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Published on: November 28, 2019
EGFR/Ras-induced CCL20 production modulates the tumour microenvironment
Andreas Hippe1, Stephan Alexander Braun1,2, Péter Oláh1,3
1Department of Dermatology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Background:
The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.
Methods:
The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.
Results:
Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.
Conclusion:
We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
Insights
The EGFR/Ras pathway drives tumor growth by producing CCL20, which promotes angiogenesis. Targeting the CCL20-CCR6 axis offers a new cancer therapy strategy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The epidermal growth factor receptor (EGFR)/Ras signaling pathway activation in tumor cells influences the tumor microenvironment via chemokine production.
- This study investigates the role of CCL20, a key chemokine, in tumor progression and angiogenesis.
Purpose of the Study:
- To analyze the effects of EGFR/Ras on CCL20 expression and translation in epithelial cancers.
- To investigate the role of CCL20 in tumor-associated vascularization and endothelial cell migration.
- To evaluate the therapeutic potential of targeting the CCL20-CCR6 axis.
Main Methods:
- Quantitative reverse transcription PCR (RT-qPCR) and ELISA were used to analyze CCL20 expression in cancer cell lines and tissues.
- Immunohistochemistry was employed to verify CCL20 production in tumors and correlate it with clinical data.
- Chemotaxis assays and studies in CCR6-deficient mice were conducted to assess CCL20's effects on endothelial cells and tumor vascularization.
Main Results:
- EGFR/Ras-induced CCL20 production facilitates tumor progression, correlating with advanced stage, lymph node metastasis, and reduced patient survival.
- Microvascular endothelial cells express the CCL20 receptor CCR6, and CCR6 signaling promotes angiogenesis.
- CCR6 deficiency in stromal cells significantly reduced tumor growth and vascularization in mice.
Conclusions:
- The CCL20-CCR6 chemokine axis is a novel target for modulating the tumor microenvironment.
- Targeting this axis presents an innovative multimodal strategy for cancer therapy.
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