CCR5

Gene Summary

Gene:CCR5; chemokine (C-C motif) receptor 5 (gene/pseudogene)
Aliases: CKR5, CCR-5, CD195, CKR-5, CCCKR5, CMKBR5, IDDM22, CC-CKR-5
Location:3p21.31
Summary:This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. This protein is expressed by T cells and macrophages, and is known to be an important co-receptor for macrophage-tropic virus, including HIV, to enter host cells. Defective alleles of this gene have been associated with the HIV infection resistance. The ligands of this receptor include monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted protein (RANTES). Expression of this gene was also detected in a promyeloblastic cell line, suggesting that this protein may play a role in granulocyte lineage proliferation and differentiation. This gene is located at the chemokine receptor gene cluster region. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:C-C chemokine receptor type 5
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CCR5 (cancer-related)

Sicoli D, Jiao X, Ju X, et al.
CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines.
Cancer Res. 2014; 74(23):7103-14 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Src family kinases (SFK) integrate signal transduction for multiple receptors, regulating cellular proliferation, invasion, and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. To determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cell lines were grown in vivo versus tissue cultures. The whole body, bone, and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors.

Mahalingam J, Lin CY, Chiang JM, et al.
CD4⁺ T cells expressing latency-associated peptide and Foxp3 are an activated subgroup of regulatory T cells enriched in patients with colorectal cancer.
PLoS One. 2014; 9(9):e108554 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Latency-associated peptide (LAP) - expressing regulatory T cells (Tregs) are important for immunological self-tolerance and immune homeostasis. In order to investigate the role of LAP in human CD4⁺Foxp3⁺ Tregs, we designed a cross-sectional study that involved 42 colorectal cancer (CRC) patients. The phenotypes, cytokine-release patterns, and suppressive ability of Tregs isolated from peripheral blood and tumor tissues were analyzed. We found that the population of LAP-positive CD4⁺Foxp3⁺ Tregs significantly increased in peripheral blood and cancer tissues of CRC patients as compared to that in the peripheral blood and tissues of healthy subjects. Both LAP⁺ and LAP⁻ Tregs had a similar effector/memory phenotype. However, LAP⁺ Tregs expressed more effector molecules, including tumor necrosis factor receptor II, granzyme B, perforin, Ki67, and CCR5, than their LAP⁻ negative counterparts. The in vitro immunosuppressive activity of LAP⁺ Tregs, exerted via a transforming growth factor-β-mediated mechanism, was more potent than that of LAP⁻ Tregs. Furthermore, the enrichment of LAP⁺ Treg population in peripheral blood mononuclear cells (PBMCs) of CRC patients correlated with cancer metastases. In conclusion, we found that LAP⁺ Foxp3⁺ CD4⁺ Treg cells represented an activated subgroup of Tregs having more potent regulatory activity in CRC patients. The increased frequency of LAP⁺ Tregs in PBMCs of CRC patients suggests their potential role in controlling immune response to cancer and presents LAP as a marker of tumor-specific Tregs in CRC patients.

Velasco-Velázquez M, Xolalpa W, Pestell RG
The potential to target CCL5/CCR5 in breast cancer.
Expert Opin Ther Targets. 2014; 18(11):1265-75 [PubMed] Related Publications
INTRODUCTION: Chemokines play a crucial role in breast cancer tumorigenesis and progression. Recently, the chemokine (C-C motif) ligand 5 (CCL5), which can be secreted either by tumor cells or by mesenchymal stromal cells recruited to the tumor, has been identified as a key node in the bidirectional communication between breast cancer and normal cells.
AREAS COVERED: In this review, the authors discuss the role of CCL5/chemokine receptor 5 (CCR5) axis in promoting breast cancer onset and progression. Interrogation of large clinical databases has demonstrated increased expression of the CCL5/CCR5 axis in specific subtypes of breast cancer. The activation of the receptor CCR5 in breast cancer cells controls their invasiveness serving as a driver for metastasis. Furthermore, the CCL5/CCR5 axis participates in the recruitment of specific immune cells into tumors, inducing local immunosuppression and favoring tumor progression.
EXPERT OPINION: The role of CCR5 in HIV infection led to the development of specific and potent CCR5 antagonists. The data reviewed here includes basic and translational studies that support the use of such CCR5 antagonists in breast cancer patients as adjuvant therapy to block the metastasis.

Razmkhah M, Arabpour F, Taghipour M, et al.
Expression of chemokines and chemokine receptors in brain tumor tissue derived cells.
Asian Pac J Cancer Prev. 2014; 15(17):7201-5 [PubMed] Related Publications
Chemokine and chemokine receptor expression by tumor cells contributes to tumor growth and angiogenesis and thus these factors may be considered as tumor markers. Here we aimed to characterize cells directly extracted from glioma, meningioma, and secondary brain tumors as well as non-tumoral cells in vitro. Cells were isolated from brain tissues using 0.2% collagenase and characterized by flow cytometry. Expression of SDF-1, CXCR4, CXCR7, RANTES, CCR5, MCP-1 and IP-10 was defined using flow cytometry and qRT-PCR methods. Brain tissue isolated cells were observed as spindle-shaped cell populations. No significant differences were observed for expression of SDF-1, CXCR4, CXCR7, RANTES, CCR5, and IP-10 transcripts. However, the expression of CXCR4 was approximately 13-fold and 110-fold higher than its counterpart, CXCR7, in meningioma and glioma cells, respectively. CXCR7 was not detectable in secondary tumors but CXCR4 was expressed. In non tumoral cells, CXCR7 had 1.3-fold higher mRNA expression than CXCR4. Flow cytometry analyses of RANTES, MCP- 1, IP-10, CCR5 and CXCR4 expression showed no significant difference between low and high grade gliomas. Differential expression of CXCR4 and CXCR7 in brain tumors derived cells compared to non-tumoral samples may have crucial impacts on therapeutic interventions targeting the SDF-1/CXCR4/CXCR7 axis.

Pehlivan M, Sahin HH, Ozdilli K, et al.
Gene polymorphisms and febrile neutropenia in acute leukemia--no association with IL-4, CCR-5, IL-1RA, but the MBL-2, ACE, and TLR-4 are associated with the disease in Turkish patients: a preliminary study.
Genet Test Mol Biomarkers. 2014; 18(7):474-81 [PubMed] Related Publications
AIMS: The aim of this study was to investigate the mannose-binding lectin 2 (MBL-2), interleukin (IL)-4, Toll-like receptor 4 (TLR-4), angiotensin converting enzyme (ACE), chemokine receptor 5 (CCR-5), and IL-1 receptor antagonist (RA) gene polymorphisms (GPs) in acute leukemias (ALs) and to evaluate their roles in febrile neutropenia (FN) resulting from chemotherapy.
METHODS: The study included 60 AL patients hospitalized between the period of July 2001 and August 2006. Polymorphisms for the genes ACE(I/D), CCR-5, IL-1RA, MBL-2, TLR-4, and IL-4 were typed by polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymerase. Genotype frequencies for these genes were compared in the patient and control groups. The relationships between the genotypes and the body distribution of infections, pathogens, the duration of neutropenia, and febrile episodes in AL patients were evaluated.
RESULTS: No significant differences in either the genotype distribution or the allelic frequencies of TLR-4, IL-4, CCR-5, IL-1RN GPs were observed between patients and healthy controls. The AB/BB genotype (53.3%) in the MBL-2 gene was found to be significantly higher in the AL patients compared with control groups. There were correlations between the presence of MBL-2, TLR-4, and ACE polymorphisms and clinical parameters due to FN. Overall, bacteremia was more common in MBL BB and ACE DD. Gram-positive bacteremia was more common in ACE for ID versus DD genotype. Gram-negative bacteremia was more common for both the MBL-2 AB/BB genotype and TLR-4 AG genotype. Median durations of febrile episodes were significantly shorter in ACE DD and MBL AB/BB.
CONCLUSION: Although TLR-4, ACE, and MBL-2 GPs have been extensively investigated in different clinical pictures, this is the first study to evaluate the role of these polymorphisms in the genetic etiopathogenesis of FN in patients with ALs. As a conclusion, TLR-4, ACE, and MBL-2 genes might play roles in the genetic etiopathogenesis of FN in patients with ALs.

Chaturvedi P, Gilkes DM, Takano N, Semenza GL
Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.
Proc Natl Acad Sci U S A. 2014; 111(20):E2120-9 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony-stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple-negative breast cancers have increased expression of genes regulated by hypoxia-inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs.

Rezaeifard S, Razmkhah M, Robati M, et al.
Adipose derived stem cells isolated from omentum: a novel source of chemokines for ovarian cancer growth.
J Cancer Res Ther. 2014 Jan-Mar; 10(1):159-64 [PubMed] Related Publications
BACKGROUND: The main site of ovarian cancer metastasis is the omentum. Omental adipose tissue is known for contribution to the tumor growth and metastasis through different mechanisms.
AIMS: In the present study, adipose derived stem cells (ASCs) were isolated from the omentum of patients with ovarian cancer and those with ovarian cysts and the expression of chemokines, chemokine receptors and cytokines were analyzed.
MATERIALS AND METHODS: ASCs were isolated from omental adipose tissues obtained of 10 ovarian cancer and 25 ovarian benign cyst patients. Our investigations were done by quantitative real time-polymerase chain reaction, flowcytometry, western blot and also enzyme-linked immunosorbent assay.
RESULT: Expression of CXCL-10 and CCR5 showed statistically significant difference between omentum derived ASCs of ovarian cancer patients compared with those with benign cysts (P < 0.05). Expression of interleukin-10 also detected in the supernatant of cultured malignant ASCs.
CONCLUSION: Omental adipose tissue may play crucial roles for tumor promotion through the expression of tumor promoting chemokines. Accordingly, tumor surrounding adipose tissue may be a novel target for immunotherapy of cancer.

Aldinucci D, Colombatti A
The inflammatory chemokine CCL5 and cancer progression.
Mediators Inflamm. 2014; 2014:292376 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Until recently, inflammatory chemokines were viewed mainly as indispensable "gate keepers" of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion.

Singh V, Jaiswal PK, Kapoor R, et al.
Impact of chemokines CCR5∆32, CXCL12G801A, and CXCR2C1208T on bladder cancer susceptibility in north Indian population.
Tumour Biol. 2014; 35(5):4765-72 [PubMed] Related Publications
Chemokines are small inducible pro-inflammatory cytokines. In the present study, we tested association of chemokine single nucleotide polymorphisms (SNPs) viz., CCR5∆32, CXCL12G801A and CXCR2C1208T genes in bladder cancer (BC) patients and normal healthy controls of north Indians. Genotyping of the above SNPs were done in 200 BC cases and 200 healthy controls, using RFLP and amplification refractory mutation system-polymerase chain reaction methodology. A significant association was found in CXCL12G801A with BC risk. In case of CXCL12G801A polymorphism, the heterozygous (GA) genotype showed significantly high risk (p < 0.001, odds ratio (OR) = 2.72), whereas A allele carrier (GA + AA) also showed risk with BC (p < 0.001, OR = 2.44). In CXCR2C1208T polymorphism, the variant genotype (TT) showed significant risk for BC (p = 0.028, OR = 1.58). The variant allele (T) of CXCR2C1208T polymorphism was found to be associated with BC risk (p = 0.003, OR = 1.29). Interestingly, smoking was also found to modulate 1.16-fold risks for BC in case of CXCR2C1208T, variant genotype (TT). Upon analyzing the gene-gene interaction between CXCR2C1208T and CXCL12G801A, the combination CT-GA showed 4-fold risk for BC (p = 0.009). Our results indicated that polymorphism in CXCR2C1208T and CXCL12G801A showed high risk for BC in north Indian population. However, CCR5∆32 exhibited no association. Study with large sample size and diverse ethnicity are required to validate these observations.

Zaia JA, Forman SJ
Transplantation in HIV-infected subjects: is cure possible?
Hematology Am Soc Hematol Educ Program. 2013; 2013:389-93 [PubMed] Related Publications
With the advent of effective antiretroviral therapy, the treatment of patients with HIV-related malignancies, especially lymphoma, has greatly improved, yielding results comparable to those seen in patients with lymphoma unrelated to HIV. The platform of transplantation of hematopoietic stem cells has facilitated studies of genetically modified stem cells engineered to express antiretroviral genes to resist infection by the HIV virus, testing the concept that engraftment of these cells will lead to HIV resistance and elimination of the reservoir of virus in the body. Results in patients with HIV and lymphoma have now led to studies that will test these principles in HIV patients without concomitant malignancy. In addition, in a patient with HIV and acute myeloid leukemia, the success of an allogeneic transplantation from an unrelated donor carrying a mutation in the CCR5 genes has demonstrated that, in principle, such an approach could also lead to cure of patients with HIV. Case studies in HIV patients with leukemia undergoing allogeneic transplantation also suggest that there may be a therapeutic effect on the HIV reservoir that could alter the natural history of HIV in the allogeneic setting.

Zhang Y, Meng FY, Li WL, et al.
Association of chemotactic factor receptor 5 gene with breast cancer.
Genet Mol Res. 2013; 12(4):5289-300 [PubMed] Related Publications
We designed a 2-stage study to investigate chemotactic factor receptor 5 (CCR5) gene expression in breast cancer tissues and axillary lymph nodes and analyze the association between the CCR5-Î"32 gene polymorphism and the clinical features and prognosis of breast cancer patients. The first stage examined 72 cases of invasive ductal carcinoma and axillary lymph node tissue, 50 cases of breast fibroadenoma tissue, and 40 cases of normal breast tissue. The tissues specimens were embedded in paraffin, and CCR5 expression was detected using immunohistochemical methods. C-erbB-2, p53, Ki-67, estrogen receptor, and progesterone receptor expression were also detected in the breast cancer tissues. The second stage examined 35 cases of surgically removed tissue. Relative expression levels of CCR5 messenger RNA (mRNA) in primary foci, axillary lymph node, and cancer-adjacent tissues of the breast cancer and breast fibroadenoma samples were detected using real-time quantitative reverse transcription-polymerase chain reaction assay. We found that 1) CCR5 mRNA relative expression levels in breast cancer tissue were significantly higher than those in adjacent normal tissue (P < 0.01) and benign tumors (P < 0.05). The relative CCR5 mRNA relative expression level between phase II and phase III breast cancer tissues was statistically significant (P < 0.05). The CCR5 mRNA relative expression level between adjacent normal tissues and fibroadenoma tissues was not significantly different (P > 0.05). 2) Relative CCR5 mRNA expression level was significantly higher in metastatic lymph node tissues than that in non-metastatic lymph nodes (P < 0.05), and 3) CCR5 expression in breast cancer tissue was positively correlated with axillary lymph node metastasis (chi-square = 4.982, P = 0.026, r = 0.305). CCR5 expression was mildly and positively correlated with the oncogene C-erbB-2 (P < 0.05, r = 0.291). 4) CCR5 expression in breast cancer tissue was not correlated with age, menopause, maximum tumor size, tumor phase, p53, Ki-67, estrogen receptor, progesterone receptor, or other clinical features (P > 0.05). We concluded that CCR5 expression significantly increases in breast cancer tissues and metastatic lymph nodes. CCR5 plays a role in breast cancer development and axillary lymph node metastasis. It can be used indirectly as an indicator of axillary lymph node metastasis and prognosis.

Iancu EM, Gannon PO, Laurent J, et al.
Persistence of EBV antigen-specific CD8 T cell clonotypes during homeostatic immune reconstitution in cancer patients.
PLoS One. 2013; 8(10):e78686 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Persistent viruses are kept in check by specific lymphocytes. The clonal T cell receptor (TCR) repertoire against Epstein-Barr virus (EBV), once established following primary infection, exhibits a robust stability over time. However, the determinants contributing to this long-term persistence are still poorly characterized. Taking advantage of an in vivo clinical setting where lymphocyte homeostasis was transiently perturbed, we studied EBV antigen-specific CD8 T cells before and after non-myeloablative lympho-depleting chemotherapy of melanoma patients. Despite more advanced T cell differentiation, patients T cells showed clonal composition comparable to healthy individuals, sharing a preference for TRBV20 and TRBV29 gene segment usage and several co-dominant public TCR clonotypes. Moreover, our data revealed the presence of relatively few dominant EBV antigen-specific T cell clonotypes, which mostly persisted following transient lympho-depletion (TLD) and lymphocyte recovery, likely related to absence of EBV reactivation and de novo T cell priming in these patients. Interestingly, persisting clonotypes frequently co-expressed memory/homing-associated genes (CD27, IL7R, EOMES, CD62L/SELL and CCR5) supporting the notion that they are particularly important for long-lasting CD8 T cell responses. Nevertheless, the clonal composition of EBV-specific CD8 T cells was preserved over time with the presence of the same dominant clonotypes after non-myeloablative chemotherapy. The observed clonotype persistence demonstrates high robustness of CD8 T cell homeostasis and reconstitution.

Mango RL, Wu QP, West M, et al.
C-C chemokine receptor 5 on pulmonary mesenchymal cells promotes experimental metastasis via the induction of erythroid differentiation regulator 1.
Mol Cancer Res. 2014; 12(2):274-82 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
UNLABELLED: C-C Chemokine receptor 5 knockout (Ccr5(-/-)) mice develop fewer experimental pulmonary metastases than wild-type (WT) mice. This phenomenon was explored by applying gene expression profiling to the lungs of mice with these metastases. Consequently, erythroid differentiation regulator 1 (Erdr1) was identified as upregulated in the WT mice. Though commonly associated with bone marrow stroma, Erdr1 was differentially expressed in WT pulmonary mesenchymal cells (PMC) and murine embryonic fibroblasts (MEF). Moreover, the Ccr5 ligand Ccl4 increased its expression by 3.36 ± 0.14-fold. Ccr5 signaling was dependent on the mitogen-activated protein kinase kinase (Map2k) but not the phosphoinositide 3-kinase (Pi3k) pathway because treatment with U0126 inhibited upregulation of Erdr1, but treatment with LY294002 increased the expression by 3.44 ± 0.92-fold (P < 0.05). The effect Erdr1 on B16-F10 melanoma metastasis was verified by the adoptive transfer of WT MEFs into Ccr5(-/-) mice. In this model, MEFs that had been transduced with Erdr1 short hairpin RNA (shRNA) lowered metastasis by 33% compared with control transduced MEFs. The relevance of ERDR1 on human disease was assessed by coculturing chronic lymphocytic leukemia (CLL) cells with M2-10B4 stromal cells that had been transfected with shRNA or control plasmids. After 96 hours of coculture, the cell counts were higher with control cell lines than with Erdr1 knockdown lines [odds ratio (OR), 1.88 ± 0.27, 2.52 ± 0.66, respectively]. This increase was associated with a decrease in apoptotic cells (OR, 0.69 ± 0.18, 0.58 ± 0.12, respectively).
IMPLICATIONS: Therefore, ERDR1 is a stromal-derived factor that promotes cancer cell survival in vitro and in an experimental metastasis model.

Baba T, Naka K, Morishita S, et al.
MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia.
J Exp Med. 2013; 210(12):2661-73 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene-transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL(+)lineage(-)c-kit(-) immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1α/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal.

Bedognetti D, Spivey TL, Zhao Y, et al.
CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2.
Br J Cancer. 2013; 109(9):2412-23 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression.
METHODS: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50).
RESULTS: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR.
CONCLUSION: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.

Staudt ND, Jo M, Hu J, et al.
Myeloid cell receptor LRP1/CD91 regulates monocyte recruitment and angiogenesis in tumors.
Cancer Res. 2013; 73(13):3902-12 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 was deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly increased in these mice, compared with control mice. LRP1-deficient bone marrow-derived macrophages (BMDM) expressed higher levels of multiple chemokines, including, most prominently, macrophage inflammatory protein-1α/CCL3, which is known to amplify inflammation. Increased levels of CCL3 were detected in LRP1-deficient tumor-associated macrophages (TAM), isolated from PanO2 tumors, and in RAW 264.7 macrophage-like cells in which LRP1 was silenced. LRP1-deficient BMDMs migrated more rapidly than LRP1-expressing cells in vitro. The difference in migration was reversed by CCL3-neutralizing antibody, by CCR5-neutralizing antibody, and by inhibiting NF-κB with JSH-23. Inhibiting NF-κB reversed the increase in CCL3 expression associated with LRP1 gene silencing in RAW 264.7 cells. Tumors formed in mice with LRP1-deficient myeloid cells showed increased angiogenesis. Although VEGF mRNA expression was not increased in LRP1-deficient TAMs, at the single-cell level, the increase in TAM density in tumors with LRP1-deficient myeloid cells may have allowed these TAMs to contribute an increased amount of VEGF to the tumor microenvironment. Our results show that macrophage density in tumors is correlated with cancer angiogenesis in a novel model system. Myeloid cell LRP1 may be an important regulator of cancer progression.

Zambra FM, Biolchi V, Brum IS, Chies JA
CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer.
Hum Immunol. 2013; 74(8):1003-8 [PubMed] Related Publications
Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are two chronic conditions, very common in aged men, that have been associated to inflammatory process. Chemokines and their receptors are recognized as critical mediators of inflammatory responses, they regulate immune cell migration and are implicated in tumor pathogenesis. The impact of two chemokine receptor gene polymorphisms, CCR2-64I (rs1799864) and CCR5-Δ32 (rs333), was evaluated in BPH and PCa. 385 DNA samples (130 BPH, 136 PCa, 119 healthy control) were genotyped. The allele frequencies were similar among control, BPH and PCa groups. Median of serum PSA levels was different between groups: 0.79, 1.45 and 6.91 ng/mL in control, BPH and PCa groups, respectively (all p<0.001). The prostate volume median was 20.00 cm(3) in the control group, thus, lower than BPH (35.35 cm(3)) and PCa (35.80 cm(3)) (both p<0.001), nevertheless no statistical significant difference was observed between BPH and PCa patients (p=0.172). Remarkably, CCR2-64I was a protective factor to PCa when compared with BPH (OR=0.550; 95%CI=0.311-0.975), although the statistically significant difference was lost after correction for multiple comparisons. No significant associations of CCR5-Δ32 variant were observed with BPH, PCa or PCa clinicopathologic status. Our data suggest the influence of CCR2-64I variant in the development of prostate cancer.

Sundarasetty BS, Singh VK, Salguero G, et al.
Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia.
Hum Gene Ther. 2013; 24(2):220-37 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4) was used to transduce human monocytes ex vivo. Overnight transduction induced self-differentiation of monocytes into immunophenotypically stable "SmartDC/tWT1" (GM-CSF(+), IL-4(+), tWT1(+), IL-6(+), IL-8(+), TNF-α(+), MCP-1(+), HLA-DR(+), CD86(+), CCR2(+), CCR5(+)) that were viable for 3 weeks in vitro. SmartDC/tWT1 were produced with peripheral blood mononuclear cells (PBMC) obtained from an FLT3-ITD(+) AML patient and surplus material from a donor lymphocyte infusion (DLI) and used to expand CD8(+) T cells in vitro. Expanded cytotoxic T lymphocytes (CTLs) showed antigen-specific reactivity against WT1 and against WT1(+) leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1(-/-).IL2rγc(-/-) mice were viable in vivo for more than three weeks. Migration of human T cells (huCTLs) to the immunization site was demonstrated following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore, SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1(+) tumor. Gene array analyses of SmartDC/tWT1 demonstrated upregulation of several genes related to innate immunity. Thus, SmartDC/tWT1 can be produced in a single day of ex vivo gene transfer, are highly viable in vivo, and have great potential for use as immunotherapy against malignant transformation overexpressing WT1.

Razmkhah M, Jaberipour M, Safaei A, et al.
Chemokine and chemokine receptors: a comparative study between metastatic and nonmetastatic lymph nodes in breast cancer patients.
Eur Cytokine Netw. 2012 Jul-Sep; 23(3):72-7 [PubMed] Related Publications
BACKGROUND: Lymph nodes (LNs) are among the first sites of tumor metastasis. The expression of chemokines and chemokine receptors in LNs are involved in cancer prognosis and are considered to be good predictors of tumor progression. The main aim of this study was to assess the expression of important, tumor-promoting chemokines and chemokine receptors in LNs of breast cancer patients. LNs were isolated from eighteen women diagnosed with breast cancer. Data were compared between positive and negative LNs. Expression of chemokines and chemokine receptors were determined by quantitative real-time PCR (qRT-PCR) and flow cytometry.
RESULTS: Results of qRT-PCR showed that all chemokines, in particular MCP-1, IL-8, SDF-1 and CXCL13, and chemokine receptors CXCR3, CXCR4 and CCR5 showed greater mRNA expression in LN(+) compared to LN(-) samples. However, these differences were not statistically significant. IL-8 and CXCR5 gene transcripts had significantly higher expression in LN(+ )patients with stage III compared to those with stage II tumors (P value = 0.04). Results of flow cytometry analysis showed a higher, significant presence of CD69(+), CCR5(+) and CD3(+)CCR5(+) cells in LN of LN(+) compared to LN(- )breast cancer patients (P value<0.05). Expression of MCP-1 was higher in LN(+) patients, which was near significance (P value = 0.07).
CONCLUSIONS: Our findings provide additional information on the expression of essential chemokines and chemokine receptors in LN and on their relationships to important prognostic factors in breast cancer. These findings have important implications for immunotherapeutic interventions in the treatment of breast cancer.

Guleria K, Sharma S, Manjari M, et al.
p.R72P, PIN3 Ins16bp polymorphisms of TP53 and CCR5?32 in north Indian breast cancer patients.
Asian Pac J Cancer Prev. 2012; 13(7):3305-11 [PubMed] Related Publications
BACKGROUND: The present study aimed to find the prognostic implications of two polymorphisms in TP53 (p.R72P, PIN3 Ins16bp) and one in CCR5 (CCR5/32) in sporadic breast cancer patients.
METHODS: DNA samples of 80 breast cancer patients and 80 age and gender matched unrelated healthy control individuals from Punjab, North West India were analyzed.
RESULTS: For p.R72P, the genotype frequency was 13.8% (RR), 58.8% (RP), 27.5% (PP) in patients and 33.9% (RR), 40.0% (RP), 26.5% (PP) in controls. For PIN3 Ins16bp, the genotype frequencies were 53.75% (A1A1), 37.5% (A1A2), 8.75% (A2A2) in patients and 66.3% (A1A1), 31.3% (A1A2), 2.5% (A2A2) in controls. Only 4 (5%) breast cancer patients were heterozygous for CCR5Δ32 deletion. Common RR-A1A1-WT/WT genotype was lower while RP-A1A2-WT/WT genotype was higher in patients as compared to controls. RP-A1A1-WT/WT genotype was significantly higher in patients as compared to control individuals (p = 0.008).
CONCLUSION: Though a clear association of any particular genotype with sporadic breast cancer or stage was not apparent, the results of present study were suggestive that sporadic breast cancer patients with RR-A1A1-WT/WT genotype might have a better response to chemotherapy, thus improving their chances of survival.

Kucukgergin C, Isman FK, Dasdemir S, et al.
The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer.
Gene. 2012; 511(1):7-11 [PubMed] Related Publications
The gene variants of the chemokine and chemokine receptor genes associated with inflammation may be involved in cancer initiation and progression. The aim of this study was to explore the possible association of monocyte chemoattractant protein-1 (MCP-1) A2518G, stromal cell derived factor 1 (SDF-1) 3'A and chemokine receptors CCR2A V64I, CCR5 Δ32, CCR5 59029 and CXCR4 gene polymorphisms with the risk and clinicopathological characteristics of bladder cancer (BC) in a Turkish population. The genotyping was done by PCR and PCR-Restriction Fragment Length Polymorphism (RFLP) methods in 142 histologically confirmed BC patients and 197 controls. The SDF-1 3'AA genotype conferred significantly increased susceptibility to BC. The carriers with AA genotype or at least one A allele of CCR2 had an increased risk of developing BC. CCR5 wt/Δ32 genotype and CCR5 Δ32 allele were also observed to be involved in the susceptibility to BC. Additionally, the combination of CCR2 V64I and CCR5 Δ32 (i.e., GG-wt/Δ32) was found to be associated with BC risk. With respect to the stage of BC, the AA genotype of SDF-1 and at least one T allele of CXCR4 were significantly associated with high T stage as compared to GG genotype of SDF-1 and CC genotype of CXCR4. Furthermore, BC patients with AA genotype or at least one A allele of CCR2 had an increased risk of high grade and stage tumors as compared to those with GG genotype. Our results suggest that the genetic variants of SDF-1 3'A, CCR2A V64I and CCR5 Δ32 gene polymorphisms may modify the BC risk. Furthermore, SDF-1 3'A, CCR2A V64I and CXCR4 gene polymorphisms may contribute to the muscle invasive BC in a Turkish population.

Domingos-Pereira S, Decrausaz L, Derré L, et al.
Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice.
Mucosal Immunol. 2013; 6(2):393-404 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ~fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.

Wilen CB, Tilton JC, Doms RW
HIV: cell binding and entry.
Cold Spring Harb Perspect Med. 2012; 2(8) [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The first step of the human immunodeficiency virus (HIV) replication cycle-binding and entry into the host cell-plays a major role in determining viral tropism and the ability of HIV to degrade the human immune system. HIV uses a complex series of steps to deliver its genome into the host cell cytoplasm while simultaneously evading the host immune response. To infect cells, the HIV protein envelope (Env) binds to the primary cellular receptor CD4 and then to a cellular coreceptor. This sequential binding triggers fusion of the viral and host cell membranes, initiating infection. Revealing the mechanism of HIV entry has profound implications for viral tropism, transmission, pathogenesis, and therapeutic intervention. Here, we provide an overview into the mechanism of HIV entry, provide historical context to key discoveries, discuss recent advances, and speculate on future directions in the field.

Lee NJ, Choi DY, Song JK, et al.
Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model.
Carcinogenesis. 2012; 33(12):2520-8 [PubMed] Related Publications
To evaluate the significance of C-C chemokine receptor type 5 (CCR5) in lung tumor development, we compared carcinogen-induced tumor growth in CCR5 knockout (CCR5(-/-)) mice and wild-type (CCR5(+/+)) mice. CCR5(-/-) mice showed reduced urethane (1g/kg)-induced tumor incidence when compared with those of CCR5(+/+) mice. We investigated the activation of nuclear factor-kappaB/STAT3 since these are implicated transcription factors in the regulation of genes involving tumor growth. Significant inhibition of DNA-binding activity of nuclear factor-kappaB and STAT3, and the translocation of p50 and p65 into the nucleus and the phosphorylation of IĸB were found in the lungs of CCR5(-/-) mice compared with the lungs of CCR5(+/+) mice. Expression of apoptotic protein such as cleaved caspase-3, cleaved PARP and Bax was elevated, whereas the expression levels of survival protein such as Bcl-2 and cIAP1 was decreased in the lungs of CCR5(-/-) mice. Interestingly, we found that the level of monocyte chemoattractant protein-1 (MCP-1), a tumor growth-promoting cytokine, was significantly reduced in the lung tumor tissue and blood of CCR5(-/-) mice compared with the level in CCR5(+/+) mice. In addition, CCR5 small interfering RNA (siRNA) and inhibitor of MCP-1 blocked lung cancer cell growth, which was abolished by the addition of MCP-1 protein in cultured lung cancer cells. Moreover, inactivation of CD8(+) cytotoxic T cell and dendritic cells was significantly increased in the blood, lung tumors and spleens of CCR5(-/-) mice compared with that of CCR5(+/+) mice. Therefore, these results showed that CCR5 deficiency suppressed lung tumor development through the inhibition of nuclear factor-kappaB/STAT3 pathways and the downregulation of MCP-1 in the carcinogen-induced lung tumor model.

Long H, Xie R, Xiang T, et al.
Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP-9 upregulation.
Stem Cells. 2012; 30(10):2309-19 [PubMed] Related Publications
The concept of cancer stem cells (CSCs) proposes that solely CSCs are capable of generating tumor metastases. However, how CSCs maintain their invasion and migration abilities, the most important properties of metastatic cells, still remains elusive. Here we used CD133 to mark a specific population from human ovarian cancer cell line and ovarian cancer tissue and determined its hyperactivity in migration and invasion. Therefore, we labeled this population as cancer stem-like cells (CSLCs). In comparison to CD133- non-CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. Mechanistically, we identified that this enhanced invasiveness is mediated through nuclear factor κB (NF-κB) activation and the consequently elevated MMP9 secretion. Our results suggested that the autocrine activation of CCR1 and CCR3 by CCL5 represents one of major mechanisms underlying the metastatic property of ovarian CSLCs.

Gupta B, Iancu EM, Gannon PO, et al.
Simultaneous coexpression of memory-related and effector-related genes by individual human CD8 T cells depends on antigen specificity and differentiation.
J Immunother. 2012; 35(6):488-501 [PubMed] Related Publications
Phenotypic and functional cell properties are usually analyzed at the level of defined cell populations but not single cells. Yet, large differences between individual cells may have important functional consequences. It is likely that T-cell-mediated immunity depends on the polyfunctionality of individual T cells, rather than the sum of functions of responding T-cell subpopulations. We performed highly sensitive single-cell gene expression profiling, allowing the direct ex vivo characterization of individual virus-specific and tumor-specific T cells from healthy donors and melanoma patients. We have previously shown that vaccination with the natural tumor peptide Melan-A-induced T cells with superior effector functions as compared with vaccination with the analog peptide optimized for enhanced HLA-A*0201 binding. Here we found that natural peptide vaccination induced tumor-reactive CD8 T cells with frequent coexpression of both memory/homing-associated genes (CD27, IL7R, EOMES, CXCR3, and CCR5) and effector-related genes (IFNG, KLRD1, PRF1, and GZMB), comparable with protective Epstein-Barr virus-specific and cytomegalovirus-specific T cells. In contrast, memory/homing-associated and effector-associated genes were less frequently coexpressed after vaccination with the analog peptide. Remarkably, these findings reveal a previously unknown level of gene expression diversity among vaccine-specific and virus-specific T cells with the simultaneous coexpression of multiple memory/homing-related and effector-related genes by the same cell. Such broad functional gene expression signatures within antigen-specific T cells may be critical for mounting efficient responses to pathogens or tumors. In summary, direct ex vivo high-resolution molecular characterization of individual T cells provides key insights into the processes shaping the functional properties of tumor-specific and virus-specific T cells.

Guergnon J, Combadière C
Role of chemokines polymorphisms in diseases.
Immunol Lett. 2012; 145(1-2):15-22 [PubMed] Related Publications
The interest into chemokine polymorphisms came with the discovery of allelic variants of HIV co-receptors (CCR5 and CXCR4 mainly) that confers protection against virus entry into usual permissive cells. Since then, chemokines genetic background has been deeply studied in order to find associations between allelic variants and inflammation-related diseases as well as infectious diseases. In addition to HIV infection, chemokines genetic variations have been involved in other infectious diseases as HCV, Malaria and West Nile Virus, and also in a variety of non-infectious diseases such as cancer, auto-immune and cardiovascular diseases. This review aims to present genetic variations in chemokines encoding genes and discuss their role, sometimes controversial, in a variety of diseases.

Velasco-Velázquez M, Jiao X, De La Fuente M, et al.
CCR5 antagonist blocks metastasis of basal breast cancer cells.
Cancer Res. 2012; 72(15):3839-50 [PubMed] Related Publications
The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression remain unclear. Here, we conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes. The subpopulation of human breast cancer cell lines found to express CCR5 displayed a functional response to CCL5. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness. The CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells without affecting cell proliferation or viability, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Taken together, our findings provide evidence for the key role of CCL5/CCR5 in the invasiveness of basal breast cancer cells and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype.

Kucukgergin C, Isman FK, Cakmakoglu B, et al.
Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer.
DNA Cell Biol. 2012; 31(8):1418-24 [PubMed] Related Publications
The aim of our study was to determine the effect of monocyte chemotactic protein-1 (MCP-1), CC chemokine receptor 2 (CCR2), and CC chemokine receptor 5 (CCR5) gene polymorphisms on the susceptibility and clinicopathological characteristics of prostate cancer. Genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method in 156 histopathologically confirmed prostate cancer patients and 152 healthy subjects. Individuals with AA genotype or at least one A allele of CCR2 V64I gene polymorphism had a higher risk for prostate cancer as compared with those with GG genotype (p=0.010 and p=0.028, respectively). CCR5 Δ32/wt genotype and CCR5 Δ32 allele were also found to be involved in the susceptibility to prostate cancer (p=0.028 and p=0.030, respectively). However, there was no significant association between MCP-1-2518 A/G gene polymorphism and prostate cancer risk. Prostate cancer patients carrying AA genotype or at least one A allele of CCR2 V64I had significantly increased risk for high stage disease (p=0.002 and p=0.039, respectively) and metastasis (p=0.004 and p=0.022, respectively). The CCR2 A allele (64I allele) was significantly associated with high T stage (p=0.001) and metastasis (p=0.005) as compared with CCR2 G allele (64V allele). Our data indicate that gene polymorphism of CCR2 V64I may influence the susceptibility and clinicopathological characteristics of prostate cancer and CCR5 Δ32 allele may also be an important risk factor for prostate cancer in Turkish men population.

Pham K, Luo D, Liu C, Harrison JK
CCL5, CCR1 and CCR5 in murine glioblastoma: immune cell infiltration and survival rates are not dependent on individual expression of either CCR1 or CCR5.
J Neuroimmunol. 2012; 246(1-2):10-7 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Glioblastoma multiforme (GBM) is the most malignant brain tumor. Microglia/macrophages are found within human GBM where they likely promote tumor progression. We report that CCL5, CCR1, and CCR5 are expressed in glioblastoma. Individual deletion of CCR1 or CCR5 had little to no effect on survival of tumor bearing mice, or numbers of glioblastoma-infiltrated microglia/macrophages or lymphocytes. CCL5 promoted in vitro migration of wild type, CCR1- or CCR5-deficient microglia/macrophages that was blocked by the dual CCR1/CCR5 antagonist, Met-CCL5. These data suggest that CCL5 functions within the glioblastoma microenvironment through CCR1 and CCR5 in a redundant manner.

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