Gene Summary

Gene:CCR2; C-C motif chemokine receptor 2
Aliases: CKR2, CCR-2, CCR2A, CCR2B, CD192, CKR2A, CKR2B, CMKBR2, MCP-1-R, CC-CKR-2
Summary:The protein encoded by this gene is a receptor for monocyte chemoattractant protein-1, a chemokine which specifically mediates monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response against tumors. The encoded protein mediates agonist-dependent calcium mobilization and inhibition of adenylyl cyclase. This protein can also be a coreceptor with CD4 for HIV-1 infection. This gene is located in the chemokine receptor gene cluster region of chromosome 3. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-C chemokine receptor type 2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (48)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Young Adult
  • Single Nucleotide Polymorphism
  • Turkey
  • Vaginal Smears
  • Genetic Predisposition
  • Smoking
  • Macrophages
  • Wound Healing
  • Angiogenesis
  • WT1
  • Disease Progression
  • Neoplasm Metastasis
  • Temperance
  • Neoplasm Invasiveness
  • Cell Movement
  • Bladder Cancer
  • Receptors, CCR3
  • Chemokine CCL2
  • Taiwan
  • Breast Cancer
  • Cancer Gene Expression Regulation
  • Tunisia
  • Chromosome 3
  • Cell Proliferation
  • Genotype
  • Reproducibility of Results
  • Receptors, CCR2
  • DNA Sequence Analysis
  • Signal Transduction
  • Case-Control Studies
  • CXCR4
  • Polymorphism
  • Prostate Cancer
  • Cervical Cancer
  • Messenger RNA
  • Translational Medical Research
  • Xenograft Models
  • Gene Expression Profiling
  • Receptors, CCR5
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: CCR2 (cancer-related)

Kurzejamska E, Sacharczuk M, Landázuri N, et al.
Effect of Chemokine (C-C Motif) Ligand 7 (CCL7) and Its Receptor (CCR2) Expression on Colorectal Cancer Behaviors.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
Colorectal cancer is the source of one of the most common cancer-related deaths worldwide, where the main cause of patient mortality remains metastasis. The aim of this study was to determine the role of CCL7 (chemokine (C-C motif) ligand 7) in tumor progression and finding whether it could predict survival of colorectal cancer patients. Initially, our study focused on the crosstalk between mesenchymal stem cells (MSCs) and CT26 colon carcinoma cells and resulted in identifying CCL7 as a chemokine upregulated in CT26 colon cancer cells cocultured with MSCs, compared with CT26 in monoculture in vitro. Moreover, we showed that MSCs enhance CT26 tumor cell proliferation and migration. We analyzed the effect of CCL7 overexpression on tumor progression in a murine CT26 model, where cells overexpressing CCL7 accelerated the early phase of tumor growth and caused higher lung metastasis rates compared with control mice. Microarray analysis revealed that tumors overexpressing CCL7 had lower expression of immunoglobulins produced by B lymphocytes. Additionally, using Jh mutant mice, we confirmed that in the CT26 model, CCL7 has an immunoglobulin-, and thereby, B-cell-dependent effect on metastasis formation. Finally, higher expression of CCL7 receptor CCR2 (C-C chemokine receptor type 2) was associated with shorter overall survival of colorectal cancer patients. Altogether, we showed that CCL7 is essentially involved in the progression of colorectal cancer in a CT26 mouse model and that the expression of its receptor CCR2 could be related to a different outcome pattern of patients with colorectal carcinoma.

Bartneck M, Schrammen PL, Möckel D, et al.
The CCR2
Cell Mol Gastroenterol Hepatol. 2019; 7(2):371-390 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) typically arises in fibrotic or cirrhotic livers, which are characterized by pathogenic angiogenesis. Myeloid immune cells, specifically tumor-associated macrophages (TAMs), may represent potential novel therapeutic targets in HCC, complementing current ablative or immune therapies. However, the detailed functions of TAM subsets in hepatocarcinogenesis have remained obscure.
METHODS: TAM subsets were analyzed in-depth in human HCC samples and a combined fibrosis-HCC mouse model, established by i.p. injection with diethylnitrosamine after birth and repetitive carbon tetrachloride (CCl
RESULTS: We show that human CCR2
CONCLUSIONS: The HCC microenvironment in human patients and mice is characterized by functionally distinct macrophage populations, of which the CCR2

Navas A, Giraldo-Parra L, Prieto MD, et al.
Phenotypic and functional stability of leukocytes from human peripheral blood samples: considerations for the design of immunological studies.
BMC Immunol. 2019; 20(1):5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human peripheral blood mononuclear cells (PBMCs) are extensively used for research of immune cell functions, identification of biomarkers and development of diagnostics and therapeutics for human diseases, among others. The assumption that "old blood samples" are not appropriate for isolation of PBMCs for functional assays has been a dogma in the scientific community. However, partial data on the impact of time after phlebotomy on the quality and stability of human PBMCs preparations impairs the design of studies in which time-controlled blood sampling is challenging such as field studies involving multiple sampling centers/sites. In this study, we evaluated the effect of time after phlebotomy over a 24 h time course, on the stability of human blood leukocytes used for immunological analyses. Blood samples from eight healthy adult volunteers were obtained and divided into four aliquots, each of which was left in gentle agitation at room temperature (24 °C) for 2 h (control), 7 h, 12 h and 24 h post phlebotomy. All samples at each time point were independently processed for quantification of mononuclear cell subpopulations, cellular viability, gene expression and cytokine secretion.
RESULTS: A 24 h time delay in blood sample processing did not affect the viability of PBMCs. However, a significantly lower frequency of CD3+ T cells (p < 0.05) and increased LPS-induced CXCL10 secretion were observed at 12 h post-phlebotomy. Alterations in TNFα, CCL8, CCR2 and CXCL10 gene expression were found as early as 7 h after blood sample procurement.
CONCLUSIONS: These data reveal previously unrecognized early time-points for sample processing control, and provide an assay-specific time reference for the design of studies that involve immunological analyses of human blood samples.

Chen R, Keoni C, Waker CA, et al.
KIAA1549-BRAF Expression Establishes a Permissive Tumor Microenvironment Through NFκB-Mediated CCL2 Production.
Neoplasia. 2019; 21(1):52-60 [PubMed] Free Access to Full Article Related Publications
KIAA1549-BRAF is the most frequently identified genetic mutation in sporadic pilocytic astrocytoma (PA), creating a fusion BRAF (f-BRAF) protein with increased BRAF activity. Fusion-BRAF-expressing neural stem cells (NSCs) exhibit increased cell growth and can generate glioma-like lesions following injection into the cerebella of naïve mice. Increased Iba1

Natsagdorj A, Izumi K, Hiratsuka K, et al.
CCL2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells.
Cancer Sci. 2019; 110(1):279-288 [PubMed] Free Access to Full Article Related Publications
Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel-resistant and castration-resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C-C motif chemokine ligands (CCL) were shown to contribute to the castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCL as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145-TxR and DU145-TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145-TxR and DU145-TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145-TxR and DU145-TxR/CxR cells under treatments of cabazitaxel. The CCL2-CCR2 axis decreased apoptosis through the inhibition of caspase-3 and poly(ADP-ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2-CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel.

Shu L, Wang Z, Wang Q, et al.
Signature miRNAs in peripheral blood monocytes of patients with gastric or breast cancers.
Open Biol. 2018; 8(10) [PubMed] Free Access to Full Article Related Publications
The dysregulation of microRNAs (miRNAs), key posttranscriptional regulators of gene expression, is closely associated with cancer development. However, the miRNAs of monocytes, important cells of tumour immunity, have not been extensively explored. In the present study, the differentially expressed miRNAs of blood monocytes derived from gastric and breast cancer patients and healthy donors were characterized. The results indicated that 74 miRNAs were upregulated and 46 miRNAs were downregulated in monocytes of patients with breast or gastric cancers compared with the healthy donors, suggesting that these 120 miRNAs from transformed monocytes were associated with cancers. The differentially expressed miRNAs, 38 of which were novel, were further validated using quantitative real-time PCR. As an example, the results showed that miR-150-5p downregulated the CCR2 expression in monocytes by targeting Notch 3, thus leading to the suppression of tumorigenesis. The target gene analysis showed that 36 of the 120 miRNAs targeted cancer-related genes. KEGG pathway analysis indicated that the cancer-associated miRNAs were involved in pathways related to cancers, such as the HIF-1 signalling and the mTOR signalling pathways. Thus, our study provided new clues to comprehensively understand the relationship between miRNAs and cancers.

Li YL, Shi ZH, Wang X, et al.
Prognostic significance of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in diffuse large B cell lymphoma.
Ann Hematol. 2019; 98(2):413-422 [PubMed] Related Publications
Aberrant monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) expression in malignant tissues have been reported; however, their role in hematological malignancies prognosis remains little known. The aim of this study was to investigate the prognostic value of MCP-1 and CCR2 expression in patients with diffuse large B cell lymphoma (DLBCL). The study included 221 patients with DLBCL. MCP-1 and CCR2 expression was analyzed by immunohistochemical staining and its correlations with clinicopathologic features and prognosis were evaluated. High expression of MCP-1 or CCR2 was correlated with clinicopathological characteristics, and an adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) of DLBCL patients. Also, significant positive correlation between MCP-1 and CCR2 expression was revealed (r = 0.545, P < 0.001). Patients with high MCP-1 or high CCR2 expression had significantly poorer OS and PFS than those with low MCP-1 or low CCR2 expression (OS: P < 0.001, P < 0.001; PFS: P < 0.001, P < 0.001), respectively, even in the rituximab era, and MCP-1 or CCR2 expression could further identify high-risk patients otherwise classified as low/intermediate risk by the International Prognostic Index (IPI) alone. Furthermore, incorporation of MCP-1 or CCR2 expression into the IPI score could improve prognostic value for OS. This is the first report describing the clinicopathological features and survival outcome according to expression of MCP-1 and CCR2 in DLBCL.

Duan S, Dong X, Hai J, et al.
MicroRNA-135a-3p is downregulated and serves as a tumour suppressor in ovarian cancer by targeting CCR2.
Biomed Pharmacother. 2018; 107:712-720 [PubMed] Related Publications
MicroRNAs have been demonstrated to play a crucial role in the development of ovarian cancer. Many studies prove that forms of miR-135a, including miR-135a-5p and miR-135a-3p, serve as tumour suppressors in multiple cancers. Nevertheless, the precise function of miR-135a-3p and the molecular mechanisms underlying the involvement of miR-135a-3p in ovarian carcinoma cell growth and metastasis remain largely unknown. Herein, we report that miR-135a-3p expression was significantly downregulated in ovarian carcinoma tissues compared with corresponding adjacent non-tumour tissues. Ectopic miR-135a-3p expression inhibited ovarian carcinoma cell proliferation, migration and invasion in vitro. Additionally, the overexpression of miR-135a-3p inhibited epithelial-mesenchymal transition (EMT) in ovarian cancer cells. A luciferase reporter assay confirmed that the C-C chemokine receptor type 2 (CCR2) gene was the target of miR-135a-3p. In addition, CCR2 depletion mimicked the inhibitory effects of miR-135a-3p on ovarian cancer cells in vitro. Rescue experiments using CCR2 overexpression further verified that CCR2 was a functional target of miR-135a-3p. Xenograft model assays demonstrated that miR-135a-3p functions as an anti-oncogene by targeting CCR2 in vivo. Taken together, these data prove that miR-135a-3p serves as a tumour suppressor gene in ovarian cancer by regulating CCR2.

Li H, Li H, Li XP, et al.
C‑C chemokine receptor type 2 promotes epithelial‑to‑mesenchymal transition by upregulating matrix metalloproteinase‑2 in human liver cancer.
Oncol Rep. 2018; 40(5):2734-2741 [PubMed] Related Publications
C‑C chemokine receptor type 2 (CCR2) is aberrantly expressed in a variety of tumor cells, and participates in the regulation of tumor cell progression, metastasis and immune escape. However, the mechanism of action of CCR2 in liver cancer remains unclear. In the present study, the aim was to elucidate the molecular mechanism underlying the regulation of epithelial‑to‑mesenchymal transition (EMT) by CCR2 in liver cancer cells. Initially, CCR2 expression in liver cancer tissues was measured, and the survival time of patients was analyzed by Kaplan‑Meier analysis. In liver cancer cells, the mRNA and protein expression levels of CCR2, matrix metalloproteinase‑2 (MMP2), E‑cadherin and vimentin were evaluated by reverse transcription‑quantitative polymerase chain reaction and western blotting. Cell viability, migration and invasion were determined by Cell Counting Kit‑8, wound healing and Transwell chamber assays, respectively. Additionally, the binding between CCR2 and MMP2 was identified by co‑immunoprecipitation (Co‑IP). It was observed that CCR2 was abnormally upregulated in liver cancer tissues and significantly associated with the tumor diameter, metastasis and stage. The survival of patients with high CCR2 expression was lower compared with that of patients with low CCR2 expression. In addition, the number of cells that penetrated the transwell chamber membrane was significantly reduced following treatment with CCR2‑small interfering RNA (siRNA). Furthermore, CCR2 was found to participate in MMP2‑induced EMT, while CCR2‑siRNA transfection reduced the expression and activity of MMP2, and confirmed the specific binding between CCR2 and MMP2. Co‑IP also identified the independent interaction between endogenous proteins in HepG2 cells. These results revealed that CCR2 promotes EMT in liver cancer. Thus, CCR2 is an attractive novel target for inhibiting invasion and metastasis of liver cancer cells.

Kuguyo O, Tsikai N, Thomford NE, et al.
Genetic Susceptibility for Cervical Cancer in African Populations: What Are the Host Genetic Drivers?
OMICS. 2018; 22(7):468-483 [PubMed] Related Publications
Human papillomavirus (HPV) is an essential but not a sufficient cervical cancer etiological factor. Cancer promoters, such as host genetic mutations, significantly modulate therapeutic responses and susceptibility. In cervical cancer, of interest have been viral clearing genes and HPV oncoprotein targets, for which conflicting data have been reported among different populations. This expert analysis evaluates cervical cancer genetic susceptibility biomarkers studied in African populations. Notably, the past decade has seen Africa as a hotbed of biomarker and precision medicine innovations, thus potentially informing worldwide biomarker development strategies. We conducted a critical literature search in PubMed/MEDLINE, Google Scholar, and Scopus databases for case-control studies reporting on cervical cancer genetic polymorphisms among Africans. We found that seven African countries conducted cervical cancer molecular epidemiology studies in one of Casp8, p53, CCR2, FASL, HLA, IL10, TGF-beta, and TNF-alpha genes. This analysis reveals a remarkable gap in cervical cancer molecular epidemiology among Africans, whereas cervical cancer continues to disproportionately have an impact on African populations. Genome-wide association, whole exome- and whole-genome sequencing studies confirmed the contribution of candidate genes in cervical cancer. With such advances and omics technologies, the role of genetic susceptibility biomarkers can be exploited to develop novel interventions to improve current screening, diagnostic and prognostic methods worldwide. Exploring these genetic variations is crucial because African populations are genetically diverse and some variants or their combined effects are yet to be discovered and translated into tangible clinical applications. Thus, translational medicine and flourishing system sciences in Africa warrant further emphasis in the coming decade.

Kozireva S, Rudevica Z, Baryshev M, et al.
Upregulation of the Chemokine Receptor CCR2B in Epstein‒Barr Virus-Positive Burkitt Lymphoma Cell Lines with the Latency III Program.
Viruses. 2018; 10(5) [PubMed] Free Access to Full Article Related Publications
CCR2 is the cognate receptor to the chemokine CCL2. CCR2⁻CCL2 signaling mediates cancer progression and metastasis dissemination. However, the role of CCR2⁻CCL2 signaling in pathogenesis of B-cell malignancies is not clear. Previously, we showed that CCR2B was upregulated in ex vivo peripheral blood B cells upon Epstein‒Barr virus (EBV) infection and in established lymphoblastoid cell lines with the EBV latency III program. EBV latency III is associated with B-cell lymphomas in immunosuppressed patients. The majority of EBV-positive Burkitt lymphoma (BL) tumors are characterized by latency I, but the BL cell lines drift towards latency III during in vitro culture. In this study, the CCR2A and CCR2B expression was assessed in the isogenic EBV-positive BL cell lines with latency I and III using RT-PCR, immunoblotting, and immunostaining analyses. We found that CCR2B is upregulated in the EBV-positive BL cells with latency III. Consequently, we detected the migration of latency III cells toward CCL2. Notably, the G190A mutation, corresponding to SNP CCR2-V64I, was found in one latency III cell line with a reduced migratory response to CCL2. The upregulation of CCR2B may contribute to the enhanced migration of malignant B cells into CCL2-rich compartments.

Dutta P, Sarkissyan M, Paico K, et al.
MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis.
Breast Cancer Res Treat. 2018; 170(3):477-486 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression.
EXPERIMENTAL DESIGN: ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay.
RESULTS: Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin.
CONCLUSION: Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities.

Skonieczna K, Styczyński J, Krenska A, et al.
Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies.
Pol J Pathol. 2017; 68(3):210-217 [PubMed] Related Publications
This study aimed to find novel genetic variants of susceptibility to aspąergillosis in paediatric patients with haematological malignancies. Complete sequences of fifteen genes of human innate immunity (CCL2, CCR2, CD209, CLEC6A, CLEC7A and ten TLR genes) were studied in 40 patients diagnosed with haematological disorders (20 unaffected and 20 affected by aspergillosis). All samples were sequenced with MiSeq (Illumina) and 454 (Roche Diagnostics) technologies. Statistical significance of the differences between studied groups was determined using the two-tailed Fisher's exact test. Sixty variants of potential importance were identified, the vast majority of which are located in non-coding parts of the targeted genes. At the threshold of p < 0.000005, one intergenic (TLR2 rs4585282) and one intronic variant (CLEC6A rs12099687) were found significant between the case and control groups for genotype and allele frequencies, respectively. Rs12099687 in CLEC6A was predicted to constitute an alternative isoform or cryptic splice site, which potentially changes activity of the Dectin-2 protein. Overall, we assume that the two strongest associations reported in this study are expected to be reproducible even in the absence of other evidence, while another twelve associations may be strong enough to justify additional research in larger cohorts.

Walczak A, Przybyłowska-Sygut K, Sygut A, et al.
An association of the MCP-1 and CCR2 single nucleotide polymorphisms with colorectal cancer prevalence.
Pol Przegl Chir. 2017; 89(5):1-5 [PubMed] Related Publications
THE AIM OF THE STUDY: We evaluated the connection between the presence of the -2518 A/G MCP-1 as well as 190 G/A CCR2 polymorphic variants and colorectal cancer (CRC) occurrence.
MATERIAL AND METHODS: Study group consisted of subjects with different stages of CRC as well as healthy controls. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
RESULTS: W observed an association between the colorectal cancer and the GG genotype of the -2518 A/G MCP-1 single nucleotide polymorphism. No statistically significant correlation was found between CRC and the 190 G/A CCR2 polymorphism.
CONCLUSION: The results of this study support the hypothesis that polymorphism in the MCP-1 gene may contribute to the etiology of colorectal cancer.

Brummer G, Acevedo DS, Hu Q, et al.
Chemokine Signaling Facilitates Early-Stage Breast Cancer Survival and Invasion through Fibroblast-Dependent Mechanisms.
Mol Cancer Res. 2018; 16(2):296-308 [PubMed] Free Access to Full Article Related Publications
Ductal carcinoma

Zhuang H, Cao G, Kou C, Liu T
CCL2/CCR2 axis induces hepatocellular carcinoma invasion and epithelial-mesenchymal transition in vitro through activation of the Hedgehog pathway.
Oncol Rep. 2018; 39(1):21-30 [PubMed] Free Access to Full Article Related Publications
Chemokine (C-C motif) ligand 2 (CCL2) has been shown to play an important role in the regulation of tumor cell growth, metastasis and host immune response. CCL2 preferentially binds to the C-C chemokine receptor type 2 (CCR2), which is expressed in various tissues. However, the role of the CCL2/CCR2 axis in hepatocellular carcinoma (HCC) invasion and its molecular mechanisms remain unclear. The aim of this study was to elucidate this issue. The human HCC cell line MHCC-97H was treated with CCL2. Cyclopamine, a smoothened (SMO) antagonist, was used to inhibit SMO activity. CCR2 siRNA and Gli-1 siRNA were used to inhibit CCR2 and Gli-1 expression respectively. The effect of CCL2 and Hedgehog (Hh) signaling on cancer cell epithelial-mesenchymal transition (EMT) and invasion was evaluated by quantitative real‑time PCR analysis, western blotting and Transwell invasion assay. Our results revealed that CCL2 induced HCC cell invasion and EMT. This effect was accompanied by the activation of Hh signaling, the upregulation of Snail and vimentin and the reduction of E-cadherin. Notably, prior silencing of CCR2 with siRNA abolished CCL2-induced Hh signaling activation, Snail and vimentin upregulation, E-cadherin reduction, as well as HCC cell invasion and EMT. Furthermore, pretreatment with cyclopamine or predepletion of Gli-1 by siRNA also eliminated the changes of Snail, vimentin and E-cadherin, and HCC invasion and EMT caused by CCL2. Collectively, our results revealed that the link between the CCL2/CCR2 axis and the Hh pathway plays an important role in HCC progression. Therefore, the CCL2/CCR2 axis may represent a promising therapeutic target to prevent HCC progression.

Cortés M, Sanchez-Moral L, de Barrios O, et al.
Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles.
EMBO J. 2017; 36(22):3336-3355 [PubMed] Free Access to Full Article Related Publications
Accumulation of tumor-associated macrophages (TAMs) associates with malignant progression in cancer. However, the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. ZEB1 is best known for driving an epithelial-to-mesenchymal transition (EMT) in cancer cells to promote tumor progression. However, a role for ZEB1 in macrophages and TAMs has not been studied. Here we describe that TAMs require ZEB1 for their tumor-promoting and chemotherapy resistance functions in a mouse model of ovarian cancer. Only TAMs that expressed full levels of

Sivakumar S, Lucas FAS, McDowell TL, et al.
Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.
Cancer Res. 2017; 77(22):6119-6130 [PubMed] Free Access to Full Article Related Publications
There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic

Chen H, Liu D, Guo L, et al.
Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre-metastatic niche through activating β-adrenergic signaling.
J Pathol. 2018; 244(1):49-60 [PubMed] Related Publications
Numerous studies have indicated that primary tumors induce the formation of a pre-metastatic niche in distant organs by secreting tumor-derived factors. The present study shows that pre-exposure to chronic stress enhanced lung colonization efficiency by circulating tumor cells, suggesting that chronic stress critically influences pre-metastatic lungs before the arrival of disseminated tumor cells. Ablation of the sympathetic nerve function by 6-OHDA or blockage of the β-adrenergic signaling by propranolol remarkably suppressed stress-induced lung metastasis. Depletion of circulating monocytes or lung macrophages strongly abolished stress-induced lung seeding by tumor cells, whereas treatment of mice with the β-adrenergic agonist isoproterenol (ISO) during the pre-metastatic phase promoted the infiltration of macrophages to the lung. Meanwhile, the numbers of monocytes in peripheral blood, spleen, and bone marrow were remarkably increased in response to ISO stimulation. These data indicate that the β-adrenergic signaling promotes lung metastatic colonization by tumor cells through increased output of monocytes in the pre-metastatic phase and infiltration of macrophages into the pre-metastatic lung. Mechanistic studies revealed that ISO stimulation upregulated the expression of CCL2 in pulmonary stromal cells and CCR2 in monocytes/macrophages, leading to the recruitment and infiltration of macrophages into the pre-metastatic lung. By inducing a response of monocytes/macrophages driven by the CCL2/CCR2 axis, stress-related catecholamine may act as a crucial factor in regulating the pre-metastatic niche for and lung colonization by tumor cells. Our data demonstrate that disturbance of host macro-environmental homeostasis has an influence on future metastatic organs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Hu J, Li X, Guo X, et al.
J Cell Sci. 2017; 130(19):3399-3413 [PubMed] Related Publications
Diverse RNA transcripts acting as competing endogenous RNAs (ceRNAs) can co-regulate each other's expression by competing for shared microRNAs. CCR2 protein, the receptor for CCL2, is implicated in cancer progression. However, we found that a higher

Jiang J, Ye F, Yang X, et al.
Peri-tumor associated fibroblasts promote intrahepatic metastasis of hepatocellular carcinoma by recruiting cancer stem cells.
Cancer Lett. 2017; 404:19-28 [PubMed] Related Publications
Fibroblasts have been reported to play an important role in hepatocellular carcinoma (HCC). However, the role of fibroblasts have not been fully understood. Conditioned medium collected from human peri-tumor tissue-derived fibroblasts (CM-pTAFs) showed high metastasis ability than human HCC tissues-derived fibroblasts (CM-TAFs). To determine what component was secreted from fibroblasts, we used Bio-Plex analysis system and compared the factors secreted from CM-pTAFs and CM-TAFs, found a series of up-regulated cytokines in the CM-pTAFs, including IL-6, CCL2, CXCL1, CXCL8, SCGF-β, HGF and VEGF. Pretreatment of IL-6 inhibitor Tocilizumab could inhibit metastasis the HCC cell treated with CM-pTAFs in vitro and in vivo. The expression of CCR2 and CXCR1 were up-regulated after CM-pTAFs treatment in HCC cell line SMMC-7721. Flow cytometric analysis experiment showed that most CCR2 or CXCR1 positive cells were also EpCAM positive. In vitro studies also showed that CM-pTAFs could increase stemness of SMMC-7721. In addition, neutralization of SCGF-β and HGF could significantly reduce metastasis and viability of cancer stem cells treated with CM-pTAFs. Taken together, these results indicated that the peri-tumor tissues derived fibroblasts may promote development of HCC by recruiting cancer stem cells and maintaining their stemness characteristic.

Lu B, Zhou Y, Su Z, et al.
Effect of CCL2 siRNA on proliferation and apoptosis in the U251 human glioma cell line.
Mol Med Rep. 2017; 16(3):3387-3394 [PubMed] Related Publications
Glioma is one of the most common types of tumor of the central nervous system. Increased expression of C‑C motif chemokine 2 (CCL2) has previously been observed in various types of cancer. The effect of CCL2 small interfering (si)RNA on the proliferation, angiogenesis and apoptosis of the glioma cell line U251 was investigated in the present study. Data on CCL2 expression in glioma and normal tissues were obtained from The Cancer Genome Atlas. A total of 30 patients with glioma were enrolled in the present study. Cell proliferation was measured using a Cell Counting kit‑8 assay, while cellular apoptosis and cell cycle distribution were examined using flow cytometric analysis. The reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to measure the expression levels of biological pathway‑associated proteins caspase‑3, caspase‑7, tumor necrosis factor receptor superfamily member 10C (TNFRSF10C), growth regulated α protein (CXCL1), C‑X‑C motif chemokine 2 (CXCL2), C‑X‑C chemokine receptor type 2 (CXCR2), vascular endothelial growth factor (VEGF)A, VEGFB and VEGF. In addition, the mechanism of cellular apoptosis was analyzed by examining the phosphorylation of extracellular signal‑related kinase (ERK)1/2 and p38 mitogen‑activated protein kinase (p38) in cells treated with the C‑C chemokine receptor type 2 inhibitor RS‑102895. CCL2 was observed to be expressed in the glioma cell line U251 and was inhibited by CCL2 siRNA. Cells transfected with CCL2 siRNA exhibited inhibited cell proliferation, cell cycle arrest and increased cellular apoptosis. The expression levels of the apoptosis‑associated proteins caspase‑3, caspase‑7 and TNFRSF10C were observed to be downregulated, in addition to those of the angiogenesis‑associated proteins CXCL1, CXCL2, CXCR2, VEGFA, VEGFB and VEGF. The decrease in the rate of phosphorylation of ERK1/2 and p38 demonstrated the involvement of the mitogen‑activated protein kinase/ERK pathway in apoptosis. In conclusion, CCL2 siRNA exhibited effective inhibition of cell proliferation and angiogenesis in the glioma cell line U251, which may provide a theoretical basis for the use of CCL2 in in vivo research and clinical treatment as a novel anticancer agent.

Yildirim G, Attar R, Gulec-Yilmaz S, et al.
Association of CCR2 (+190 G/A) Gene Variants and Ovarian Cancer Severity.
Genet Test Mol Biomarkers. 2017; 21(8):512-515 [PubMed] Related Publications
AIM: Chemokines and their receptors play an important role in tumor progression. In the current study, we aimed to determine the association between the CCR2 gene (+190 G/A) polymorphism and ovarian cancer severity.
METHODS: CCR2 (+190 G/A) genotyping was performed using real-time polymerase chain reaction for DNA isolated from blood samples from a cohort of patients with ovarian cancer (n = 44) and a control group (n = 45).
RESULTS: The CCR2 (+190 G/A) GG genotype frequencies for patients were significantly higher in the stage III-IV cancer group (p = 0.036), and A allele carriers were significantly higher in the stage I-II ovarian cancer group.
CONCLUSION: The CCR2 (+190 G/A) GG genotype may be a potential risk factor for the severe forms of ovarian cancer and the A allele may be a risk-reducing factor for severe ovarian cancer.

Xiao X, Xu Q, Sun Y, et al.
5‑aza‑2'‑deoxycytidine promotes migration of acute monocytic leukemia cells via activation of CCL2‑CCR2‑ERK signaling pathway.
Mol Med Rep. 2017; 16(2):1417-1424 [PubMed] Related Publications
5-aza‑2'-deoxycytidine (5-Aza) has been approved for clinical use in the treatment of myelodysplastic syndrome and acute myeloid leukemia (AML). It inhibits cell proliferation and induces cell differentiation by demethylating various genes, including tumor suppressor genes, transcription factors, and genes encoding cell cycle inhibitors. Although it has demonstrated efficacy in the clinic, drug resistance following 5‑Aza treatment occurs. Cell migration and invasion following 5‑Aza treatment are considered to be the key factors underlying drug resistance; however, there is currently limited information regarding the detailed mechanisms involved. In the present study, the THP‑1 monocytic leukemia cell line was employed. The anti‑leukemic functions of 5‑Aza in THP‑1 cells were first investigated. The results demonstrated that 5‑Aza induced differentiation and inhibited THP‑1 cell growth. Notably, 5‑Aza significantly promoted THP‑1 cell migration. Using reverse transcription‑polymerase chain reaction, Western blot and enzyme‑linked immunosorbent assay analyses, 5‑Aza treatment was observed to upregulate the expression of chemokine (C‑C motif) ligand 2 (CCL2) and C‑C chemokine receptor type 2 (CCR2) in THP‑1 cells. In addition, the results demonstrated that CCL2 induced extracellular signal‑regulated kinase (ERK) phosphorylation by CCR2 in 5‑Aza‑treated THP‑1 cells. Treatment with a CCR2 or ERK inhibitor inhibited the 5‑Aza‑induced increase in THP‑1 cell migration. In conclusion, the results of the present study provide an insight into the molecular mechanism underlying the 5‑Aza‑induced increase in THP‑1 cell migration, as well as a potential strategy to overcome drug resistance in AML therapy.

Zhang Y, Liu S, Qu D, et al.
Kif4A mediate the accumulation and reeducation of THP-1 derived macrophages via regulation of CCL2-CCR2 expression in crosstalking with OSCC.
Sci Rep. 2017; 7(1):2226 [PubMed] Free Access to Full Article Related Publications
Crosstalk between tumor infiltrating macrophages and tumor cells is thought to play an indispensable role in oral squamous cell carcinomas (OSCC) by induction and maintenance of tolerance microenvironment. High infiltration of M2 macrophages and increasing expression of Kinesin family member 4A (Kif4A) in primary OSCC have been proved to correlate with greater tumoral size and poor clinical outcome. However, linkage between Kif4A and infiltrating macrophages in tumorigenesis and progression remains unclear. In the present study, we show that, the interaction between THP-1derived macrophage and OSCC cell line Cal-27 may up-regulate the Kif4A expression in both of them. Additionally, elevated soluble CCL2 in medium and more expression of CCR2 on macrophage were observed during the crosstalk. SiRNA of Kif4A and neutralizing antibody of CCL2 were utilized to identify that; increasing Kif4A can promote the recruitment of macrophages towards Cal-27 and educate them to M2 polarized macrophages via regulating CCL2/CCR2. In combination, the results of the present study may provide interesting clues to understanding the Kif4A-CCL2/CCR2-macrophage axis as a novel therapeutic target to improve the clinical outcome of OSCC.

Chen Z, Feng X, Herting CJ, et al.
Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma.
Cancer Res. 2017; 77(9):2266-2278 [PubMed] Free Access to Full Article Related Publications
In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1

Steinberg SM, Shabaneh TB, Zhang P, et al.
Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors.
Cancer Res. 2017; 77(7):1599-1610 [PubMed] Free Access to Full Article Related Publications
Acquired resistance to BRAF

Amit M, Na'ara S, Leider-Trejo L, et al.
Upregulation of RET induces perineurial invasion of pancreatic adenocarcinoma.
Oncogene. 2017; 36(23):3232-3239 [PubMed] Related Publications
Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.

Yeh TC, O'Connor G, Petteruti P, et al.
Identification of CCR2 and CD180 as Robust Pharmacodynamic Tumor and Blood Biomarkers for Clinical Use with BRD4/BET Inhibitors.
Clin Cancer Res. 2017; 23(4):1025-1035 [PubMed] Related Publications

Macanas-Pirard P, Quezada T, Navarrete L, et al.
The CCL2/CCR2 Axis Affects Transmigration and Proliferation but Not Resistance to Chemotherapy of Acute Myeloid Leukemia Cells.
PLoS One. 2017; 12(1):e0168888 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) has a high mortality rate despite chemotherapy and transplantation. Both CXCR4/SDF-1 and VLA-4/VCAM1 axes are involved in leukemia protection but little is known about the role of CCL2/CCR2 in AML biology and protection against chemotherapy. We measured CCR2 expression in AML cell lines and primary AML cells by flow cytometry (FCM), real time PCR (RT-PCR) and western blot (WB). CCL2 production was quantified by solid phase ELISA in peripheral blood (PB) and bone marrow (BM) serum. We measured chemotaxis in a transwell system with different concentrations of CCL2/CCR2 blockers; cell cycle with BrDU and propidium iodide and proliferation with yellow tetrazolium MTT. We determined synergy in in vitro cell apoptosis combining chemotherapy and CCL2/CCR2 blockade. Finally, we performed chemoprotection studies in an in vivo mouse model. Of 35 patients, 23 (65%) expressed CCR2 by FCM in PB. Two cell lines expressed high levels of CCR2 (THP-1 and murine AML). RT-PCR and WB confirmed CCR2 production. CCL2 solid phase ELISA showed significantly lower levels of CCL2 in PB and BM compared to normal controls. Chemotaxis experiments confirmed a dose-dependent migration in AML primary cells expressing CCR2 and THP-1 cells. A significant inhibition of transmigration was seen after CCL2/CCR2 blockade. Proliferation of CCR2+ AML cell lines was slightly increased (1.4-fold) after axis stimulation. We observed a non-significant increase in phase S THP-1 cells exposed to CCL2 and a concomitant decrease of cells in G1. The chemotherapy studies did not show a protective effect of CCL2 on cytarabine-induced apoptosis or synergy with chemotherapy after CCL2/CCR2 blockade both in vitro and in vivo. In conclusion, CCL2/CCR2 axis is expressed in the majority of monocytoid AML blasts. The axis is involved in cell trafficking and proliferation but no in vitro and in vivo chemotherapy protective effect was seen.

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