ABSTRACT
Chronic inflammation induced by persistent microbial infection plays an essential role in tumor progression. Although it is well documented that Epstein-Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC), how EBV-induced inflammation promotes NPC progression remains largely unknown. Here, we report that tumor infiltration of tumor-associated macrophages (TAM) and expression of CCL18, the cytokine preferentially secreted by TAM, closely correlate with serum EBV infection titers and tumor progression in two cohorts of NPC patients. In vitro, compared with EBV- NPC cell lines, EBV+ NPC cell lines exhibited superior capacity to attract monocytes and skew them to differentiate to a TAM-like phenotype. Cytokine profiling analysis revealed that NPC cells with active EBV replications recruited monocytes by VEGF and induced TAM by GM-CSF in an NF-κB-dependent manner. Reciprocally, TAM induced epithelial-mesenchymal transition and furthered NF-κB activation of tumor cells by CCL18. In humanized mice, NPC cells with active EBV replications exhibited increased metastasis, and neutralization of CCL18, GM-CSF, and VEGF significantly reduced metastasis. Collectively, our work defines a feed-forward loop between tumor cells and macrophages in NPC, which shows how metastatic potential can evolve concurrently with virus-induced chronic inflammation. Cancer Res; 77(13); 3591-604. ©2017 AACR.
Subject(s)
Carcinoma/virology , Epstein-Barr Virus Infections/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Macrophages/immunology , Nasopharyngeal Neoplasms/virology , Vascular Endothelial Growth Factor A/immunology , Animals , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , Cell Line, Tumor , Disease Progression , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/metabolism , Epstein-Barr Virus Infections/pathology , Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis , Heterografts , Humans , Macrophage Activation/immunology , Macrophages/metabolism , Macrophages/pathology , Macrophages/virology , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Neoplasm Metastasis , Signal Transduction , Vascular Endothelial Growth Factor A/biosynthesisABSTRACT
BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) is regarded as a disease with strong genetic background and associated with hypoadiponectinemia. It is worthwhile to investigate the possible correlation between the single nucleotide polymorphisms (SNPs) in the adiponectin gene and OSAHS. METHODS: With the TaqMan polymerase chain reaction (PCR) method, the SNPs at positions 45 and 276 in the adiponectin gene were determined in Chinese of Han nationality in Nanjing district consisting of 103 OSAHS patients (OSAHS group) and 67 normal controls (control group). The association of adiponectin genotype polymorphisms at positions 45 and 276 with OSAHS was analyzed. RESULTS: No evidence of a direct association was found between OSAHS and adiponectin genotype SNP at positions 45 and 276 (P > 0.05). However, compared with those OSAHS patients having G/T + T/T genotype at position 276, the OSAHS patients with G/G genotype showed a longer neck circumference, a prolonged duration of the longest apnea event, and an elevated level of blood cholesterol and low-density lipoprotein cholesterol (P < 0.05). CONCLUSIONS: No direct association was suggested between OSAHS and adiponectin genotype distribution at positions 45 and 276 in Chinese of Han nationality in Nanjing district. However, in OSAHS patients, those with adiponectin G/G genotype at position 276, seemed to have a higher potential risk in development of OSAHS than those having adiponectin SNP276 G/T + T/T genotype.
