癌相关成纤维细胞中STAT3的活化促进结直肠癌发展
创作:爱的抉择 审核:szx 2019年12月02日
  • 收集375名结直肠癌患者的结肠组织,发现癌相关成纤维细胞(CAF)中磷酸化STAT3(pSTAT3)的表达与结肠癌患者的生存成负相关;
  • 小鼠结直肠癌模型中,CAF中的STAT3被激活,分离出的CAF可在体外被IL-6或IL-11激活;
  • 成纤维细胞中STAT3的持续性活化可促进小鼠结肠肿瘤发生,而STAT3的失活可抑制结肠肿瘤的发展;
  • STAT3的激活调控血管生成相关基因的转录,而阻断持续性STAT3激活的成纤维细胞中的促血管生成信号可显著抑制结肠肿瘤。
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szx
癌相关成纤维细胞(CAF)影响肿瘤微环境和肿瘤生长,但其对结直肠癌发展的影响尚未明确。来自Gut上发表的一项最新研究,发现在结直肠癌患者中,CAF中的STAT3活化水平与患者的生存呈负相关。而在结直肠癌小鼠模型中,成纤维细胞中STAT3的持续性活化可通过促进血管生成而促进结肠肿瘤发生。该研究结果提示,抑制CAF中的STAT3信号通路活化或可作为结直肠癌的治疗手段。
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Gut [IF:19.819]

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

癌相关成纤维细胞中IL-6/IL-11激活的STAT3促进结直肠癌的发展并与预后不良相关

10.1136/gutjnl-2019-319200

2019-11-04, Article

Abstract & Authors:展开

Abstract:收起
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.

First Authors:
Christina Heichler

Correspondence Authors:
Clemens Neufert

All Authors:
Christina Heichler,Kristina Scheibe,Anabel Schmied,Carol I Geppert,Benjamin Schmid,Stefan Wirtz,Oana-Maria Thoma,Viktoria Kramer,Maximilian J Waldner,Christian Büttner,Henner Farin,Marina Pešić,Ferdinand Knieling,Susanne Merkel,Anika Grüneboom,Matthias Gunzer,Robert Grützmann,Stefan Rose-John,Sergei Koralov,George Kollias,Michael Vieth,Arndt Hartmann,Florian Greten,Markus F Neurath,Clemens Neufert

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