Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jul;69(7):1269-1282.
doi: 10.1136/gutjnl-2019-319200. Epub 2019 Nov 4.

STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis

Christina Heichler  1 , Kristina Scheibe  1 , Anabel Schmied  1 , Carol I Geppert  2 , Benjamin Schmid  3 , Stefan Wirtz  1 , Oana-Maria Thoma  1   4 , Viktoria Kramer  1 , Maximilian J Waldner  1 , Christian Büttner  5 , Henner F Farin  6   7 , Marina Pešić  7 , Ferdinand Knieling  1   8 , Susanne Merkel  9 , Anika Grüneboom  10 , Matthias Gunzer  11 , Robert Grützmann  9 , Stefan Rose-John  12 , Sergei B Koralov  13 , George Kollias  14 , Michael Vieth  15 , Arndt Hartmann  2 , Florian R Greten  7 , Markus F Neurath  1 , Clemens Neufert  16
Affiliations

STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis

Christina Heichler et al. Gut. 2020 Jul.

Abstract

Objective: Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood.

Design: We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI-) on STAT3 activation (IL-6 vs IL-11).

Results: The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts.

Conclusion: Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.

Keywords: colorectal cancer.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Publication types

LinkOut - more resources