ACKR3

Gene Summary

Gene:ACKR3; atypical chemokine receptor 3
Aliases: RDC1, CXCR7, RDC-1, CMKOR1, CXC-R7, CXCR-7, GPR159
Location:2q37.3
Summary:This gene encodes a member of the G-protein coupled receptor family. Although this protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP), it is now considered to be an orphan receptor, in that its endogenous ligand has not been identified. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:atypical chemokine receptor 3
HPRD
Source:NCBIAccessed: 17 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 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.

  • Flow Cytometry
  • CXCR4
  • Chromosome 2
  • RNA Interference
  • Acute Lymphocytic Leukaemia
  • Western Blotting
  • Leukemic Gene Expression Regulation
  • Heterocyclic Compounds
  • Receptors, CXCR
  • Bone Marrow
  • Cell Movement
  • Chemokine CXCL12
  • JM 3100
  • U937 Cells
  • RTPCR
  • Jurkat Cells
  • K562 Cells
  • CXCR7
  • Leukocytes
  • Young Adult
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: ACKR3 (cancer-related)

Liu Y, Carson-Walter E, Walter KA
Targeting chemokine receptor CXCR7 inhibits glioma cell proliferation and mobility.
Anticancer Res. 2015; 35(1):53-64 [PubMed] Related Publications
BACKGROUND: The functional contribution of chemokine receptor CXCR7 to malignant brain tumor biology remains controversial.
MATERIALS AND METHODS: Complementary methods were used to confirm CXCR7 expression in clinical glioblastoma multiforme (GBM) specimens and multiple GBM cell lines. Loss-of-function studies were performed using small interfering RNA (siRNA) technology.
RESULTS: Elevated CXCR7 levels correlated with reduced survival in glioma patients. CXCR7 was expressed by GBM cell lines and stem-like progenitor cells. Knockdown of CXCR7 by siRNA attenuated phosphorylation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway in response to CXCL12 and resulted in significantly reduced cell proliferation, invasion and migration. Similarly, treatment of glioma cells with a small molecule antagonist of CXCR7, CCX771, significantly inhibited cell proliferation and invasion.
CONCLUSION: CXCR7 actively promotes the proliferation and invasive behavior of glioma tumor cells and stem-like progenitor cells and may be a potential target for glioma therapy.

Clatot F, Cornic M, Berghian A, et al.
CXCL12 and CXCR4, but not CXCR7, are primarily expressed by the stroma in head and neck squamous cell carcinoma.
Pathology. 2015; 47(1):45-50 [PubMed] Related Publications
The CXCL12/CXCR4 axis is involved in numerous models of metastatic dissemination, including head and neck squamous cell carcinoma (HNSCC). We assessed the relative expressions of CXCL12, CXCR4 and CXCR7 in the stroma and the tumour of HNSCC, and evaluated the methylation status of the CXCL12 promoter.Snap-frozen, HPV negative HNSCC samples were micro-dissected to isolate the tumoural and stromal compartments. The expression levels of CXCL12, CXCR4 and CXCR7 were assessed by qRT-PCR, and the methylation level of the CXCL12 promoter was evaluated by pyrosequencing.In total, 23 matched tumour/stroma samples were analysed. Higher expressions of CXCR4 and CXCL12 were observed in the stroma (p = 0.012 and p < 0.0001, respectively). No significant difference in expression was observed for CXCR7. A high methylation level (>40%) of the CXCL12 promoter was observed in only a few tumoural samples (5/23) and was associated with a lower expression of the gene (p = 0.03).Stromal cells, rather than the tumour itself, are mainly responsible for the expression of both CXCL12 and CXCR4 expression in HNSCC. CXCR7 expression did not differ between the two compartments and was not related to CXCL12 or CXCR4 expression. Finally, the methylation of the CXCL12 promoter could only explain the low intra-tumoural expression of this gene in 20% of cases.

Kurban S, Tursun M, Kurban G, Hasim A
Role of CXCR7 and effects on CXCL12 in SiHa cells and upregulation in cervical squamous cell carcinomas in Uighur women.
Asian Pac J Cancer Prev. 2014; 15(21):9211-6 [PubMed] Related Publications
CXCR7 is involved in tumor development and metastasis in multiple malignancies. However, the function and molecular mechanisms of action of CXCR7 in human cervical cancer are still unclear. In the present study a loss of-function approach was used to observe the effects of recombinant CXCR7 specific small interfering RNA pBSilence1.1 plasmids on biological behavior including proliferative activity and invasive potential, as indicated by MTT assays with the cervical cancer SiHa cell line in vitro. Reverse transcription polymerase chain reaction and Western blotting revealed that CXCR7 was downregulated in transfected compared with control cells, associated with inhibited cell growth, invasiveness and migration. The expression of CXCR7 and CXCL12 was also determined immunohistochemically in 152 paraffin-embedded, cervical squamous cell carcinoma (CSCC) and cervical intraepithelial neoplasia (CIN), or normal cervical epithelial to assess clinico-pathological pattern and CXCR7 status with respect to cell differentiation and lymph node metastasis in Uighur patients with CSCC. CXCR7 and CXCL12 expression was higher in cervical cancer than CIN and normal cervical mucosa, especially in those with higher stage and lymph node metastasis. CXCL12 appeared to be positively regulated by CXCR7 at the post-transcriptional level in CSCC. We propose that aberrant expression of CXCR7 plays a role in carcinogenesis, differentiation and metastasis of CSCC, implying its use as a potential target for clinical biomarkers in differentiation and lymph node metastasis.

Ribas R, Ghazoui Z, Gao Q, et al.
Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor-positive breast cancers.
Breast Cancer Res. 2014; 16(5):447 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents.
METHODS: Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor-positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed.
RESULTS: By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid- and leucine-rich protein 1, an ER coactivator.
CONCLUSIONS: These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC.

Hu SC, Yu HS, Yen FL, et al.
CXCR7 expression correlates with tumor depth in cutaneous squamous cell carcinoma skin lesions and promotes tumor cell survival through ERK activation.
Exp Dermatol. 2014; 23(12):902-8 [PubMed] Related Publications
The chemokine receptor CXCR7 has been demonstrated to be involved in the development of certain cancers, but its role in cutaneous squamous cell carcinoma (SCC) has not been previously investigated. We seek to determine whether CXCR7 is expressed in human cutaneous SCC skin lesions and SCC cell lines. In addition, we evaluate whether CXCR7 plays a role in SCC cell proliferation, survival and migration and which signalling pathways are involved. Using quantitative RT-PCR to analyse the mRNA expression of 19 different chemokine receptors, we found that CXCR7 was much more highly expressed compared to other chemokine receptors in cutaneous SCC cell lines (HSC-1 and HSC-5). On immunohistochemical staining, CXCR7 was found to be expressed in 70% (28 of 40) of human cutaneous SCC tissue specimens, and its expression correlated with tumor depth >4 mm and cancer stage ≥II. CXCR7 but not CXCR4 protein was expressed on the surface of HSC-1 and HSC-5 cells by flow cytometry. Activation of the CXCR7 receptor by CXCL12 promoted survival of HSC-1 and HSC-5 cells through the ERK pathway, but had no significant effect on cell proliferation or migration. In summary, our findings indicate that CXCR7 is frequently expressed in cutaneous SCC skin lesions and its expression correlates with tumor depth and cancer stage. CXCR7 is the predominant chemokine receptor expressed in SCC cell lines, and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway. These findings provide new insights into the significance of CXCR7 in the pathophysiology of SCC.

Xue TC, Jia QA, Bu Y, et al.
CXCR7 correlates with the differentiation of hepatocellular carcinoma and suppresses HNF4α expression through the ERK pathway.
Oncol Rep. 2014; 32(6):2387-96 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a malignancy with dysregulated differentiation. However, effective differentiation therapy for HCC is lacking. Previous evidence suggests that CXCR7 is associated with the differentiation of embryonic stem cells. Here, we evaluated the potential role of CXCR7 in the differentiation of HCC. In HCC cell lines, the expression of cancer stem cell-related markers was assessed by flow cytometry and confirmed by western blot and immunofluorescence analyses. Dimethyl sulfoxide, oncostatin M and dexamethasone were used to induce the differentiation of HCC. Immunohistochemical assay was performed on a tissue microarray based on 112 HCC cases that received hepatectomy. Ligand activation, inhibition assays and RNA interference were used to analyze the regulation of hepatocyte nuclear factor 4α (HNF4α) by the CXCR7 pathway. Huh7 and HCCLM3 cell lines were screened for differentiation induction based on biomarkers of hepatic cancer stem cells. CXCR7 was found to be closely associated with the differentiation of HCC, and an inverse expression trend between CXCR7 and HNF4α was found upon induced differentiation. Clinically, high CXCR7 expression was negatively correlated with HNF4α expression in patients with relatively well-differentiated HCC. Moreover, high CXCR7 expression was correlated with poor overall survival and accelerated post-resection metastasis in HCC with a low HNF4α level. Mechanistically, CXCR7 signaling inhibited HNF4α through extracellular regulated protein kinase (ERK) activation, which was inhibited by U0126, an inhibitor of MAPK/ERK kinases 1 and 2. Knockdown of CXCR7 further confirmed that CXCR7 signaling can regulate HNF4α expression. Taken together, our findings indicate that CXCR7 participates in the differentiation of HCC by regulating HNF4α. The CXCR7-ERK-HNF4α cascade represents a new target for the differentiation therapy of HCC.

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.

Miyoshi K, Kohashi K, Fushimi F, et al.
Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma.
Hum Pathol. 2014; 45(9):1900-9 [PubMed] Related Publications
CXC chemokine receptor 4 (CXCR4) expression is reportedly correlated with both vascular endothelial growth factor (VEGF) expression and poor prognosis in a variety of cancers. Its relation to CXC chemokine receptor 7 (CXCR7) is also noted in several malignancies, including rhabdomyosarcoma (RMS) cell lines. However, the correlations between these chemokine receptors and angiogenic factors have not yet been adequately investigated in RMS clinical specimens. By immunohistochemistry, we assessed CXCR4, CXCR7, CC chemokine receptor 6, CC chemokine receptor 7, VEGF expression, microvessel density, and MIB-1 labeling index in 82 formalin-fixed RMS specimens, including 34 primary alveolar RMS and 44 primary embryonal RMS (ERMS). Twenty-six frozen samples were available for investigation by quantitative reverse transcription polymerase chain reaction to detect the messenger RNA expression levels of these molecules. We also evaluated their significance with respect to clinicopathological factors and patient survival rates. Primary RMS showed high expression of CXCR7 (83.1%) regardless of the histologic subtype. High cytoplasmic CXCR4 and high VEGF expression revealed significant correlations in both ERMS and alveolar RMS (P = .0051 and P = .0003, respectively). By univariate analysis of ERMS cases, the tumors with high VEGF expression showed significantly poor prognoses (P = .0017). High VEGF expression also was the independent adverse prognostic factor for ERMS. Because CXCR4, CXCR7, and VEGF are widely expressed in RMS, the combination of these antagonists may provide a potential target for molecular therapy.

Lucansky V, Krmencikova-Fliegl M, Stanek L, Vonka V
Administration of a plasmid that expresses SDF-1α affects the oncogenic potential of mouse bcr-abl-transformed cells.
Mol Med Rep. 2014; 10(4):2116-22 [PubMed] Related Publications
Stromal-derived factor 1α (SDF‑1α, also known as CXCL12) is a chemokine that exerts its effects through the G-protein coupled receptors, C-X-C chemokine receptor type 4 (CXCR4) and 7 (CXCR7). There is marked evidence that the SDF-1/CXCR4 axis is involved in the pathogenesis of leukemia and therapies that target this axis are under development. The present study aimed to increase the efficacy of a DNA-based bcr-abl vaccine by simultaneously immunizing mice with a plasmid carrying the whole SDF-1α gene. Bcr-abl‑transformed 12B1 cells were used to challenge the mice. These cells have the oncogenic potential to induce both leukemia following intravenous inoculation and lymphoma-type solid tumors after subcutaneous inoculation. Administering an SDF‑1 carrying plasmid together with the bcr-abl vaccine resulted in increased survival following a challenge with subcutaneously administered 12B1 cells, although the difference was not statistically significant. However, there was a difference when the animals that developed subcutaneous tumors were only taken into consideration. In doubly-treated mice, significantly more mice failed to develop solid tumors than mice that had only received the bcr-abl vaccine. By contrast, the occurrence of fatal leukemia was significantly higher in the mice that were treated with the SDF-1 plasmid, regardless of whether they were immunized with the bcr-abl-vaccine. No humoral or cellular immune responses against SDF‑1 were detected in the treated mice, which suggested that the changes in oncogenic potential of 12B1 cells were due to the activity of SDF-1 itself.

Li XX, Zheng HT, Huang LY, et al.
Silencing of CXCR7 gene represses growth and invasion and induces apoptosis in colorectal cancer through ERK and β-arrestin pathways.
Int J Oncol. 2014; 45(4):1649-57 [PubMed] Related Publications
The CXC chemokine receptor 7 (CXCR7) has been reported to be involved in cell growth, metastasis and apoptosis in certain cancers. However, the function and molecular mechanisms of CXCR7 in human colorectal cancer (CRC) are still undefined. In the present study, sixty-eight cases of CRC tissues and corresponding adjacent non-cancer tissues (ANCT) were collected, and the expression of CXCR7 was assessed using immunohistochemistry (IHC) in biopsy samples. Furthermore, CXCR7 gene was silenced by small hairpin RNA-mediated lentiviral vector (Lv-shCXCR7), by transfection into human CRC cells (SW480 and HT-29). The levels of p-ERK, β-arrestin, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-2 (MMP-2) and caspase-3 (CAS-3) were detected by western blotting. Cell proliferative activities and invasive capability were respectively measured by MTT and Transwell assays. Cell apoptosis was analyzed by flow cytometry. The results demonstrated that CXCR7 expression was significantly upregulated in CRC tissues compared with the ANCT (54.4 vs. 36.8%, P=0.041), and correlated with Dukes staging and depth of invasion (P=0.007; P=0.002). Silencing of CXCR7 gene suppressed cell proliferation and invasion, and induced cell apoptosis in CRC cells with decreased expression of p-ERK, β-arrestin, PCNA and MMP-2 but increased expression of CAS-3. The tumor volumes in the SW480 subcutaneous tumor models treated with Lv-shCXCR7 were significantly smaller than those of the negative control (NC) and PBS groups (P<0.01). In conclusion, our findings indicate that upregulation of CXCR7 expression is associated with tumor invasion, and silencing of the CXCR7 gene represses the development of CRC cells through ERK and β-arrestin pathways, suggesting that CXCR7 may serve as a potential therapeutic target for the treatment of CRC.

Boudot A, Kerdivel G, Lecomte S, et al.
COUP-TFI modifies CXCL12 and CXCR4 expression by activating EGF signaling and stimulates breast cancer cell migration.
BMC Cancer. 2014; 14:407 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The orphan receptors COUP-TF (chicken ovalbumin upstream promoter transcription factor) I and II are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis. The involvement of COUP-TFs in cancer development has recently been suggested by several studies but remains poorly understood.
METHODS: MCF-7 breast cancer cells overexpressing COUP-TFI and human breast tumors were used to investigate the role of COUP-TFI in the regulation of CXCL12/CXCR4 signaling axis in relation to cell growth and migration. We used Immunofluorescence, western-blot, RT-PCR, Formaldehyde-assisted Isolation of Regulatory Elements (FAIRE) assays, as well as cell proliferation and migration assays.
RESULTS: Previously, we showed that COUP-TFI expression is enhanced in breast cancer compared to normal tissue. Here, we report that the CXCL12/CXCR4 signaling pathway, a crucial pathway in cell growth and migration, is an endogenous target of COUP-TFI in breast cancer cells. The overexpression of COUP-TFI in MCF-7 cells inhibits the expression of the chemokine CXCL12 and markedly enhances the expression of its receptor, CXCR4. Our results demonstrate that the modification of CXCL12/CXCR4 expression by COUP-TFI is mediated by the activation of epithelial growth factor (EGF) and the EGF receptor. Furthermore, we provide evidence that these effects of COUP-TFI increase the growth and motility of MCF-7 cells in response to CXCL12. Cell migration toward a CXCL12 gradient was inhibited by AMD3100, a specific antagonist of CXCR4, or in the presence of excess CXCL12 in the cell culture medium. The expression profiles of CXCR4, CXCR7, CXCL12, and COUP-TFI mRNA in 82 breast tumors and control non-tumor samples were measured using real-time PCR. CXCR4 expression was found to be significantly increased in the tumors and correlated with the tumor grade, whereas the expression of CXCL12 was significantly decreased in the tumors compared with the healthy samples. Significantly higher COUP-TFI mRNA expression was also detected in grade 1 tumors.
CONCLUSIONS: Together, our mechanistic in vitro assays and in vivo results suggest that a reduction in chemokine CXCL12 expression, with an enhancement of CXCR4 expression, provoked by COUP-TFI, could be associated with an increase in the invasive potential of breast cancer cells.

Hong TS, Ryan DP, Borger DR, et al.
A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma.
Int J Radiat Oncol Biol Phys. 2014; 89(4):830-8 [PubMed] Related Publications
PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients.
METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood.
RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05).
CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

Hattermann K, Sebens S, Helm O, et al.
Chemokine expression profile of freshly isolated human glioblastoma-associated macrophages/microglia.
Oncol Rep. 2014; 32(1):270-6 [PubMed] Related Publications
Several studies have substantiated the hypothesis that tumor progression is not only driven by the tumor cells themselves but also by their interaction with intrinsic and surrounding stromal cells. Tumor-associated macrophages and microglial cells (TAMs) represent one major stromal cell component of glioblastomas. Additionally, in many gliomas, chemokines are highly expressed and some chemokines were already linked to settlement of TAMs in tumors. However, although chemoattraction mechanisms mediated by chemokines and their receptors are well documented, information on their expression and role in TAMs, particularly in patients, is limited. Therefore, we investigated the transcription of the chemokine-receptor combinations CXCL12-CXCR4-CXCR7, CXCL16-CXCR6 and CX3CL1-CX3CR1 in freshly isolated TAMs from 20 human glioblastomas in relation to in vitro polarized M1- and M2-macrophages. We demonstrated that TAMs express both M1- and M2-markers. Compared to in vitro polarized macrophages, the M1-marker interleukin (IL)-6 was similarly expressed, whereas IL-1β and tumor necrosis factor (TNF)-α were found at lower levels. The M2-marker IL-10 was comparably expressed, while CD163 and transforming growth factor (TGF)-β were detected with one tenth lower intensities in TAMs. All investigated chemokines/receptors were transcribed at moderate to high levels in TAMs as well as in vitro polarized macrophages. However, CX3CR1 was markedly higher and CXCR7 was somewhat higher expressed in TAMs, whereas M2-macrophages were characterized by the highest CXCL12 and a moderate CX3CL1 expression. Collectively, TAMs share properties of M1- and M2-macrophages and show a considerably higher expression of the chemokine receptors CXCR7 and CX3CR1.

Yu Y, Li H, Xue B, et al.
SDF-1/CXCR7 axis enhances ovarian cancer cell invasion by MMP-9 expression through p38 MAPK pathway.
DNA Cell Biol. 2014; 33(8):543-9 [PubMed] Related Publications
Ovarian cancer is an aggressive gynecological malignancy with high metastatic potential. Recently, the CXC receptor (CXCR7) has been identified as a new receptor for stromal-derived factor-1 (SDF-1), and exerts important roles in cancer development. However, its effect on ovarian cancer and the underlying mechanism remain unknown. In this study, we detected abundant CXCR7 expression in ovarian cancer tissues and cells. Moreover, SDF-1 induced dramatically upregulation of CXCR7 mRNA and protein levels, indicating that the SDF-1/CXCR7 axis existed in ovarian cancer. Further analysis confirmed that SDF-1 enhanced cell adhesion and subsequent invasion, which were significantly attenuated when pretreated with CXCR7 small interference RNA (siRNA), indicating the critical function of SDF-1/CXCR7 in cell invasion. Further mechanistic analysis indicated that SDF-1/CXCR7 enhanced cell invasion by matrix metalloproteinase (MMP)-9, as pretreatment with MMP-9 siRNA significantly abrogated a number of invading cells. Additionally, SDF-1/CXCR7 induced phosphorylation of the p38 MAPK pathway, which was accounted for MMP-9 expression as preconditioning with the p38 MAPK inhibitor SB203580 obviously decreased MMP-9 expression. Together, our data implied that SDF-1/CXCR7 enhanced ovarian cancer cell invasion by MMP-9 expression through the p38 MAPK pathway. Thus, these findings confirmed the critical role of SDF-1/CXCR7 during the pathological processes of ovarian cancer and supported its potential targets for further development of antiovarian cancer therapy.

Totonchy JE, Clepper L, Phillips KG, et al.
CXCR7 expression disrupts endothelial cell homeostasis and causes ligand-dependent invasion.
Cell Adh Migr. 2014; 8(2):165-76 [PubMed] Free Access to Full Article Related Publications
The homeostatic function of endothelial cells (EC) is critical for a number of physiological processes including vascular integrity, immunity, and wound healing. Indeed, vascular abnormalities resulting from EC dysfunction contribute to the development and spread of malignancies. The alternative SDF-1/CXCL12 receptor CXCR7 is frequently and specifically highly expressed in tumor-associated vessels. In this study, we investigate whether CXCR7 contributes to vascular dysfunction by specifically examining the effect of CXCR7 expression on EC barrier function and motility. We demonstrate that CXCR7 expression in EC results in redistribution of CD31/PECAM-1 and loss of contact inhibition. Moreover, CXCR7+ EC are deficient in barrier formation. We show that CXCR7-mediated motility has no influence on angiogenesis but contributes to another motile process, the invasion of CXCR7+ EC into ligand-rich niches. These results identify CXCR7 as a novel manipulator of EC barrier function via alteration of PECAM-1 homophilic junctions. As such, aberrant expression of CXCR7 in the vasculature has the potential to disrupt vascular homeostasis and could contribute to vascular dysfunction in cancer systems.

Romain B, Hachet-Haas M, Rohr S, et al.
Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer.
Mol Cancer. 2014; 13:58 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: HIF-1α and CXCR4/CXCL12 have crucial roles in the metastatic process of colorectal cancer. Our aim was to study the significance of targeting HIF-1α and the CXCR4/CXCL12 axis in colorectal cancer to prevent the dissemination process in vitro.
METHODS: We investigated CXCR4 and CXCR7 mRNA and protein expression in human colon carcinomas and the modulation of their expression by hypoxia and HIF-1α in colon cancer cell lines. The migration of tumor cells in a Boyden chamber was studied after CXCR4 inhibition with siRNA or the CXCR4/CXCL12 neutraligand, chalcone 4.
RESULTS: Analysis of a cohort of colon polyps and chromosome-unstable carcinomas showed that the expression of CXCR4 and CXCR7 was similar to that of the normal mucosa in the polyps and early-stage carcinomas but significantly increased in late stage carcinomas. Our data demonstrate that hypoxia strongly induced the expression of CXCR4 transcript and protein at the cell membrane, both regulated by HIF-1α, whereas CXCR7 expression was independent of hypoxia. After transient hypoxia, CXCR4 levels remained stable at the cell membrane up to 48 hours. Furthermore, reducing CXCR4 expression impaired CXCL12-induced Akt phosphorylation, whereas Erk activation remained unchanged. In contrast, reducing CXCR7 expression did not affect Akt nor Erk activation. In the presence of CXCR4 or CXCR7 siRNAs, a significant reduction in cell migration occurred (37% and 17%, respectively). Although irinotecan inhibited cell migration by 20% (p <0.001), the irinotecan and chalcone 4 combination further increased inhibition to 40% (p <0.001).
CONCLUSION: We demonstrated, for the first time, that hypoxia upregulated CXCR4 but not CXCR7 expression in tumor cells and that the CXCR4 receptor protein level remains high at the cell membrane when the tumor cells return to normoxia for up to 48 hours. In addition we showed the interest to inhibit the CXCR4 signaling by inhibiting both the HIF-1α and CXCR4/CXCL12 pathway. CXCR4 seems to be a relevant target because it is continuously expressed and functional both in normoxic and hypoxic conditions in tumor cells.

Roy I, Zimmerman NP, Mackinnon AC, et al.
CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.
PLoS One. 2014; 9(3):e90400 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

Wang S, Zhang S, Li J, et al.
CXCL12-induced upregulation of FOXM1 expression promotes human glioblastoma cell invasion.
Biochem Biophys Res Commun. 2014; 447(1):1-6 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor; it is highly aggressive and is associated with a poor prognosis. Binding of the chemokine CXCL12 to its receptors (CXCR4 and CXCR7) contributes to the activation of many downstream signaling pathways and promotes the invasion of various malignant tumor cells, including GBM cells. FOXM1, a transcription factor involved in cell cycle regulation, is overexpressed in GBM and is involved in GBM progression. However, the molecular mechanisms by which CXCL12 promotes the invasion of human GBM cells remain unclear. In this study, we demonstrate that CXCL12 increases the production of FOXM1 by binding to CXCR4 in GBM cell lines. Furthermore, pretreatment with an inhibitor of the PI3K/AKT pathway abrogated the CXCL12-induced expression of FOXM1. In addition, there was a positive correlation between CXCL12/CXCR4 expression and FOXM1 expression in human malignant glioma tissues. Finally, a functional assay revealed that CXCL12 does not stimulate GBM cell invasion when FOXM1 expression is silenced using a small interfering RNA (siRNA). Collectively, these findings suggest that CXCL12 promotes GBM cell invasion in part by increasing the expression of FOXM1, which is mediated in part by a PI3K/AKT-dependent mechanism in vitro.

Melo Rde C, Longhini AL, Bigarella CL, et al.
CXCR7 is highly expressed in acute lymphoblastic leukemia and potentiates CXCR4 response to CXCL12.
PLoS One. 2014; 9(1):e85926 [PubMed] Free Access to Full Article Related Publications
Recently, a novel CXCL12-binding receptor, has been identified. This CXCL12-binding receptor commonly known as CXCR7 (CXC chemokine receptor 7), has lately, based on a novel nomenclature, has received the name ACKR3 (atypical chemokine receptor 3). In this study, we aimed to investigate the expression of CXCR7 in leukemic cells, as well as its participation in CXCL12 response. Interesting, we clearly demonstrated that CXCR7 is highly expressed in acute lymphoid leukemic cells compared with myeloid or normal hematopoietic cells and that CXCR7 contributed to T-acute lymphoid leukemic cell migration induced by CXCL12. Moreover, we showed that the cellular location of CXCR7 varied among T-lymphoid cells and this finding may be related to their migration capacity. Finally, we hypothesized that CXCR7 potentiates CXCR4 response and may contribute to the maintenance of leukemia by initiating cell recruitment to bone marrow niches that were once occupied by normal hematopoietic stem cells.

Walentowicz-Sadlecka M, Sadlecki P, Bodnar M, et al.
Stromal derived factor-1 (SDF-1) and its receptors CXCR4 and CXCR7 in endometrial cancer patients.
PLoS One. 2014; 9(1):e84629 [PubMed] Free Access to Full Article Related Publications
PURPOSE: One of the most important function of stromal derived factor-1 (SDF-1) and its receptors, is regulating the process of metastasis formation. The aim of our study was to investigate the correlation between SDF-1, CXCR4 and CXCR7 protein levels measured by immunohistochemistry with the clinicopathological features and the survival of endometrial cancer patients.
MATERIALS AND METHODS: 92 patients aged 37-84 (mean 65.1±9.5) were enrolled to our study between January 2000 and December 2007. After the diagnosis of endometrial cancer, all women underwent total abdominal hysterectomy, with bilateral salpingoophorectomy and pelvic lymph node dissection. In all patients clinical stage (according to FIGO classification), histologic grade, myometrial invasion, lymph node and distant metastases were determined.Furthermore, the survival time was assessed. Immunohistochemical analyses of SDF-1, CXCR4 and CXCR7 were performed on archive formalin fixed paraffin embedded tissue sections.
RESULTS: Statistically significant correlations (p<0.01) were reported between SDF-1 and the clinical stage of disease, lymph node metastases, distant metastases, deep myometrial invasion (≥50%), cervical involvement, involvement of adnexa. Statistically significant correlation (p<0.01) was found between SDF-1 expression and the risk of the recurrence. Higher SDF-1 expression was associated with a higher risk of recurrence (p = 0.0001). The results of CXCR4 and CXCR7 expression didn't reveal any significant differences(p>0.05) between the proteins expression in the primary tumor cells and the clinicopathological features. Moreover, the Kaplan-Meier analyses demonstrated a stepwise impairment of cancer overall survival (OS) with increasing SDF-1 expression.
CONCLUSION: The important role of SDF-1 as a predictor of negative clinicopathological characteristics of a tumor suggests that the expression of this stromal factor should be included in the panel of accessory pathomorphological tests and could be helpful in establishing a more accurate prognosis in endometrial cancer patients.

Sobolik T, Su YJ, Wells S, et al.
CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways.
Mol Biol Cell. 2014; 25(5):566-82 [PubMed] Free Access to Full Article Related Publications
Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.

Guo JC, Li J, Yang YC, et al.
Oligonucleotide microarray identifies genes differentially expressed during tumorigenesis of DMBA-induced pancreatic cancer in rats.
PLoS One. 2013; 8(12):e82910 [PubMed] Free Access to Full Article Related Publications
The extremely dismal prognosis of pancreatic cancer (PC) is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA)-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes) were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation.

Dang S, Peng Y, Ye L, et al.
Stimulation of TLR4 by LMW-HA induces metastasis in human papillary thyroid carcinoma through CXCR7.
Clin Dev Immunol. 2013; 2013:712561 [PubMed] Free Access to Full Article Related Publications
In inflammatory sites, high molecular weight hyaluronan fragments are degraded into lower molecular weight hyaluronan fragments (LMW-HA) to regulate immune responses. However, the function of LMW-HA in PTC progression remains to be elucidated. In this study, we found that receptor of LMW-HA, TLR4, was aberrantly overexpressed in PTC tissues and cell line W3. Exposure of W3 cells to LMW-HA promoted cell proliferation and migration via TLR4. Knockdown of TLR4 has provided evidence that TLR4 is essential for LMW-HA-induced CXCR7 expression, which is responsible for LMW-HA-induced proliferation and migration of W3 cells. In tumor-bearing adult nude mice, stimulation of LMW-HA on W3 cells promotes CXCR7 expression in tumor masses (P = 0.002) and tumor growth (P < 0.001). To further confirm our findings, we investigated the clinicopathologic significance of TLR4 and CXCR7 expression using immumohistochemistry in 135 human PTC tissues and 56 normal thyroid tissue samples. Higher rates of TLR4 (53%) and CXCR7 (24%) expression were found in PTC tissues than in normal tissues. Expression of TLR4 or CXCR7 is associated with tumor size and lymph node metastasis. Therefore, LMW-HA may contribute to the development of PTC via TLR4/CXCR7 pathway, which may be a novel target for PTC immunomodulatory therapy.

Whitman SP, Kohlschmidt J, Maharry K, et al.
GAS6 expression identifies high-risk adult AML patients: potential implications for therapy.
Leukemia. 2014; 28(6):1252-8 [PubMed] Free Access to Full Article Related Publications
Emerging data demonstrate important roles for the TYRO3/AXL/MERTK receptor tyrosine kinase (TAM RTK) family in diverse cancers. We investigated the prognostic relevance of GAS6 expression, encoding the common TAM RTK ligand, in 270 adults (n=71 aged<60 years; n=199 aged ⩾60 years) with de novo cytogenetically normal acute myeloid leukemia (CN-AML). Patients expressing GAS6 (GAS6+), especially those aged ⩾60 years, more often failed to achieve a complete remission (CR). In all patients, GAS6+ patients had shorter disease-free (DFS) and overall (OS) survival than patients without GAS6 expression (GAS6-). After adjusting for other prognostic markers, GAS6+ predicted CR failure (P=0.02), shorter DFS (P=0.004) and OS (P=0.04). To gain further biological insights, we derived a GAS6-associated gene-expression signature (P<0.001) that in GAS6+ patients included overexpressed BAALC and MN1, known to confer adverse prognosis in CN-AML, and overexpressed CXCL12, encoding stromal cell-derived factor, and its receptor genes, chemokine (C-X-C motif) receptor 4 (CXCR4) and CXCR7. This study reports for the first time that GAS6 expression is an adverse prognostic marker in CN-AML. Although GAS6 decoy receptors are not yet available in the clinic for GAS6+ CN-AML therapy, potential alternative therapies targeting GAS6+-associated pathways, for example, CXCR4 antagonists, may be considered for GAS6+ patients to sensitize them to chemotherapy.

Heckmann D, Maier P, Laufs S, et al.
The disparate twins: a comparative study of CXCR4 and CXCR7 in SDF-1α-induced gene expression, invasion and chemosensitivity of colon cancer.
Clin Cancer Res. 2014; 20(3):604-16 [PubMed] Related Publications
PURPOSE: In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor-1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood.
EXPERIMENTAL DESIGN: In tumor tissue of 52 patients with colorectal cancer, we observed that expression of CXCR7 and CXCR4 increased with tumor stage and tumor size. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α.
RESULTS: Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Differentially regulated genes were assigned by gene ontology to migration, proliferation, and lipid metabolic processes. Expressions of AKR1C3, AXL, C5, IGFBP7, IL24, RRAS, and TNNC1 were confirmed by quantitative real-time PCR. Using the in silico gene set enrichment analysis, we showed that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. Functionally, exposure to SDF-1α increased invasiveness of CXCR4 and CXCR7 cells, AXL knockdown hampered invasion. Compared with controls, CXCR4 cells showed increased sensitivity against 5-FU, whereas CXCR7 cells were more chemoresistant.
CONCLUSIONS: These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists such as plerixafor.

Ge XS, Ma HJ, Zheng XH, et al.
HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway.
Cancer Sci. 2013; 104(12):1675-82 [PubMed] Related Publications
Long non-coding RNAs (LncRNAs) have been recently found to be pervasively transcribed in the genome and critical regulators of the epigenome. HOTAIR, as a well-known LncRNA, has been found to play important roles in several tumors. Herein, the clinical application value and biological functions of HOTAIR were focused and explored in esophageal squamous cell carcinoma (ESCC). It was found that there was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro. Then some specific molecules with great significance were investigated after HOTAIR overexpression using microarray and quantitative real time-polymerase chain reaction (qPCR). WIF-1 playing an important role in Wnt/β-catenin signaling pathway was selected and further tested by immunehistochemistry. Generally, inverse correlation between HOTAIR and WIF-1 expression was demonstrated both in ESCC cells and tissues. Mechanistically, HOTAIR directly decreased WIF-1 expression by promoting its histone H3K27 methylation in the promoter region and then activated the Wnt/β-catenin signaling pathway. This newly identified HOTAIR/WIF-1 axis clarified the molecular mechanism of ESCC cell metastasis and represented a novel therapeutic target in patients with ESCC.

Windus LC, Glover TT, Avery VM
Bone-stromal cells up-regulate tumourigenic markers in a tumour-stromal 3D model of prostate cancer.
Mol Cancer. 2013; 12(1):112 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The cellular and molecular mechanisms that mediate interactions between tumour cells and the surrounding bone stroma are to date largely undetermined in prostate cancer (PCa) progression. The purpose of this study was to evaluate the role of alpha 6 and beta 1 integrin subunits in mediating tumour-stromal interactions.
METHODS: Utilising 3D in vitro assays we evaluated and compared 1. Monocultures of prostate metastatic PC3, bone stromal derived HS5 and prostate epithelial RWPE-1 cells and 2. Tumour-stromal co-cultures (PC3 + HS5) to ascertain changes in cellular phenotype, function and expression of metastatic markers.
RESULTS: In comparison to 3D monocultures of PC3 or HS5 cells, when cultured together, these cells displayed up-regulated invasive and proliferative qualities, along with altered expression of epithelial-to-mesenchymal and chemokine protein constituents implicated in metastatic dissemination. When co-cultured, HS5 cells were found to re-express N-Cadherin and chemokine receptor CXCR7. Alterations in N-Cadherin expression were found to be mediated by soluble factors secreted by PC3 tumour cells, while chemokine receptor re-expression was dependent on direct cell-cell interactions. We have also shown that integrins beta 1 and alpha 6 play an integral role in maintaining cell homeostasis and mediating expression of E-Cadherin, N-Cadherin and vimentin, in addition to chemokine receptor CXCR7.
CONCLUSIONS: Collectively our results suggest that both PC3 and HS5 cells provide a "protective" and reciprocal milieu that promotes tumour growth. As such 3D co-cultures may serve as a more complex and valid biological model in the drug discovery pipeline.

Brennecke P, Arlt MJ, Muff R, et al.
Expression of the chemokine receptor CXCR7 in CXCR4-expressing human 143B osteosarcoma cells enhances lung metastasis of intratibial xenografts in SCID mice.
PLoS One. 2013; 8(9):e74045 [PubMed] Free Access to Full Article Related Publications
More effective treatment of metastasizing osteosarcoma with a current mean 5-year survival rate of less than 20% requires more detailed knowledge on mechanisms and key regulatory molecules of the complex metastatic process. CXCR4, the receptor of the chemokine CXCL12, has been reported to promote tumor progression and metastasis in osteosarcoma. CXCR7 is a recently deorphanized CXCL12-scavenging receptor with so far not well-defined functions in tumor biology. The present study focused on a potential malignancy enhancing function of CXCR7 in interaction with CXCR4 in osteosarcoma, which was investigated in an intratibial osteosarcoma model in SCID mice, making use of the human 143B osteosarcoma cell line that spontaneously metastasizes to the lung and expresses endogenous CXCR4. 143B osteosarcoma cells stably expressing LacZ (143B-LacZ cells) were retrovirally transduced with a gene encoding HA-tagged CXCR7 (143B-LacZ-X7-HA cells). 143B-LacZ-X7-HA cells co-expressing CXCR7 and CXCR4 exhibited CXCL12 scavenging and enhanced adhesion to IL-1β-activated HUVEC cells compared to 143B-LacZ cells expressing CXCR4 alone. SCID mice intratibially injected with 143B-LacZ-X7-HA cells had significantly (p<0.05) smaller primary tumors, but significantly (p<0.05) higher numbers of lung metastases than mice injected with 143B-LacZ cells. Unexpectedly, 143B-LacZ-X7-HA cells, unlike 143B-LacZ cells, also metastasized with high incidence to the auriculum cordis. In conclusion, expression of the CXCL12 scavenging receptor CXCR7 in the CXCR4-expressing human 143B osteosarcoma cell line enhances its metastatic activity in intratibial primary tumors in SCID mice that predominantly metastasize to the lung and thereby closely mimic the human disease. These findings point to CXCR7 as a target, complementary to previously proposed CXCR4, for more effective metastasis-suppressive treatment in osteosarcoma.

Wang L, Zhang X, Jia LT, et al.
c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma.
Hepatology. 2014; 59(5):1850-63 [PubMed] Related Publications
UNLABELLED: The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, we report that the c-Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR-101, an important tumor-suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c-Myc-mediated manner. miR-101, in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double-negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR-101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR-101 by inhibition of PRC2 activation. In addition, co-overexpression of c-Myc and EZH2 in HCC samples was closely associated with lower expression of miR-101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01).
CONCLUSIONS: c-Myc collaborates with EZH2-containing PRC2 complex in silencing tumor-suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC.

Maussang D, Mujić-Delić A, Descamps FJ, et al.
Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo.
J Biol Chem. 2013; 288(41):29562-72 [PubMed] Free Access to Full Article Related Publications
The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled receptor superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or small interference (si)RNA has shown promising therapeutic benefits in several tumor models. With the increased interest and effectiveness of biologicals inhibiting membrane-bound receptors we made use of the "Nanobody platform" to target CXCR7. Previously we showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools to efficiently tackle difficult drug targets such as G protein-coupled receptors. In this study we developed and characterized highly selective and potent Nanobodies against CXCR7. Interestingly, the CXCR7-targeting Nanobodies displayed antagonistic properties in contrast with previously reported CXCR7-targeting agents. Several high affinity CXCR7-specific Nanobodies potently inhibited CXCL12-induced β-arrestin2 recruitment in vitro. A wide variety of tumor biopsies was profiled, showing for the first time high expression of CXCR7 in head and neck cancer. Using a patient-derived CXCR7-expressing head and neck cancer xenograft model in nude mice, tumor growth was inhibited by CXCR7-targeting Nanobody therapy. Mechanistically, CXCR7-targeting Nanobodies did not inhibit cell cycle progression but instead reduced secretion of the angiogenic chemokine CXCL1 from head and neck cancer cells in vitro, thus acting here as inverse agonists, and subsequent angiogenesis in vivo. Hence, with this novel class of CXCR7 inhibitors, we further substantiate the therapeutic relevance of targeting CXCR7 in head and neck cancer.

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