EGFR/Ras-induced CCL20 production modulates the tumour microenvironment.

Animals Cells, Cultured Chemokine CCL20 / biosynthesis ErbB Receptors / physiology Extracellular Signal-Regulated MAP Kinases / physiology Humans Male Mice Mice, Inbred C57BL Neoplasm Staging Neoplasms / drug therapy Neovascularization, Pathologic / etiology Receptors, CCR6 / physiology Signal Transduction / physiology Tumor Microenvironment ras Proteins / physiology

Journal

British journal of cancer

ISSN: 1532-1827

Titre abrégé: Br J Cancer

Pays: England

ID NLM: 0370635

Informations de publication

Date de publication:
09 2020

Historique:

received: 13 07 2019

accepted: 28 05 2020

revised: 07 04 2020

pubmed: 1 7 2020

medline: 16 3 2021

entrez: 1 7 2020

Statut: ppublish

Résumé

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 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1038/s41416-020-0943-2 PMID: 32601464 PMC: PMC7493992

pubmed: 32601464

doi: 10.1038/s41416-020-0943-2

pii: 10.1038/s41416-020-0943-2

pmc: PMC7493992

doi:

Substances chimiques

Chemokine CCL20 0

Receptors, CCR6 0

ErbB Receptors EC 2.7.10.1

Extracellular Signal-Regulated MAP Kinases EC 2.7.11.24

ras Proteins EC 3.6.5.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

942-954

Subventions

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)

ID : SPP1190

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)

ID : HO 2092/8-1

Organisme : NCI NIH HHS

ID : R01 CA161373

Pays : United States

Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)

ID : I4300-B

Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)

ID : W1212

Organisme : Vienna Science and Technology Fund (Wiener Wissenschafts-, Forschungs- und Technologiefonds)

ID : LS16-025

Organisme : Austrian Science Fund FWF

ID : I 4300

Pays : Austria

Commentaires et corrections

Type : ErratumIn

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