Gene Summary

Gene:CCR7; C-C motif chemokine receptor 7
Aliases: BLR2, EBI1, CCR-7, CD197, CDw197, CMKBR7, CC-CKR-7
Summary:The protein encoded by this gene is a member of the G protein-coupled receptor family. This receptor was identified as a gene induced by the Epstein-Barr virus (EBV), and is thought to be a mediator of EBV effects on B lymphocytes. This receptor is expressed in various lymphoid tissues and activates B and T lymphocytes. It has been shown to control the migration of memory T cells to inflamed tissues, as well as stimulate dendritic cell maturation. The chemokine (C-C motif) ligand 19 (CCL19/ECL) has been reported to be a specific ligand of this receptor. Signals mediated by this receptor regulate T cell homeostasis in lymph nodes, and may also function in the activation and polarization of T cells, and in chronic inflammation pathogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-C chemokine receptor type 7
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (55)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: CCR7 (cancer-related)

Hong CH, Lin SH, Lee CH
CCL21 Induces mTOR-dependent MALAT1 Expression, Leading to Cell Migration in Cutaneous T-Cell Lymphoma.
In Vivo. 2019 May-Jun; 33(3):793-800 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mycosis fungoides (MF) is indolent, but may disseminate to leukemia. We reported that C-C motif chemokine ligand 21 (CCL21) is associated with MF invasion and progression. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA, is associated with several cancer types, however, how it interacts with CCL21 to regulate MF progression, remains unclear.
MATERIALS AND METHODS: Expression of long noncoding RNAs MALAT1, antisense noncoding RNA in the INK4 locus (ANRIL), Hox antisense intergenic RNA (HOTAIR), highly up-regulated in liver cancer RNA (HULC), and leukemia-associated non-coding insulin-like growth factor 1 receptor activator RNA 1 (LUNAR1) in tissues from MF was studied using polymerase chain reaction and RNA interference in MF cell line MyLa were used to address this question.
RESULTS: Expression of MALAT1 was selectively increased in MF tissues. C-C Chemokine receptor type 7 (CCR7) expression was found to be increased in MyLa cells. CCL21 was found not only to mediate migration, but also to enhance MALAT1 and mammalian target of rapamycin (mTOR) activation in MyLa cells. Knockdown of MALAT1 abrogated CCL21-mediated migration, but not mTOR activation. In contrast, mTOR inhibition reduced CCL21-mediated migration and MALAT1 expression.
CONCLUSION: CCL21 induced mTOR activation in MyLa cells, followed by expression of MALAT1, causing cell migration. MALAT1 and mTOR are potential therapeutic targets for MF.

Duan M, Goswami S, Shi JY, et al.
Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma.
Clin Cancer Res. 2019; 25(11):3304-3316 [PubMed] Related Publications
PURPOSE: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC).
RESULTS: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7
CONCLUSIONS: HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.

Pu J, Tang X, Zhuang X, et al.
Matrine induces apoptosis via targeting CCR7 and enhances the effect of anticancer drugs in non-small cell lung cancer in vitro.
Innate Immun. 2018; 24(7):394-399 [PubMed] Related Publications
This study mainly investigated the effects of matrine on cell apoptosis and the effects of anticancer drugs in non-small cell lung cancer (NSCLC) cell lines (A549 and LK2 cells). The results showed that matrine (≥10 μM) caused a significant inhibition on cell viability and 10 and 100 μM matrine induced cell apoptosis via influencing p53, bax, casp3, and bcl-2 expressions in A549 cells. In addition, matrine significantly down-regulated C-C chemokine receptor type 7 (CCR7) expression, and blocking the down-regulation of CCR7 by exogenous chemokine ligand 21 (CCL21) treatment alleviated matrine-caused effects of apoptosis genes in A549 cells. The results were further validated in LK2 cells that matrine regulated apoptosis gene expressions, which were reversed by CCL21 treatment. Furthermore, matrine enhances the effects of cisplatin, 5-fluorouracil, and paclitaxel in A549 cells, and the anticancer effects exhibit a dosage-dependent manner. In summary, matrine induced cell apoptosis and enhanced the effects of anticancer drugs in NSCLC cells; the mechanism might be associated with the CCR7 signal.

Le KS, Amé-Thomas P, Tarte K, et al.
CXCR5 and ICOS expression identifies a CD8 T-cell subset with T
Blood Adv. 2018; 2(15):1889-1900 [PubMed] Free Access to Full Article Related Publications
A better characterization of T-cell subsets in the microenvironment of classical Hodgkin lymphoma (cHL) would help to develop immunotherapies. Using multicolor flow cytometry, we identified in 6 of 43 cHL tissue samples a previously unrecognized subset of CD8 T cells coexpressing CXCR5 and inducible T-cell costimulator (ICOS) molecules (CD8

Wu J, Li L, Liu J, et al.
CC chemokine receptor 7 promotes triple-negative breast cancer growth and metastasis.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(9):835-842 [PubMed] Related Publications
Metastasis is the leading cause of breast cancer-related death. Chemokine (C-C motif) receptor 7 (CCR7) plays important roles in breast cancer metastasis. However, the role of CCR7 in triple-negative breast cancer (TNBC) has not been fully elucidated. In this study, we found that CCR7 is highly expressed in both TNBC cell lines and breast cancer tissues. CCR7 was knocked down by shRNA in 4T1 and MDA-MB-231, two TNBC cell lines, and we found that the depletion of CCR7 significantly decreased TNBC cell proliferation, migration and invasion in vitro. Furthermore, we confirmed that the knockdown of CCR7 reduced the distant metastasis of 4T1 cells in an orthotopic mouse model. Proteomic analysis in 4T1 cells indicated that several signaling pathways such as epithelial cell adhesion molecule might contribute to CCR7's function in breast cancer metastasis. Our results suggest that CCR7 promotes TNBC metastasis and may serve as a target for breast cancer diagnosis and treatment.

Stock S, Hoffmann JM, Schubert ML, et al.
Influence of Retronectin-Mediated T-Cell Activation on Expansion and Phenotype of CD19-Specific Chimeric Antigen Receptor T Cells.
Hum Gene Ther. 2018; 29(10):1167-1182 [PubMed] Related Publications
Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production. Peripheral blood mononuclear cells of healthy donors and untreated chronic lymphocytic leukemia (CLL) patients without or with positive selection for CD3+ T cells were transduced with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Activation of peripheral blood mononuclear cells was performed by CD3/CD28, CD3/CD28/retronectin, or CD3/retronectin. Interleukin-7 and -15 were supplemented to all cultures. Retronectin was used in all three activation protocols for retroviral transduction. Expansion was assessed by trypan blue staining. Viability, transduction efficiency, immune phenotype, and cytokine production were longitudinally analyzed by flow cytometry. Cytotoxic capacity of generated CART cells was evaluated using a classical chromium-51 release assay. Retronectin-mediated activation resulted in an enrichment of CD8+ cytotoxic CART cells and less-differentiated naïve-like T cells (CD45RA+CCR7+). Retronectin-activated CART cells showed increased cytotoxic activity. However, activation with retronectin decreased viability, expansion, transduction efficiency, and cytokine production, particularly of CLL patient-derived CART cells. Both retronectin-mediated activation protocols promoted a less-differentiated CART cell phenotype without comprising cytotoxic properties of healthy donor-derived CART cells. However, up-front retronectin resulted in reduced viability and expansion in CLL patients. This effect is probably attributed to the retronectin-mediated activation of B cells with prolonged CLL persistence. Consequently, CART cell expansion and generation failed. In summary, activation with retronectin should be performed with caution and may be limited to patients without a higher percentage of tumor cells in the peripheral blood.

Wu H, Pang P, Liu MD, et al.
Upregulated miR‑20a‑5p expression promotes proliferation and invasion of head and neck squamous cell carcinoma cells by targeting of TNFRSF21.
Oncol Rep. 2018; 40(2):1138-1146 [PubMed] Related Publications
MicroRNAs (miRNAs) play important roles in regulation of proliferation, migration, and invasion of head and neck squamous cell carcinoma (HNSCC). The present study assessed expression, functions and mechanisms of miR‑20a‑5p in the regulation of HNSCC cell proliferation, migration and invasion. miR‑20a‑5p expression in HNSCC cell lines and tissues was detected using qRT‑PCR, while miR‑20a‑5p mimics and inhibitor were transfected into HNSCC cells for assessment of the effects using different assays (CCK‑8, wound healing and Transwell assays) and expression of miR‑20a‑5p‑targeting genes (using western blot and luciferase reporter assays). The data revealed that miR‑20a‑5p was upregulated in both HNSCC tissues and metastatic HNSCC cells. Upregulated miR‑20a‑5p expression in HNSCC cells promoted tumor cell proliferation, migration and invasion capacities, but resulted in downregulation of TNFRSF21 expression and in turn upregulation of C‑C motif chemokine receptor 7 (CCR7) in HNSCC cells. Concordantly, knockdown of miR‑20a‑5p in HNSCC had the opposite results. In conclusion, miR‑20a‑5p functioned as an oncogene in HNSCC by downregulating TNFRSF21 and subsequently, upregulating CCR7 expression.

González-Arriagada WA, Lozano-Burgos C, Zúñiga-Moreta R, et al.
Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas.
J Oral Pathol Med. 2018; 47(8):755-763 [PubMed] Related Publications
BACKGROUND: Head and neck squamous cell carcinoma shows high prevalence of lymph node metastasis at diagnosis, and despite the advances in treatment, the overall 5-year survival is still under 50%. Chemokine receptors have a role in the development and progression of cancer, but their effect in head and neck carcinoma remains poorly characterised. This study aimed to assess the prognostic value of CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4 in head and neck squamous cell carcinomas.
METHODS: Immunohistochemical expression of chemokine receptors was evaluated in a retrospective cohort of 76 cases of head and neck squamous cell carcinoma. Clinicopathological associations were analysed using the chi-square test, survival curves were analysed according to the Kaplan-Meier method, and the Cox proportional hazard model was applied for multivariate survival analysis.
RESULTS: The chemokine receptors were highly expressed in primary carcinomas, except for CCR1 and CCR3. Significant associations were detected, including the associations between CCR5 expression and lymph node metastasis (N stage, P = .03), advanced clinical stage (P = .003), poor differentiation of tumours (P = .05) and recurrence (P = .01). The high expression of CCR5 was also associated with shortened disease-free survival (HR: 2.85, 95% CI: 1.09-8.14, P = .05), but the association did not withstand the Cox multivariate survival analysis. At univariate analysis, high expression of CCR7 was associated with disease-free survival and low levels of CXCR4 were significantly associated with both disease-specific and disease-free survival.
CONCLUSIONS: These findings show that chemokine receptors may have an important role in head and neck squamous cell carcinoma progression, regional lymph node metastasis and recurrence.

Zizzari IG, Napoletano C, Botticelli A, et al.
TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway.
Cancer Immunol Res. 2018; 6(6):711-722 [PubMed] Related Publications
Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/β-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4

Le Moignic A, Malard V, Benvegnu T, et al.
Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells.
J Control Release. 2018; 278:110-121 [PubMed] Related Publications
Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Their proper delivery to dendritic cells (DCs) requires their protection against RNase degradation and more specificity for dose reduction. Lipid-Polymer-RNA lipopolyplexes (LPR) are attractive mRNA delivery systems and their equipment with mannose containing glycolipid, specific of endocytic receptors present on the membrane of DCs is a valuable strategy. In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of α-d-mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency. We demonstrated that triMN-LPR provided high induction of a local inflammatory response two days after intradermal injection to C57BL/6 mice, followed by the recruitment and activation of DCs in the corresponding draining lymph nodes. This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration. High number of E7-specific T cells was detected after E7-encoded mRNA triMN-LPR vaccination. When evaluated in three therapeutic pre-clinical murine tumor models such as E7-expressing TC1 cells, OVA-expressing EG7 cells and MART-1-expressing B16F0 cells, triMN-LPR carrying mRNA encoding the respective antigens significantly exert curative responses in mice vaccinated seven days after initial tumor inoculation. These results provide evidence that triMN-LPR give rise to an efficient stimulatory immune response allowing for therapeutic anti-cancer vaccination in mice. This mRNA formulation should be considered for anti-cancer vaccination in Humans.

Fan W, Ye G
Microarray analysis for the identification of specific proteins and functional modules involved in the process of hepatocellular carcinoma originating from cirrhotic liver.
Mol Med Rep. 2018; 17(4):5619-5626 [PubMed] Free Access to Full Article Related Publications
In order to identify the potential pathogenesis of hepatocellular carcinoma (HCC) developing from cirrhosis, a microarray‑based transcriptome profile was analyzed. The GSE63898 expression profile was downloaded from the Gene Expression Omnibus database, which included data from 228 HCC tissue samples and 168 cirrhotic tissue samples. The Robust Multi‑array Average in the Affy package of R was used for raw data processing and Student's t‑test was used to screen differentially expressed genes (DEGs). An enrichment analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery online tool, and the protein‑protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. Furthermore, the MCODE plug‑in of Cytoscape was used to conduct a sub‑module analysis. A total of 634 DEGs were identified between HCC and cirrhosis, of which 165 were upregulated and 469 were downregulated. According to the cut‑off criteria, the PPI network was constructed and Jun proto‑oncogene, AP‑1 transcription factor subunit (degree, 39), Fos proto‑oncogene, AP‑1 transcription factor subunit (degree, 34) and v‑myc avian myelocytomatosis viral oncogene homolog (degree, 32) were identified as the hub nodes of the PPI network. Based on the sub‑module analysis, four specific modules were identified. In particular, module 1 was significantly enriched in the chemokine signaling pathway, and C‑X‑C motif chemokine ligand 12, C‑C motif chemokine receptor 7 (CCR7) and C‑C motif chemokine ligand 5 (CCL5) were three important proteins in this module. Module 4 was significantly enriched in chemical carcinogenesis, and cytochrome P450 family 2 subfamily E member 1, cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily A member 6 (CYP2A6) were three important proteins in this module. In conclusion, the present study revealed that CCR7, CCL5, CYP2C9 and CYP2A6 are novel genes identified in the development of HCC; however, the actual functions of these genes require verification.

Liu MD, Wu H, Wang S, et al.
MiR-1275 promotes cell migration, invasion and proliferation in squamous cell carcinoma of head and neck via up-regulating IGF-1R and CCR7.
Gene. 2018; 646:1-7 [PubMed] Related Publications
PURPOSE: miRNAs can play vital role in migration, invasion and proliferation in Squamous cell carcinoma of head and neck (SCCHN). In our study, we attempted to validate the expression and function of miR-1275 in SCCHN, and we also identified the mechanism by which miR-1275 affects migration, invasion and proliferation of SCCHN.
METHODS: Real-time polymerase chain reaction (RT-PCR) was employed to evaluate the expression of miR-1275 in both SCCHN tissues and cell lines. The role of miR-1275 in SCCHN cells was verified by cell function experiments upon transfection with miR-1275 mimics and inhibitor. Western blot analysis was employed to test the target gene expression of miR-1275. Survival analysis was made with the information of SCCHN patients expressed miR-1275 from The Cancer Genome Atlas (TCGA) database.
RESULTS: miR-1275 expression was up-regulated in SCCHN tissues and advanced metastatic SCCHN cells. Increasing miR-1275 expression in SCCHN could promote cell migration, invasion and proliferation probably by upregulating Insulin-like growth factor 1 receptor (IGF-1R) and C-C chemokine receptor type 7(CCR7) protein levels, whereas inhibition of miR-1275 could lead the opposite effects, although others have already demonstrated that IGF-1R is a direct target of miR-1275. Survival analysis suggested that patients with lower miR-1275 expression may have a better outcome.
CONCLUSIONS: Herein we report for the first time that miR-1275 could act as a tumor-promoter in SCCHN possibly by regulating its target gene via novel miRNA mechanisms. MiR-1275 plays an important role in promoting SCCHN progression. The miR-1275 may be a potential therapeutic target for SCCHN treatment in the future.

Tang G, Du R, Tang Z, Kuang Y
MiRNALet-7a mediates prostate cancer PC-3 cell invasion, migration by inducing epithelial-mesenchymal transition through CCR7/MAPK pathway.
J Cell Biochem. 2018; 119(4):3725-3731 [PubMed] Related Publications
Prostate cancer is one of the most common malignancies in older men. Recent evidence has demonstrated microRNA (miRNA) Let-7a expression decreased in prostate cancer, while the expression of CC chemokine receptor type 7 (CCR7) increased. In this study, we investigated whether CCR7 overexpression was associated with a decrease in the expression of miRNA Let-7a in invasion and metastasis of prostate cancer cell. Synthetic Let-7a mimics and Let-7a inhibitors were transfected into prostate cancer PC-3 cells, respectively. Then Western blot was used to detect the expression of CCR7, ERK, p38, MMP-9, and Epithelial-Mesenchymal Transition (EMT)-related proteins. Matrigel invasion assays were performed to assess the migratory and invasive activities of PC3 cells. To confirm the fact that 3'UTR of CCR7 is a direct target of Let-7a, a luciferase assay for the reporter gene expressing the Let-7a binding sites of CCR7 3'UTR was used. Synthetic Let-7a mimics decreased prostate cancer cell migration and invasion, as well as the expression of CCR7, phospho-p38, phospho-ERK1/2, MMP-9, N-cadherin, and Snail in PC-3 cells. The Let-7a inhibitors reversed the effects of Let-7a on PC-3 cells. The 3'UTR of CCR7 was confirmed as a direct target of Let-7a by using the luciferase assay. All findings demonstrated that Let-7a/CCR7 axis regulated EMT progress in prostate cancer cells and mediated the tumor cell invasion and migration process via activation of P38/ERK signal pathway. Our results suggested that the therapeutic potential of Let-7a as an antitumor and antimetastatic manager in prostate cancer and CCR7 may be regarded as a therapeutic target for the prostate cancer treatment.

Li X, Sun S, Li N, et al.
High Expression of CCR7 Predicts Lymph Node Metastasis and Good Prognosis in Triple Negative Breast Cancer.
Cell Physiol Biochem. 2017; 43(2):531-539 [PubMed] Related Publications
BACKGROUND/AIMS: Previous preclinical and clinical studies have reported a positive correlation between the expression of the C-C chemokine receptor 7 (CCR7) and the incidence of lymph node metastasis in breast cancer. However, the prognostic relevance of CCR7 expression in breast cancer remains contradictory till now. The aim of this study is to assess the correlation of the CCR7 expression with other clinicopathological features and prognosis in breast cancer.
METHODS: The CCR7 gene amplification and mRNA expression levels from approximately 3,000 patients were retrieved from human breast cancer databases and analyzed. Furthermore, a total of 188 primary triple negative breast cancer patients were enrolled in this study (diagnosed since January 2009 to January 2013 from the Second Hospital of Dalian Medical University). The protein levels of CCR7 were examined by immunohistochemistry using paraffin-embedded tumor tissues.
RESULTS: The analysis of gene amplification and mRNA levels showed the expression of CCR7 in breast cancer correlated with better prognosis. When we compared the CCR7 expressions in different subtypes, the basal-like group showed the highest expression of CCR7 and exhibited a better prognosis. Consistently, Kaplan-Meier analysis of 188 triple negative breast cancer patients showed that the prognosis of patients with positive CCR7 expression was significantly better than those with negative expression (HR=0.642, p=0.0275). Additionally, we also observed a positive correlation between lymph node metastasis and the CCR7 expression (p=0.0096).
CONCLUSIONS: Our results indicated that elevated CCR7 expression as a marker for increased lymph node metastasis, in addition to serve as an independent prognostic indicator for better overall survival in triple negative breast cancer patients.

Wolf C, Garding A, Filarsky K, et al.
NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib.
Int J Cancer. 2018; 142(2):322-333 [PubMed] Related Publications
B cell receptor (BCR) signaling is a key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. To detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2,192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL. Intriguingly, NFATC1 promoter DNA hypomethylation levels were significantly variant in clinical trial cohorts from different disease progression stages and furthermore correlated with Binet disease staging and thymidine kinase levels, strongly suggesting a central role of NFATC1 in CLL development. Functionally, DNA hypomethylation at NFATC1 promoter inversely correlated with RNA levels of NFATC1 and dysregulation correlated with expression of target genes BCL-2, CCND1 and CCR7. The inhibition of the NFAT regulator calcineurin with tacrolimus and cyclosporin A and the BCR signaling inhibitor ibrutinib significantly reduced NFAT activity in leukemic cell lines, and NFAT inhibition resulted in increased apoptosis of primary CLL cells. In summary, our results indicate that the aberrant activation of NFATC1 by DNA hypomethylation and BCR signaling plays a major role in the pathomechanism of CLL.

Fankhauser M, Broggi MAS, Potin L, et al.
Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma.
Sci Transl Med. 2017; 9(407) [PubMed] Related Publications
In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naïve T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.

Dubey B, Jackson MD, Zeigler-Johnson C, et al.
Inflammation polymorphisms and prostate cancer risk in Jamaican men: Role of obesity/body size.
Gene. 2017; 636:96-102 [PubMed] Free Access to Full Article Related Publications
African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR≥0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score≥7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent.

Haghshenas MR, Ashraf MJ, Khademi B, et al.
Chemokine and chemokine receptor patterns in patients with benign and malignant salivary gland tumors: a distinct role for CCR7.
Eur Cytokine Netw. 2017; 28(1):27-35 [PubMed] Related Publications
To explore the molecular mechanisms involved in pathophysiology of malignant and benign salivary gland tumors (SGTs), we investigated main tumor-inducing chemokines and chemokine receptors, CXCL12/CXCR4/ACKR3 (CXCR7), CXCR3/CXCL10, CCR5/CCL5, CCL21/CCR7, CCL2, CCR4, CXCR5, CCR6, and CXCL8 in tumor tissues. Parotid tissues were obtained from 30 patients with malignant and benign SGTs. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the mRNA expression pattern of the mentioned chemokines/chemokine receptors and immunohistochemistry (IHC) was performed to verify the expression of CCR7. Expression levels of CCR7 and CCR4 transcripts were higher in the tumor tissues of malignant cases in comparison to benign ones (p = 0.03 and 0.02). Immunohistochemistry analysis confirmed that the protein level of CCR7 concurred with the mRNA expression. CCL2 gene transcripts were observed with a higher expression in patients with tumor-free lymph nodes (LN

Mao FY, Kong H, Zhao YL, et al.
Increased tumor-infiltrating CD45RA
Cell Death Dis. 2017; 8(8):e3002 [PubMed] Free Access to Full Article Related Publications
Regulatory T cells (Tregs) are major components of tumor-infiltrating immune cells with potent immunosuppressive properties in gastric cancer (GC) microenvironment. However, different subsets of the Tregs and their relevance to GC are unknown. Here, we found that patients with GC showed a significantly higher Tregs infiltration in tumors, and CD45RA

Wu L, Ehlin-Henriksson B, Zhou X, et al.
Epstein-Barr virus (EBV) provides survival factors to EBV
Immunology. 2017; 152(4):562-573 [PubMed] Free Access to Full Article Related Publications
Diffuse large B-cell lymphoma (DLBCL), the most common type of malignant lymphoma, accounts for 30% of adult non-Hodgkin lymphomas. Epstein-Barr virus (EBV) -positive DLBCL of the elderly is a newly recognized subtype that accounts for 8-10% of DLBCLs in Asian countries, but is less common in Western populations. Five DLBCL-derived cell lines were employed to characterize patterns of EBV latent gene expression, as well as response to cytokines and chemotaxis. Interleukin-4 and interleukin-21 modified LMP1, EBNA1 and EBNA2 expression depending on cell phenotype and type of EBV latent programme (type I, II or III). These cytokines also affected CXCR4- or CCR7-mediated chemotaxis in two of the cell lines, Farage (type III) and Val (type II). Further, we investigated the effect of EBV by using dominant-negative EBV nuclear antigen 1(dnEBNA1) to eliminate EBV genomes. This resulted in decreased chemotaxis. By employing an alternative way to eliminate EBV genomes, Roscovitine, we show an increase of apoptosis in the EBV-positive lines. These results show that EBV plays an important role in EBV-positive DLBCL lines with regard to survival and chemotactic response. Our findings provide evidence for the impact of microenvironment on EBV-carrying DLBCL cells and might have therapeutic implications.

Zanon V, Pilipow K, Scamardella E, et al.
Curtailed T-cell activation curbs effector differentiation and generates CD8
Eur J Immunol. 2017; 47(9):1468-1476 [PubMed] Free Access to Full Article Related Publications
Human T memory stem (T

Lopez PA, Denny M, Hartmann AK, et al.
Transcutaneous immunization with a novel imiquimod nanoemulsion induces superior T cell responses and virus protection.
J Dermatol Sci. 2017; 87(3):252-259 [PubMed] Related Publications
BACKGROUND: Transcutaneous immunization (TCI) is a novel vaccination strategy utilizing the skin associated lymphatic tissue to induce immune responses. TCI using a cytotoxic T lymphocyte (CTL) epitope and the Toll-like receptor 7 (TLR7) agonist imiquimod mounts strong CTL responses by activation and maturation of skin-derived dendritic cells (DCs) and their migration to lymph nodes. However, TCI based on the commercial formulation Aldara only induces transient CTL responses that needs further improvement for the induction of durable therapeutic immune responses.
OBJECTIVE: Therefore we aimed to develop a novel imiquimod solid nanoemulsion (IMI-Sol) for TCI with superior vaccination properties suited to induce high quality T cell responses for enhanced protection against infections.
METHODS: TCI was performed by applying a MHC class I or II restricted epitope along with IMI-Sol or Aldara (each containing 5% Imiquimod) on the shaved dorsum of C57BL/6, IL-1R, Myd88, Tlr7 or Ccr7 deficient mice. T cell responses as well as DC migration upon TCI were subsequently analyzed by flow cytometry. To determine in vivo efficacy of TCI induced immune responses, CTL responses and frequency of peptide specific T cells were evaluated on day 8 or 35 post vaccination and protection in a lymphocytic choriomeningitis virus (LCMV) infection model was assessed.
RESULTS: TCI with the imiquimod formulation IMI-Sol displayed equal skin penetration of imiquimod compared to Aldara, but elicited superior CD8
CONCLUSION: Our data demonstrate that IMI-Sol TCI can overcome current limitations of previous imiquimod based TCI approaches opening new perspectives for transcutaneous vaccination strategies and allowing the use of this enhanced cutaneous drug-delivery system to be tailored for the improved prevention and treatment of infectious diseases and cancers.

Kogure Y, Kataoka K
Genetic alterations in adult T-cell leukemia/lymphoma.
Cancer Sci. 2017; 108(9):1719-1725 [PubMed] Free Access to Full Article Related Publications
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. It is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. A long latency period from HTLV-1 infection to ATL onset suggests that not only HTLV-1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated. Recently, a large-scale integrated genetic analysis revealed the entire landscape of somatic aberrations in ATL. This neoplasm is characterized by frequent gain-of-function alterations in components of the T-cell receptor/NF-κB signaling pathway, including activating mutations in the PLCG1, PRKCB, CARD11 and VAV1 genes, and CTLA4-CD28 and ICOS-CD28 fusions. Importantly, molecules associated with immune surveillance, such as HLA-A/B, CD58 and FAS, are affected recurrently. Among them, one notable lesion occurs as frequent structural variations that truncate the PD-L1 3'-untranslated region, leading to its overexpression. Other genetic targets include transcription factors (IRF4, IKZF2, and GATA3) and chemokine receptors (CCR4, CCR7 and GPR183), which are functionally relevant in normal T cells. A substantial proportion of ATL cases show widespread accumulation of repressive epigenetic changes, such as trimethylation of histone H3 lysine 27 and DNA hypermethylation of CpG islands, which coordinately modulate multiple pathways, including Cys2-His2 zinc finger genes involved in silencing retroelements. Here we review the current understanding of the genetic/epigenetic aberrations in ATL, focusing on their relevance in its molecular pathogenesis.

Xiong Y, Huang F, Li X, et al.
CCL21/CCR7 interaction promotes cellular migration and invasion via modulation of the MEK/ERK1/2 signaling pathway and correlates with lymphatic metastatic spread and poor prognosis in urinary bladder cancer.
Int J Oncol. 2017; 51(1):75-90 [PubMed] Free Access to Full Article Related Publications
Lymph node metastasis in patients with urinary bladder cancer (UBC) is always associated with poor prognosis and is the determinant for tumor staging and the development of treatment regimens; however, its underlying mechanisms remain to be studied. Immunohistochemical staining of tumor sections from 62 UBC patients was performed using CCR7, D2-40 and CD34 antibodies. We showed that increased CCR7 expression was significantly associated with positive lymph node status (P=0.008), pT3-T4 tumor stage (P=0.015), tumor grade (P=0.010) and worse overall survival (OS, P<0.001) and that both CCR7 expression and lymph node metastasis were independent prognostic factors for OS (P=0.031 and P=0.001, respectively) based on multivariate analysis. We found that there was a significant association between MLVD and lymph node status (P=0.006), but this relation was not observed for MVD. Furthermore, we showed that increased CCR7 expression correlated significantly with higher MLVD (P=0.014) and MVD (P=0.002). Wound-healing and matrigel transwell assays indicated that activation of CCR7 with CCL21 significantly enhanced the invasion and migration abilities of UM-UC-3 cells, and this enhanced effect was significantly abrogated by CCR7 knockdown using siRNA. Western blot analysis revealed that the phospho-ERK1/2 level was markedly increased when UM-UC-3 cells were treated with CCL21 and significantly decreased when the CCR7 gene was silenced. MEK/ERK1/2 inhibition with PD98059 significantly suppressed the migration and invasion abilities of UM-UC-3 cells and also significantly abrogated the effects of CCL21/CCR7 on cell migration and invasion. Based on these results, we conclude that activation of the CCL21/CCR7 chemoaxis promotes lymph node metastasis of UBC in at least two ways. Firstly, although CCR7 is a promoting factor that induces both lymphangiogenesis and angiogenesis, it may promote lymph node metastasis through its lymphangiogenic effect rather than through its angiogenic effect. Secondly, the CCL21/CCR7 chemoaxis promotes the migration and invasion of UBC cells via the MEK/ERK1/2 signaling pathway rather than the PI3K/AKT pathway.

Zhong G, Chen L, Yin R, et al.
Chemokine (C‑C motif) ligand 21/C‑C chemokine receptor type 7 triggers migration and invasion of human lung cancer cells by epithelial‑mesenchymal transition via the extracellular signal‑regulated kinase signaling pathway.
Mol Med Rep. 2017; 15(6):4100-4108 [PubMed] Free Access to Full Article Related Publications
C-C chemokine receptor type 7 (CCR7) has been implicated in lymph node metastasis of various cancers. Previous studies have revealed that epithelial‑mesenchymal transition (EMT) is involved in the chemotactic process mediated by CCR7 and its ligands in various types of carcinoma. However, the underlying mechanism of this process remains to be fully elucidated. The present study investigated whether chemokine (C‑C motif) ligand 21 (CCL21)/CCR7 may activate EMT of lung cancer cells and their associated signaling pathways. A549 and H520 lung cancer cell lines were examined in vitro in the present study. The results indicated that A549 and H520 expressed CCR7, but reduced levels of CCL21. Following stimulation of lung cancer cell lines with CCL21, the expression of the epithelial marker E‑cadherin was downregulated, and the mesenchymal markers Vimentin/Slug and extracellular signal‑regulated kinase (ERK) were upregulated. In addition, the ERK inhibitor PD98059 may inhibit EMT caused by CCL21, and decreased cell migration and invasion initiated by CCL21. Furthermore, lung adenocarcinoma tissues from 50 patients who underwent lung cancer operations were investigated by immunohistochemistry. The findings revealed that CCR7, Slug and Vimentin were highly expressed in lung carcinoma tissues, and were significantly associated with lymph node metastasis and clinical pathological stages, respectively. CCR7 expression was correlated positively with expression levels of Slug and Vimentin. CCL21 was expressed positively in the endothelium of lymphatic vessels adjacent to cancer cells, and weakly in lung cancer cells. Collectively, these results demonstrated that CCL21/CCR7 may activate EMT in lung cancer cells via the ERK1/2 signaling pathway. The current study provides evidence that a close interaction exists between CCL21/CCR7chemotaxis and EMT procedures in lung cancer metastasis, providing a basis for the development of therapeutic targets.

Kallemeijn MJ, de Ridder D, Schilperoord-Vermeulen J, et al.
Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte leukemia.
PLoS One. 2017; 12(4):e0175670 [PubMed] Free Access to Full Article Related Publications
TCRγδ+ T-LGL leukemia is a rare form of chronic mature T cell disorders in elderly, which is generally characterized by a persistently enlarged CD3+CD57+TCRγδ+ large granular lymphocyte population in the peripheral blood with a monoclonal phenotype. Clinically, the disease is heterogeneous, most patients being largely asymptomatic, although neutropenia, fatigue and B symptoms and underlying diseases such as autoimmune diseases or malignancies are also often observed. The etiology of TCRγδ+ T-LGL proliferations is largely unknown. Here, we aimed to investigate underlying molecular mechanisms of these rare proliferations by performing gene expression profiling of TCRγδ+ T-LGL versus normal TCRγδ+ T cell subsets. From our initial microarray dataset we observed that TCRγδ+ T-LGL leukemia forms a separate group when compared with different healthy control TCRγδ+ T cell subsets, correlating best with the healthy TemRA subset. The lowest correlation was seen with the naive subset. Based on specific comparison between healthy control cells and TCRγδ+ T-LGL leukemia cells we observed up-regulation of survival, proliferation and hematopoietic system related genes, with a remarkable down-regulation of apoptotic pathway genes. RQ-PCR validation of important genes representative for the dataset, including apoptosis (XIAP, CASP1, BCLAF1 and CFLAR), proliferation/development (ID3) and inflammation (CD28, CCR7, CX3CR1 and IFNG) processes largely confirmed the dysregulation in proliferation and apoptosis. Based on these expression data we conclude that TCRγδ+ T-LGL leukemia is likely the result of an underlying aberrant molecular mechanisms leading to increased proliferation and reduced apoptosis.

Xu B, Zhou M, Qiu W, et al.
CCR7 mediates human breast cancer cell invasion, migration by inducing epithelial-mesenchymal transition and suppressing apoptosis through AKT pathway.
Cancer Med. 2017; 6(5):1062-1071 [PubMed] Free Access to Full Article Related Publications
Chemokine and the chemokine receptor have a key role in the tumor progress. Here, we supposed that CCR7 might induce the invasion, migration, and epithelial-mesenchymal transition (EMT) process of breast cancer. In this research, human breast cancer MCF-7 and MDA-MB-231cells were treated with CCL19 and small-interfering RNA (CCR7 siRNA) for activation and inhibition of CCR7, respectively. Cell invasion and transwell assays were used to detect the effect of CCR7 on invasion and migration. The results demonstrated that CCL19 mediated cell invasion and migration by inducing the EMT, with downregulation of E-cadherin and up-regulation of N-cadherin and vimentin levels. On the other hand, knockdown of CCR7 revealed the changes compared with CCL19 group and the control group. Knockdown of CCR7 inhibits CCL19-induced breast cancer cell proliferation, the cell cycle, migration, invasion and EMT. Moreover, we demonstrated that CCL19-induced AKT phosphorylation; however, CCR7 siRNA suppressed CCL19-induced AKT phosphorylation, a key regulator of tumor metastasis. In conclusion, all findings demonstrated that CCL19/CCR7 axis regulated EMT progress in breast cancer cells and mediated the tumor cell invasion and migration process via activation of AKT signal pathway. Our results suggested that CCR7 may regard as a therapeutic target for the breast cancer treatment.

Watanabe T
Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells.
Blood. 2017; 129(9):1071-1081 [PubMed] Free Access to Full Article Related Publications
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor-NF-κB signaling such as

Kang H, Zhang J, Wang B, et al.
Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway.
Int J Oncol. 2017; 50(2):545-554 [PubMed] Related Publications
Non-small cell lung carcinoma (NSCLC) metastasis is responsible for most of cancer-related mortality. The tumor associated macrophages (TAMs) are known to be crucial cells in lung cancer and are usually divided into two antagonistic types, M1 and M2. Puerarin has a wide spectrum of pharmacological properties. The present study explores puerarin on macrophage polarization and metastasis of NSCLC. The results demonstrated that puerarin inhibited tumor growth and tumor volumes in NSCLC xenograft model, increased M1 markers [CD197+, inducible nitric oxide synthase (iNOS)+, CD40+)] and reduced M2 markers (CD206+, Arg-1+ and CD163+). Besides, puerarin elevated the level of pro-inflammatory cytokine interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-12, decreased the expression of pro-tumor cytokines IL-10, IL-4 and transforming growth factor (TGF)-β. To explore whether puerarin directly acts on macrophages, we purified macrophages from NSCLC model, the results showed that puerarin inhibited macrophages polarized to M2 phenotype and did not require the auxiliary of other cells. In addition, puerarin suppressed the invasion and migration of NSCLC macrophages, restrained the expression of angiogenesis factors. Puerarin also inhibited the activation of mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) 1/2 pathway through inhibition of ERK nucleus translocation. Finally, IL-4 induced M2 macrophage polarization and metastasis were partially offset by puerarin through inactivating the MEK/ERK 1/2 pathway. Taken together, this study validated that puerarin is able to skew macrophage populations back to M1 subsets to stimulate antitumor effects and suggests puerarin is a negative metastatic regulator of NSCLC.

Gracio F, Burford B, Gazinska P, et al.
Splicing imbalances in basal-like breast cancer underpin perturbation of cell surface and oncogenic pathways and are associated with patients' survival.
Sci Rep. 2017; 7:40177 [PubMed] Free Access to Full Article Related Publications
Despite advancements in the use of transcriptional information to understand and classify breast cancers, the contribution of splicing to the establishment and progression of these tumours has only recently starting to emerge. Our work explores this lesser known landscape, with special focus on the basal-like breast cancer subtype where limited therapeutic opportunities and no prognostic biomarkers are currently available. Using ExonArray analysis of 176 breast cancers and 9 normal breast tissues we demonstrate that splicing levels significantly contribute to the diversity of breast cancer molecular subtypes and explain much of the differences compared with normal tissues. We identified pathways specifically affected by splicing imbalances whose perturbation would be hidden from a conventional gene-centric analysis of gene expression. We found that a large fraction of them involve cell-to-cell communication, extracellular matrix and transport, as well as oncogenic and immune-related pathways transduced by plasma membrane receptors. We identified 247 genes in which splicing imbalances are associated with clinical patients' outcome, whilst no association was detectable at the gene expression level. These include the signaling gene TGFBR1, the proto-oncogene MYB as well as many immune-related genes such as CCR7 and FCRL3, reinforcing evidence for a role of immune components in influencing breast cancer patients' prognosis.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. CCR7, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 30 August, 2019     Cancer Genetics Web, Established 1999