Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-κB signaling pathway

• Published in: Oncogene Vol. 37; no. 23; pp. 3070 - 3087
• Main Authors: Jin, Peng, Shin, Seung-Hyun, Chun, Yang-Sook, Shin, Hyun-Woo, Shin, Yong Jae, Lee, Yeri, Kim, Donggeon, Nam, Do-Hyun, Park, Jong-Wan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2018; Nature Publishing Group
• Subjects: 13/109; 13/21; 13/89; 13/95; 14/19; 38/79; 631/67/327; 631/80/86/820; 82/29; 82/51; 82/80; Animals; Apoptosis; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cancer; CCL20 protein; CCR6 protein; Cell Biology; Cell Hypoxia; Cell Line, Tumor; Chemokine CCL20 - genetics; Chemokine CCL20 - metabolism; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chromatin; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Human Genetics; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunoblotting; Immunoprecipitation; Internal Medicine; Male; Medicine; Medicine & Public Health; Mice, Inbred BALB C; NF-kappa B - metabolism; NF-κB protein; Oncology; Phenotypes; Polymerase chain reaction; Receptors, CCR6 - metabolism; Signal Transduction; Stromal cells; Tumors; Vascularization; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0182-7

During tumor development, stromal cells are co-opted to the tumor milieu and provide favorable conditions for the tumor. Hypoxia stimulates cancer cells to acquire a more malignant phenotype via activation of hypoxia-inducible factor 1 (HIF-1). Given that cancer cells and astrocytes in glioblastomas coexist in a hypoxic microenvironment, we examined whether astrocytes affect the adaptation of glioblastoma cells to hypoxia. Immunoblotting, reporter assays, quantitative RT-PCR, and chromatin immunoprecipitation were performed to evaluate HIF-1 signaling in glioblastoma cells. Astrocyte-derived chemokine C–C motif ligand 20 (CCL20) was identified using cytokine arrays, and its role in glioblastoma development was evaluated in orthotopic xenografts. Astrocytes augmented HIF-1α expression in glioblastoma cells under hypoxia. The expression of HIF-1 downstream genes, cancer colony formation, and Matrigel invasion of glioblastoma cells were stimulated by conditioned medium from astrocytes pre-exposed to hypoxia. CCL20 was secreted in a hypoxia-dependent manner from astrocytes and busted the hypoxic induction of HIF-1α in glioblastoma cells. Mechanistically, the CCL20/CCR6 signaling pathway upregulates HIF-1α by stimulating nuclear factor kappa B-driven transactivation of the HIF1A gene. Compared with the control tumors, CCR6-deficient glioblastoma xenografts grew more slowly, with poor vascularization, and expressed lower levels of HIF-1α and its downstream proteins. Furthermore, CCR6 expression was correlated with HIF-1α expression in GEO and TCGA datasets from human glioblastoma tissues. These results suggest that glioblastoma cells adapt well to hypoxic stress by virtue of CCL20 derived from neighboring astrocytes.