Abstract
BackgroundThe activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.MethodsThe 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.ResultsTumours 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.ConclusionWe 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.
Highlights
The activation of the epidermal growth factor receptor (EGFR)/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment
The EGFR/Ras-signalling pathway regulates chemokine production The Ras–mitogen-activated protein kinase (MAPK) pathway is frequently deregulated in tumours arising from epithelial tissues as a result of genetic alterations and upstream activation of cell surface growth factor receptors (e.g. EGFR)
Tumour cells drive the establishment of their microenvironment by secretion of cytokines and chemokines, which act on the surrounding stroma cells and infiltrating immune cells, which in turn provide factors supporting tumour growth and progression
Summary
The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. 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. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. Continuous paracrine communication between the tumour cells and the surrounding microenvironment creates a dynamic signalling circuitry that promotes cancer initiation, growth and metastasis, resulting in the demise of the patient.[1] The tumour microenvironment is composed of distinct cell types, including endothelial cells, pericytes, fibroblasts as well as resident and infiltrating leukocyte subsets.[2] Changes in the microenvironment are initiated, in part, by the activation of growth factor receptors. Uncontrolled activation of the EGFR/Ras-signalling pathway is, an important step towards carcinogenesis and the co-evolution of a tumoursupporting microenvironment
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