Dataset Information

Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice.

ABSTRACT:

Background

Tumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3(+) regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown.

Methodology/principal findings

CRC was either induced by N-methyl-N-nitrosourea (MNU) and H. pylori or established by subcutaneous injection of mouse colorectal tumor cell line (CMT93) in mice. CMT93 cells were co-cultured with primary macrophages in a transwell apparatus. Recruitment of FoxP3 green fluorescence protein positive (FoxP3(GFP+)) Treg-cells was assessed using the IVIS Imaging System or immunofluorescence staining. A role for macrophages in trafficking of Treg-cells and in the development of CRC was investigated in CD11b diphtheria toxin receptor (CD11b-DTR) transgenic C57BL/6J mice in which macrophages can be selectively depleted. Treg-cells remarkably infiltrated solid tumor, and predominantly expressed the homing chemokine receptor (CCR) 6 in the induced CRC model. Both CMT93 cancer cells and macrophages produced a large amount of CCL20, the sole ligand of CCR6 in vitro and in vivo. Injection of recombinant mouse CCL20 into tumor sites promoted its development with a marked recruitment of Treg-cells in the graft CRC model. Conditional macrophage ablation decreased CCL20 levels, blocked Treg-cell recruitment and inhibited tumor growth in CD11b-DTR mice grafted with CMT93.

Conclusions/significance

TAMs recruit CCR6(+) Treg-cells to tumor mass and promote its development via enhancing the production of CCL20 in a CRC mouse model.

SUBMITTER: Liu J

PROVIDER: S-EPMC3084880 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Publications

Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice.

Liu Jinlin J Zhang Ning N Li Qun Q Zhang Weiwei W Ke Fang F Leng Qibin Q Wang Hong H Chen Jinfei J Wang Honglin H

PloS one 20110429 4

<h4>Background</h4>Tumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3(+) regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown.<h4>Methodology/principal findings</h4>CRC was either induced by N-methyl-N-nitrosourea (MNU) ...[more]

PMID: 21559338

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Project description:BackgroundEndometriosis (EMs) is a common benign gynecological disease that affects approximately 10% of females of reproductive age. Endometriosis ectopic lesions could recruit macrophages, which in turn facilitates endometriosis progression. Several studies have indicated that CCL20 derived from macrophages activates the expression of CCR6 in several cells and induces cell proliferation and migration. However, the function of the CCL20/CCR6 axis in the interactions between macrophages and endometriotic stromal cells (ESCs) in EMs has yet to be elucidated.MethodsEctopic and normal endometrial tissues were collected from 35 ovarian endometriosis patients and 21 control participants for immunohistochemical staining. It was confirmed that macrophages secreted CCL20 to promote CCR6 activation of ESCs during co-culture by ELISA, qRT-PCR and western blot analysis. CCK8 and Edu assays were used to detect cell proliferation, and wound healing and Transwell assay were used to detect cell migration. Autophagic flux was detected by measuring the protein expression levels of LC3 and P62by western blot and analyzing the red/yellow puncta after ESCs were transfected with mRFP-GFP-LC3 double fluorescence adenovirus (Ad-LC3). Lysosomal function was tested by quantifying the fluorescent intensities of Lyso-tracker and Gal3 and activity of acid phosphatase. In addition, co-IP experiments verified the binding relationship between CCR6 and TFEB. Finally, the suppressive effect of CCL20-NAb on endometriosis lesions in vivo was demonstrated in mice models.ResultsWe demonstrated that macrophages secreted CCL20 to promote CCR6 activation of ESCs during co-culture, which further induced the proliferation and migration of ESCs. We observed that the CCL20/CCR6 axis impaired lysosomal function and then blocked the autolysosome degradation process of autophagic flux in ESCs. The combination of CCR6 and TFEB to inhibit TFEB nuclear translocation mediates the role of the CCL20/CCR6 axis in the above process. We also found that co-culture with ESCs upregulated the production and secretion of CCL20 by macrophages. The suppression effect of CCL20-NAb on endometriosis lesions in vivo was demonstrated in mice models.ConclusionsOur data indicate that macrophages block TFEB-mediated autolysosome degradation process of autophagic flux in ESCs via the CCL20/CCR6 axis, thereby promoting ESC proliferation and migration.

Project description:BackgroundChemokine networks play a key and complex role in tumor progression. CCL20 and its unique receptor CCR6 have been reported to mediate malignant biological activities in various cancers, but their role in ovarian cancer metastasis remains unclear.PurposeOur study aims to explore the effect of CCL20-CCR6 axis on ovarian cancer metastasis and its potential mechanism.MethodsThe transwell assay was used to detect the cell migration and invasion after CCL20 treatment. The CCK-8 assay was used to detect the cell viability after CCL20 treatment and CCR6 depletion. The mRNA and protein expression were assayed through qRT-PCR and Western blotting. The siRNAs and CRISPR-Cas9 system were adopted to suppress CCR6 expression. Intraperitoneal xenograft mouse model was constructed to test the pro-metastasis effect of CCL20-CCR6 axis in vivo. The differentially expressed genes induced by CCL20 were identified through RNA-sequencing, and immunohistochemistry staining was used to detect their protein expression in tumor tissues.ResultsOur results revealed that CCL20 treatment selectively promoted the migration and invasion of CCR6high ovarian cancer cells, but had no effect on CCR6low cells. Blockade of CCR6 expression effectively reversed the cell migration and invasion induced by CCL20 stimulation. Animal experiment proved that CCL20-CCR6 axis mediated ovarian cancer metastasis in vivo. The differentially expressed genes after CCL20 stimulation were associated with metastasis, and CCL20 induced an increased expression of CDH2 and VCAN and decreased CDH1 expression in cancer cells. Moreover, CCL20 stimulated the expression of N-cadherin and versican in tumor tissues and inhibited the expression of E-cadherin, while CCR6 knockout successfully blocked the expression changes.ConclusionOur findings revealed that CCL20-CCR6 axis promotes ovarian cancer metastasis both in vivo and in vitro, probably through increasing cancer cell adhesion and epithelial-mesenchymal transition. Blockade of CCL20-CCR6 axis might become a novel anti-tumor therapeutic target for ovarian cancer.

Dataset Information

Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice.

Background

Methodology/principal findings

Conclusions/significance

Publications

Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice.

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