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 1269
OP 1282
DO 10.1136/gutjnl-2019-319200
VO 69
IS 7
A1 Heichler, Christina
A1 Scheibe, Kristina
A1 Schmied, Anabel
A1 Geppert, Carol I
A1 Schmid, Benjamin
A1 Wirtz, Stefan
A1 Thoma, Oana-Maria
A1 Kramer, Viktoria
A1 Waldner, Maximilian J
A1 Büttner, Christian
A1 Farin, Henner F
A1 Pešić, Marina
A1 Knieling, Ferdinand
A1 Merkel, Susanne
A1 Grüneboom, Anika
A1 Gunzer, Matthias
A1 Grützmann, Robert
A1 Rose-John, Stefan
A1 Koralov, Sergei B
A1 Kollias, George
A1 Vieth, Michael
A1 Hartmann, Arndt
A1 Greten, Florian R
A1 Neurath, Markus F
A1 Neufert, Clemens
YR 2020
UL http://gut.bmj.com/content/69/7/1269.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.