The chemokine stromal cell–derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell α chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.
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.angiogenesis ͉ cancer ͉ chemokine
CXCR7 binds chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1) but does not act as a classical chemoattractant receptor. Using CCX771, a novel small molecule with high affinity and selectivity for CXCR7, we found that, although CXCR7 is dispensable for “bare filter” in vitro chemotaxis, CXCR7 plays an essential role in the CXCL12/CXCR4-mediated transendothelial migration (TEM) of CXCR4+CXCR7+ human tumor cells. Importantly, although CXCL11 is unable to stimulate directly the migration of these cells, it acts as a potent antagonist of their CXCL12-induced TEM. Furthermore, even though this TEM is driven by CXCR4, the CXCR7 ligand CCX771 is substantially more potent at inhibiting it than the CXCR4 antagonist AMD3100, which is more than 100 times weaker at inhibiting TEM when compared with its ability to block bare filter chemotaxis. Far from being a “silent” receptor, we show that CXCR7 displays early hallmark events associated with intracellular signaling. Upon cognate chemokine binding, CXCR7 associates with β-arrestin2, an interaction that can be blocked by CXCR7-specific mAbs. Remarkably, the synthetic CXCR7 ligand CCX771 also potently stimulates β-arrestin2 recruitment to CXCR7, with greater potency and efficacy than the endogenous chemokine ligands. These results indicate that CXCR7 can regulate CXCL12-mediated migratory cues, and thus may play a critical role in driving CXCR4+CXCR7+ tumor cell metastasis and tissue invasion. CXCR7 ligands, such as the chemokine CXCL11 and the newly described synthetic molecule CCX771, may represent novel therapeutic opportunities for the control of such cells.
In humans and animal models of herpes simplex virus infection, zosteriform skin lesions have been described which result from anterograde spread of the virus following invasion of the nervous system. Such routes of viral spread have not been fully examined following corneal infection, and the possible pathologic consequences of such spread are unknown. To investigate this, recombinant viruses expressing reporter genes were generated to quantify and correlate gene expression with replication in eyes, trigeminal ganglia, and periocular tissue. Reporter activity peaked in eyes 24 h postinfection and rapidly fell to background levels by 48 h despite the continued presence of viral titers. Reporter activity rose in the trigeminal ganglia at 60 h and peaked at 72 h, concomitant with the appearance and persistence of infectious virus. Virus was present in the periocular skin from 24 h despite the lack of significant reporter activity until 84 h postinfection. This detection of reporter activity was followed by the onset of periocular disease on day 4. Corneal infection with a thymidine kinase-deleted reporter virus displayed a similar profile of reporter activity and viral titer in the eyes, but little or no detectable activity was observed in trigeminal ganglia or periocular tissue. In addition, no periocular disease symptoms were observed. These findings demonstrate that viral infection of periocular tissue and subsequent disease development occurs by zosteriform spread from the cornea to the periocular tissue via the trigeminal ganglion rather than by direct spread from cornea to the periocular skin. Furthermore, clinical evidence is discussed suggesting that a similar mode of spreading and disease occurs in humans following primary ocular infection.
Toxoplasma gondii has an unusual population structure consisting of three widely distributed clonal lineages. Acute virulence in mice is strictly observed in type I strains, indicating that a genetic determinant(s) unique to this lineage controls acute pathogenesis. We have analyzed several naturally occurring recombinant strains of T. gondii that carry allele 1 at the SAG1 locus; this allele is characteristic of the type I strains and was previously found to be 100% correlated with the acute virulence phenotype. Recombinant strains G622-M and ROD both had a predominantly type III genotype, with the significant exception of allele 1 at the SAG1 locus. Although these two strains had virtually identical multilocus genotypes, they differed in their virulence in mice. Strain ROD was virulent whereas strain G622-M was nonvirulent, thus demonstrating that the presence of
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