).

Share This




More Health & Medicine News

Tuesday, July 29, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Ebola Virus Threatens West Africa

Deadly Ebola Virus Threatens West Africa

AP (July 28, 2014) West African nations and international health organizations are working to contain the largest Ebola outbreak in history. It's one of the deadliest diseases known to man, but the CDC says it's unlikely to spread in the U.S. (July 28) Video provided by AP
Powered by NewsLook.com
$15B Deal on Vets' Health Care Reached

$15B Deal on Vets' Health Care Reached

AP (July 28, 2014) A bipartisan deal to improve veterans health care would authorize at least $15 billion in emergency spending to fix a veterans program scandalized by long patient wait times and falsified records. (July 28) Video provided by AP
Powered by NewsLook.com
Two Americans Contract Ebola in Liberia

Two Americans Contract Ebola in Liberia

Reuters - US Online Video (July 28, 2014) Two American aid workers in Liberia test positive for Ebola while working to combat the deadliest outbreak of the virus ever. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins