Miao Z, Luker K, Summers B, Berahovich R, Bhojani M, Rehemtulla A, Kleer C, Essner J, Nasevicius A, Luker G, Howard M, Schall TCXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA 104: 15735-15740

ChemoCentryx, Inc., Mountain View, CA 94043, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(40):15735-40. DOI: 10.1073/pnas.0610444104
Source: PubMed


Chemokines and chemokine receptors have been posited to have important roles in several common malignancies, including breast and lung cancer. Here, we demonstrate that CXCR7 (RDC1, CCX-CKR2), recently deorphanized as a chemokine receptor that binds chemokines CXCL11 and CXCL12, can regulate these two common malignancies. Using a combination of overexpression and RNA interference, we establish that CXCR7 promotes growth of tumors formed from breast and lung cancer cells and enhances experimental lung metastases in immunodeficient as well as immunocompetent mouse models of cancer. These effects did not depend on expression of the related receptor CXCR4. Furthermore, immunohistochemistry of primary human tumor tissue demonstrates extensive CXCR7 expression in human breast and lung cancers, where it is highly expressed on a majority of tumor-associated blood vessels and malignant cells but not expressed on normal vasculature. In addition, a critical role for CXCR7 in vascular formation and angiogenesis during development is demonstrated by using morpholino-mediated knockdown of CXCR7 in zebrafish. Taken together, these data suggest that CXCR7 has key functions in promoting tumor development and progression.

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Available from: Jeffrey J Essner, Jan 08, 2015
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    • "Mice genetically deficient in CXCR7 have abnormalities in cardiovascular and central nervous systems [12]. CXCR7 expression in non-small cell lung (NSCL) and breast cancer promotes their growth [13]. Breast cancer cells expressing CXCR7 mediate signaling through β-arrestin in a ligand-dependent manner rather than through Gior Ca2+ mobilization [14-16]. "
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    ABSTRACT: Introduction Although C-X-C motif chemokine 12 (CXCL12) has been shown to bind to C-X-C chemokine receptor type 7 (CXCR7), the exact molecular mechanism regulations by CXCL12/CXCR7 axis in breast tumor growth and metastasis are not well understood. CXCR7 expression has been shown to be upregulated during pathological processes such as inflammation and cancer. Methods Breast cancer cell lines were genetically silenced or pharmacologically inhibited for CXCR7 and/or its downstream target signal transducer and activator of transcription 3 (STAT3). 4T1 or 4T1 downregulated for CXCR7 and 4T1.2 breast cancer cell lines were injected in mammary gland of BALB/c mice to form tumors, and the molecular pathways regulating tumor growth and metastasis were assessed. Results In this study, we observed that CXCL12 enhances CXCR7-mediated breast cancer migration. Furthermore, genetic silencing or pharmacologic inhibition of CXCR7 reduced breast tumor growth and metastasis. Further elucidation of mechanisms revealed that CXCR7 mediates tumor growth and metastasis by activating proinflammatory STAT3 signaling and angiogenic markers. Furthermore, enhanced breast tumorigenicity and invasiveness were associated with macrophage infiltration. CXCR7 recruits tumor-promoting macrophages (M2) to the tumor site through regulation of the macrophage colony-stimulating factor (M-CSF)/macrophage colony-stimulating factor receptor (MCSF-R) signaling pathway. In addition, CXCR7 regulated breast cancer metastasis by enhancing expression of metalloproteinases (MMP-9, MMP-2) and vascular cell-adhesion molecule-1 (VCAM-1). We also observed that CXCR7 is highly expressed in invasive ductal carcinoma (IDC) and metastatic breast tissue in human patient samples. In addition, high CXCR7 expression in tumors correlates with worse prognosis for both overall survival and lung metastasis-free survival in IDC patients. Conclusion These observations reveal that CXCR7 enhances breast cancer growth and metastasis via a novel pathway by modulating the tumor microenvironment. These findings identify CXCR7-mediated STAT3 activation and modulation of the tumor microenvironment as novel regulation of breast cancer growth and metastasis. These studies indicate that new strategies using CXCR7 inhibitors could be developed for antimetastatic therapy.
    Breast cancer research: BCR 05/2014; 16(3):R54. DOI:10.1186/bcr3665 · 5.49 Impact Factor
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    • "It has high affinity to CXCL12 and CXCL11, however, unlike chemokine receptors (GPCRs), CXCR7 is an atypical chemokine receptor and is not Gi-protein-coupled and does not affect Ca+2 mobilization [3], [4], [15], [23]–[25] due to modifications in the Asp-Arg-Tyr-Leu-Ala/Ile-Val (DRYLA/IV) motif [26], [27], [28], but may act as a β-arrestin-biased receptor [23], [29], [30] and/or as a chemokine scavenging receptor for CXCL12 and CXCL11 [16], [29], [31]. In human tissues, CXCR7 expression has been described in active tumor-associated endothelial cells (ECs) and in many types of tumors, and has been shown to be essential for the survival and growth of tumor cells [3], [11], [15], [20], [23], [32], [33]. Growing evidence indicates a role for CXCR7 in cancer cell proliferation and migration, however little is known as to the contribution of this binding receptor to CXCL12– mediated effects [14], [22], [34], [35]–[37]. "
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    ABSTRACT: 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.
    PLoS ONE 01/2014; 9(1):e85926. DOI:10.1371/journal.pone.0085926 · 3.23 Impact Factor
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    • "In 2005, CXCR7 was identified as the second CXCL12-binding chemokine receptor [32] [33]. Similar to CXCR4, CXCR7 promotes cancer metastasis and its over-expression is often associated with more aggressive tumour phenotypes and bad prognosis [34] [35] [36]. "
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    ABSTRACT: The chemokine receptor CXCR4 interacts with a single endogenous chemokine, CXCL12, and regulates a wide variety of physiological and pathological processes including inflammation and metastasis development. CXCR4 also binds the HIV-1 envelope glycoprotein, gp120, resulting in viral entry into host cells. Therefore, CXCR4 and its ligands represent valuable drug targets. In this study, we investigated the inhibitory properties of synthetic peptides derived from CXCR4 extracellular loops (ECL1-X4, ECL2-X4 and ECL3-X4) towards HIV-1 infection and CXCL12-mediated receptor activation. Among these peptides, ECL1-X4 displayed anti-HIV-1 activity against X4, R5/X4 and R5 viruses (IC50=24 to 76μM) in cell viability assay without impairing physiological CXCR4-CXCL12 signalling. In contrast, ECL2-X4 only inhibited X4 and R5/X4 strains, interfering with HIV-entry into cells. At the same time, ECL2-X4 strongly and specifically interacted with CXCL12, blocking its binding to CXCR4 and its second receptor, CXCR7 (IC50=20 and 100μM). Further analysis using mutated and truncated peptides showed that ECL2 of CXCR4 forms multiple contacts with the gp120 protein and the N-terminus of CXCL12. Chemokine neutralisation was mainly driven by four aspartates and the C-terminal residues of ECL2-X4. These results demonstrate that ECL2 represents an important structural determinant in CXCR4 activation. We identified the putative site for the binding of CXCL12 N-terminus and provided new structural elements to explain the recognition of gp120 and dimeric CXCR4 ligands.
    Biochimica et Biophysica Acta 01/2014; 1843(5). DOI:10.1016/j.bbamcr.2014.01.017 · 4.66 Impact Factor
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