A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma: Implication for the intense tumor infiltration by T lymphocytes and macrophages

Tang, Kin Fai; Tan, Sioh Yang; Chan, Soh Ha; Chong, Siew Meng; Loh, Kwok Seng; Tan, Luke; Hu, Huaizhong

doi:10.1053/hupa.2001.20886

Cited by 72 publications

(58 citation statements)

References 21 publications

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“…32 It has been suggested that the characteristic leukocyte infiltration seen in NPC tumor lesions might be induced by C-C chemokines secreted by the infiltrating cells. 10 However, the upregulation of MCP-3 expression in the HK1 NPC cells suggested that the NPC tumor cells themselves could also contribute actively in recruiting lymphocytes to the tumor site.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation

Tang

Goh

et al. 2003

Intl Journal of Cancer

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In East Asia and Singapore, the human nasopharyngeal carcinoma (NPC) presented clinically is mainly of the undifferentiated type. In contrast, the well-differentiated squamous NPC is more commonly detected in the West. To study the potential differences in carcinogenesis between undifferentiated and differentiated human NPC, we employed cDNA microarrays to isolate genes that might be specific for human undifferentiated NPC. One of the genes identified to be specifically upregulated in the undifferentiated human NPC cell line CNE-2 is the human imprinting gene H19. Interestingly, H19 is not expressed in the welldifferentiated human HK1 NPC cells. Northern blot and in situ hybridization analyses also confirmed that the H19 gene is strongly expressed in the undifferentiated CNE-2 human NPC cell line but not in the well-differentiated HK1 human NPC cell line. In situ hybridization and reverse transcriptasepolymerase chain reaction also demonstrated that H19 is specifically expressed in NPC biopsies and not in non-NPC human tissue biopsies. Furthermore, we demonstrated that deregulation of H19 gene expression in the well-differentiated human HK1 NPC cells could be induced by the hypomethylation of CpG sites of the H19 promoter region. Hypermethylation of gene promoter regions might therefore be an important epigenetic event that plays a role in the differentiation of human NPC cells and the transcriptional silencing of imprinted genes.

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Section: Discussionmentioning

confidence: 99%

Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation

Tang

Goh

et al. 2003

Intl Journal of Cancer

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“…In the current study, inflammation in HN-Smad4 -/-tissues was markedly attenuated in a Smad3-heterozygous background, suggesting that Smad3 mediates, at least in part, increased TGF-β1-associated inflammation. In addition to inducing changes in cytokines critical for HNSCC tumorigenesis (56,57), inflammation and the resultant production of reactive oxygen species have been linked to the generation of genomic instability (58). Thus, Smad4 loss-associated inflammation may also contribute to the genomic instability observed in our model.…”

Section: Figurementioning

confidence: 94%

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

et al. 2009

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Smad4 is a central mediator of TGF-β signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4 -/-mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited severe inflammation, which was associated with increased expression of TGF-β1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

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“…The presence of TILs within the NPC microenvironment may indicate an active immune response directed at antigens expressed on tumour cells [17,18]. Conversely, the reciprocal interactions between tumour cells and TILs might create an immunosuppressive network that results in tumour evasion and attenuation of immunotherapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms implicated in down-regulation of z-chain expression include proteolytic degradation of z-chain by caspases [50][51][52][53] and modulation by activated macrophages through release of hydrogen peroxide or cell-contact manner in the tumour microenvironment [54,55]. Previous reports have shown that in non-keratinizing or undifferentiated NPC, tumour cells expressed membranous FasL and the intense leucocyte infiltration comprising predominantly T cells and macrophages [18,56]. The mechanisms involved in down-regulation of z-chain in the NPC remain to be established.…”

Section: Foxp3mentioning

confidence: 99%

Increase in tumour-infiltrating lymphocytes with regulatory T cell immunophenotypes and reduced ζ-chain expression in nasopharyngeal carcinoma patients

Yip

Abdullah

Yusoff

et al. 2009

Clinical and Experimental Immunology

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SummaryThe pathological significance of the mechanisms of tumour immune-evasion and/or immunosuppression, such as loss of T cell signalling and increase in regulatory T cells (Tregs), has not been well established in the nasopharyngeal carcinoma (NPC) microenvironment. To evaluate the Treg immunophenotypes in tumour-infiltrating lymphocytes (TILs), we performed a doubleenzymatic immunostaining for detection of forkhead box P3 (FoxP3) and other markers including CD4, CD8, and CD25 on 64 NPC and 36 nonmalignant nasopharyngeal (NP) paraffin-embedded tissues. Expression of CD3z and CD3e was also determined. The prevalence of CD4 + FoxP3 + cells in CD4 + T cells and the ratio of FoxP3 + /CD8 + were increased significantly in NPC compared with those in NP tissues (P < 0·001 and P = 0·025 respectively). Moreover, the ratio of FoxP3 NPC was significantly lower than that in NP tissues (P = 0·005), suggesting an imbalance favouring activated phenotype of T cells in NPC. A significant negative correlation between the abundance of FoxP3+ and CD25 + FoxP3 -cells (P < 0·001) was also identified. When histological types of NPC were considered, a lower ratio of FoxP3 + /CD25 + FoxP3 -was found in non-keratinizing and undifferentiated carcinomas. Increased CD4 + FoxP3 + /CD4 + proportion and FoxP3 + /CD8 + ratio were associated with keratinizing squamous cell carcinoma. A reduced expression of CD3z in TILs was found in 20·6% of the NPC tissues but none of the NP tissues. These data provide evidence for the imbalances of Treg and effector T cell phenotypes and down-regulation of signal-transducing molecules in TILs, supporting their role in suppression of immune response and immune evasion of NPC.

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A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma: Implication for the intense tumor infiltration by T lymphocytes and macrophages

Cited by 72 publications

References 21 publications

Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation

Regulation of the H19 imprinting gene expression in human nasopharyngeal carcinoma by methylation

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

Increase in tumour-infiltrating lymphocytes with regulatory T cell immunophenotypes and reduced ζ-chain expression in nasopharyngeal carcinoma patients

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