Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

News in Brief

T-Cell Mutation Leads to GI Polyps

DOI: 10.1158/2159-8290.CD-NB2018-115 Published October 2018
  • Article
  • Info & Metrics
  • PDF
Loading

Peutz–Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by benign gastrointestinal (GI) polyps, results from a germline mutation in STK11, the gene that encodes the tumor suppressor LKB1. A recent study provides a possible mechanism: A single-allele mutation of STK11 reduces LKB1 expression in T cells, increasing production of inflammatory immune cells in the GI tract that promote the growth of these polyps (Science 2018;361:406–11).

Previously, senior author Russell Jones, PhD, of McGill University in Montreal, Canada, and the Van Andel Institute in Grand Rapids, MI, and his team established that the absence of LKB1 in T cells increased T-cell activation and the production of inflammatory cytokines (J Immunol 2011;187:4187–98). Building on this work, the new study aimed to determine whether this inflammatory response could lead to the development of autoimmune diseases.

However, the study direction changed when the researchers unexpectedly discovered that mice with single-allele deletion of STK11 in T cells developed GI polyps akin to those observed in PJS.

“It was previously believed that it's the mutation of STK11 in epithelial cells of the gut that causes the epithelial cells to grow abnormally, and that's why you get these tumors,” Jones says. “What ended up being the new focus of the study was tackling every angle of what the T cells could be doing, who they could be talking to, what factors they could be making that would be promoting tumor growth.”

The researchers found that polyps from mice and humans contained an inflammation signature that included T cells, macrophages, neutrophils, and the cytokines IL6 and IL11.

A series of follow-up experiments in mice established a likely mechanism for how STK11 deletion in T cells leads to PJS: First, a STK11 mutation reduces LKB1 production in T cells, which unleashes a storm of inflammatory factors that are recruited to the gastrointestinal tissue. Then, these inflammatory factors activate the JAK–STAT signaling pathway, increasing STAT3 production and creating an environment where polyps are likely to grow. The production of STAT3 is also known to drive tumor development in certain inflammatory cancers.

“What's interesting about this paper is that it shows that the partial loss of a tumor suppressor in one tissue, in this case LKB1 in T cells, has a very profound effect in promoting the growth of tumors in a different compartment of the body, the gastrointestinal tract,” says Pablo Hollstein, PhD, of the Salk Institute in La Jolla, CA, who coauthored a related commentary (Science 2018;361:332–3).

In the study, treating mice with a JAK2 inhibitor reduced polyp growth, suggesting that the JAK–STAT pathway has potential as a therapeutic target for controlling benign polyp growth in patients with PJS. He adds that “it will be of great interest to see if utilizing JAK inhibitors could help treat some of the malignancies that may occur down the road,” in patients with the syndrome, such as GI, pancreatic, and gynecologic cancers.

In a related study published earlier this year, lead author Saara Ollila, PhD, and senior author Tomi Mäkelä, MD, PhD, both of the University of Helsinki in Finland, found that LKB1 deficiency in stromal cells also leads to PJS via an inflammatory response that turns on the JAK–STAT pathway (J Clin Invest 2018;128:402–14).


Embedded Image

Illustration of a growing stomach polyp, a characteristic of Peutz–Jeghers syndrome. The red cells represent proinflammatory T cells that promote polyp development.

“It seems that loss of LKB1 in different kinds of cell types can lead to similar types of responses,” Ollila says. “It's very important for the field that we ended up at the same conclusion: JAK–STAT signaling is at least one of the key pathways driving the growth of these [benign polyps].”

“What all of these studies are trying to understand is why patients with a heterozygous mutation of STK11 get polyps,” Mäkelä adds. “To me, the question is, ‘What is initiating the inflammatory response?’” –Catherine Caruso

Notes

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2018 American Association for Cancer Research.
PreviousNext
Back to top
Cancer Discovery: 8 (10)
October 2018
Volume 8, Issue 10
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Discovery article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
T-Cell Mutation Leads to GI Polyps
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
T-Cell Mutation Leads to GI Polyps
Cancer Discov October 1 2018 (8) (10) 1202-1203; DOI: 10.1158/2159-8290.CD-NB2018-115

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
T-Cell Mutation Leads to GI Polyps
Cancer Discov October 1 2018 (8) (10) 1202-1203; DOI: 10.1158/2159-8290.CD-NB2018-115
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Notes
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Immunotherapy Activates Antitumor γ9δ2 T Cells
  • Mechanisms of KRAS Inhibitor Resistance Revealed
  • Genomic Differences by Race Emerge in Colorectal Cancer
Show more News in Brief
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement