RT Journal Article
SR Electronic
T1 STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2019-319200
DO 10.1136/gutjnl-2019-319200
A1 Christina Heichler
A1 Kristina Scheibe
A1 Anabel Schmied
A1 Carol I Geppert
A1 Benjamin Schmid
A1 Stefan Wirtz
A1 Oana-Maria Thoma
A1 Viktoria Kramer
A1 Maximilian J Waldner
A1 Christian Büttner
A1 Henner F Farin
A1 Marina Pešić
A1 Ferdinand Knieling
A1 Susanne Merkel
A1 Anika Grüneboom
A1 Matthias Gunzer
A1 Robert Grützmann
A1 Stefan Rose-John
A1 Sergei B Koralov
A1 George Kollias
A1 Michael Vieth
A1 Arndt Hartmann
A1 Florian R Greten
A1 Markus F Neurath
A1 Clemens Neufert
YR 2019
UL http://gut.bmj.com/content/early/2019/11/13/gutjnl-2019-319200.abstract
AB 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.