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Interaction between CXCR4 and CCL20 pathways regulates tumor growth.

ABSTRACT: The chemokine receptor CXCR4 and its ligand CXCL12 is overexpressed in the majority of tumors and is critically involved in the development and metastasis of these tumors. CXCR4 is expressed in malignant tumor cells whereas its ligand SDF-1 (CXCL12) is expressed mainly by cancer associated fibroblasts (CAF). Similarly to CXCR4, the chemokine CCL20 is overexpressed in variety of tumors; however its role and regulation in tumors is not fully clear. Here, we show that the chemokine receptor CXCR4 stimulates the production of the chemokine CCL20 and that CCL20 stimulates the proliferation and adhesion to collagen of various tumor cells. Furthermore, overexpression of CCL20 in tumor cells promotes growth and adhesion in vitro and increased tumor growth and invasiveness in vivo. Moreover, neutralizing antibodies to CCL20 inhibit the in vivo growth of tumors that either overexpress CXCR4 or CCL20 or naturally express CCL20. These results reveal a role for CCL20 in CXCR4-dependent and -independent tumor growth and suggest a therapeutic potential for CCL20 and CCR6 antagonists in the treatment of CXCR4- and CCL20-dependent malignancies.

SUBMITTER: Beider K

PROVIDER: S-EPMC2659745 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Interaction between CXCR4 and CCL20 pathways regulates tumor growth.

Beider Katia K Abraham Michal M Begin Michal M Wald Hanna H Weiss Ido D ID Wald Ori O Pikarsky Eli E Abramovitch Rinat R Zeira Evelyne E Galun Eithan E Nagler Arnon A Peled Amnon A

PloS one 20090402 4

The chemokine receptor CXCR4 and its ligand CXCL12 is overexpressed in the majority of tumors and is critically involved in the development and metastasis of these tumors. CXCR4 is expressed in malignant tumor cells whereas its ligand SDF-1 (CXCL12) is expressed mainly by cancer associated fibroblasts (CAF). Similarly to CXCR4, the chemokine CCL20 is overexpressed in variety of tumors; however its role and regulation in tumors is not fully clear. Here, we show that the chemokine receptor CXCR4 s ...[more]

PMID: 19340288

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Project description:Receptor of activated C Kinase 1 (RACK1) is an essential scaffold and anchoring protein, which serves an important role in multiple tumorigenesis signaling pathways. The present study aimed to investigate the expression of RACK1 in gastric cancer (GC), and its association with the occurrence and development of GC. In addition, the effect and mechanism of RACK1 overexpression on the growth, and proliferation of GC cells was examined. Firstly, the protein expression of RACK1 was detected in 70 cases of GC tissues and 30 cases of noncancerous tissues using immunohistochemical staining, and the association between clinical and pathological features of GC was analyzed. Secondly, the mRNA and protein expression of RACK1 was determined in the poorly-differentiated human gastric cancer cell line HGC27 and gastric epithelial cell line GES-1. The growth of HGC27 cells following the upregulation of RACK1 was detected using MTT method. Subsequently, the interaction and co-location between RACK1, and WEE1 homolog (S. pombe) (WEE1) in HGC27 cells was confirmed using co-immunoprecipitation and indirect immunofluorescence. The expression level of RACK1 in GC was significantly lower compared with that in pericarcinous tissues (P<0.05). The protein level of RACK1 expression correlated with tumor node metastasis stage, tumor differentiation and lymph node metastasis. The mRNA and protein levels of RACK1 in HGC27 cells were significantly reduced, and overexpressed RACK1 downregulated WEE1 protein expression, thus inhibiting the growth of HGC27 cells. Co-immunoprecipitation and immunofluorescence confirmed that RACK1, and WEE1 interacted and co-located in the cytoplasm of HGC27 cells. Therefore, the abnormal expression of RACK1 in GC tissues was identified to be involved in the occurrence and development of GC. Overexpression of RACK1 was able to inhibit the growth of HGC27 cells. The current study suggests that low expression of RACK1 is an important indicator of poor prognosis of GC. RACK1 and WEE1 interact to regulate the growth of HGC27 cells.

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Interaction between CXCR4 and CCL20 pathways regulates tumor growth.

Publications

Interaction between CXCR4 and CCL20 pathways regulates tumor growth.

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