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The Chemokine CXCL16 and Its Receptor, CXCR6, as Markers and Promoters of Inflammation-Associated Cancers
research-article
Author(s):
Merav Darash-Yahana
1
,
5
,
* ,
John W. Gillespie
2 ,
Stephen M. Hewitt
3 ,
Yun-Yun K. Chen
1 ,
Shin Maeda
4 ,
Ilan Stein
5 ,
Satya P. Singh
1 ,
Roble B. Bedolla
6 ,
Amnon Peled
5 ,
Dean A. Troyer
6 ,
Eli Pikarsky
5 ,
Michael Karin
7 ,
Joshua M. Farber
1
,
*
Publication date (Electronic):
19 August 2009
Journal:
PLoS ONE
Publisher:
Public Library of Science
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Abstract
Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes.
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Most cited references34
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- Abstract: found
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Intravascular Immune Surveillance by CXCR6+ NKT Cells Patrolling Liver Sinusoids
Introduction In both rodents and humans, the liver is the largest solid organ, and performs critical immunological and metabolic functions. The liver receives nutrient-rich blood from the gut via the portal vein and oxygenated blood from the hepatic artery. It processes blood to remove toxins, synthesizes the majority of serum proteins and lipids, stores glycogen, and performs extensive lipid, cholesterol, and vitamin chemistry and storage. The liver is thought to provide a unique environment for lymphocytes, favoring tolerogenic immune system responses, possibly to prevent reactivity to harmless food antigens [1]. However, in response to certain stimuli, acute inflammatory reactions can occur, and result in hepatocyte death (hepatitis) and subsequent regeneration, with progressive fibrosis when stimuli are sustained. Several progressive liver diseases that can lead to liver failure have an autoimmune component [2]. The liver is an important site of visceral infection. The low-pressure circulation and high surface area of contact between blood and parenchymal cells and the high phagocytic capacity of multiple cell types in liver provide pathogens with an easy route of access. The tolerizing environment may additionally contribute to immune avoidance. The World Health Organization estimates that approximately 5% and 3% of the world's population carry hepatitis B and hepatitis C virus, respectively [3]. Many of these cases result in chronic infections that can lead to fatal complications, including hepatocellular carcinoma, cirrhosis, or hemorrhage. Malaria and leishmania also display important liver tropisms [4,5]. Thus, immune surveillance of the liver for pathogens is an important, but poorly understood, process. The profile of steady-state hepatic immune cells differs markedly from that in secondary lymphoid organs and in other non-lymphoid tissues, with abundant Kupffer cells and natural killer T cells (NKT cells) supplemented with αβ T cells, γδ T cells, natural killer (NK) cells, dendritic cells, and few, if any, B cells. NKT cells, present at trace levels ( 1 h) with dendritic cells [29,30]. The cytotoxic function of NKT cells has been implicated as necessary for ConA-induced hepatitis [9], although the observation that ConA triggers stopping of patrolling appears to argue against direct NKT-cell-mediated killing. NKT cell activation and subsequent cytokine production are known to recruit and activate large numbers of NK cells [31], which may instead be responsible for the direct killing. It is also possible that NKT cells resume patrolling after several hours of immotility, and in this way regain access to all the hepatocytes of the liver for direct killing. Further experiments will be required to resolve these questions. CXCR6 Controls the Accumulation of CD1d-Reactive NKT Cells in the Liver Our study shows that CXCR6, which is expressed on CD1d-reactive NKT cells, controls the selective accumulation of these cells in the liver. Accordingly, CXCR6 also influences the ability of CD1d-reactive NKT cells to induce hepatitis caused by ConA. According to the multistep paradigm of lymphocyte extravasation, chemokines play a key role in activating adhesion molecules that transform rolling cells to firmly adhered ones. Because we observed that CXCL16, the chemokine ligand for CXCR6, is expressed on sinusoidal endothelial cells, we initially hypothesized that CXCR6 was critical for the recruitment of blood-borne NKT cells to the hepatic sinusoids, either by initial tethering interactions or by signaling to initiate crawling and patrolling. Utilizing high-frame-rate imaging, such recruitment events were occasionally observed (see Video S8). Many hours of observation showed no significant difference in the frequency of these recruitment events between cxcr6gfp/+ and cxcr6gfp/gfp mice (data not shown), but the limited number of events and mouse-to-mouse variability preclude definitive conclusions regarding the role of CXCR6 in this process. In addition, we did not observe any significant deficit in hepatic recruitment of CXCR6-deficient cells after short-term transfer of T cell blasts from cxcr6gfp/+ and cxcr6gfp/gfp mice and after in vivo expansion of NKT cells with α-GalCer treatment (data not shown). These results suggest the existence of redundant mechanisms for NKT cell recruitment to liver sinusoids. We have therefore been unable to support the hypothesis that a defect in the NKT cell recruitment process contributes to the phenotype observed at steady state in CXCR6-deficient animals. Our results indicate that the CXCR6-deficient hepatic NKT cells patrol in the same manner as their CXCR6-expressing counterparts: they both crawl rapidly, lack directional bias, and rapidly stop in response to TCR stimulation. Thus, there is no defect in the patrolling behavior of CXCR6-deficient NKT cells that can explain their reduced numbers in the liver. The reduced accumulation of CXCR6-deficient CD1d-reactive NKT cells in the liver is likely to result at least partially from increased cell death due to the lack of a CXCR6-mediated survival signal. Because CXCL16 is the only known ligand for CXCR6 and is expressed on liver sinusoids, it is reasonable to hypothesize that CXCR6/CXCL16 interactions result in enhanced survival of CD1d-reactive liver NKT cells. This would be a novel role for chemokines in the homeostasis of effector T cells in peripheral tissues. As CXCR6 is expressed not only on NKT cells, but also on activated and memory T cells, it is possible that this is a general mechanism by which chemokines mediate the survival of effector/memory T cells that patrol at sites of potential toxic damage and antigen entry, thus facilitating rapid and efficient memory T cell responses. The nature of the survival signal provided by CXCR6 remains to be studied. Although unexpected, this behavior is not unprecedented, as CXCR4 and CX3CR1 have been reported to mediate survival in certain conditions [32,33,34]. Reports have suggested that Akt activation following ligand binding to the chemokine receptors CXCR4 and CX3CR1 results in enhanced survival of cells [32,33], and it has recently been shown that CXCR6 can similarly activate Akt [35]. It is also noteworthy that the defect in CXCR6 expression only affects hepatic NKT cells, and not NKT cells in other locations, suggesting that either the liver is an especially inhospitable environment, or that other survival signals are provided in other NKT-rich organs such as the spleen. The former seems a particularly attractive hypothesis since there is evidence for the liver being a pro-apoptotic environment for lymphocytes [1]. The results of this paper lead us to a model in which the number of intravascular patrolling NKT cells, which is regulated by CXCR6–CXCL16 interactions, influences the immune response in liver in two important ways: (1) it determines the frequency of new antigen detection by affecting the visitation rate of parenchymal liver cells, and (2) it governs the total cytokine “power” (pooled secretion capacity) of the hepatic NKT cell population. In the case of the ConA hepatitis model, the first factor is non-applicable because the “antigen” is in excess. However, in infectious pathogen models in which rare hepatocytes may be infected, there are likely to be agonist glycolipids that react with only a small subset of NKT cells and thus may escape detection for hours, or even days, if NKT cell density is too low. Potential examples include the recent finding that small subsets of NKT cells recognize the mycobacterial cell-wall antigen PIM4 [36] and lipophosphoglycan of leishmania [37]. In conclusion, we have described a model that may explain how the immune system monitors the status of the liver. Future experiments will be required to identify the molecules involved in both NKT cell crawling and stopping processes and the cells that are surveyed by NKT cells, and to determine the relevance of this system for the pathogenesis of hepatitis and for various immune responses in the liver. Materials and Methods Animals cxcr6gfp/+ knock-in mice were generated as described [20] and backcrossed three to eight times onto C57BL/6. Tie2-GFP mice on the FVB/NJ background and tcrα−/− mice on the C57BL/6 background were purchased from Jackson Laboratory (Bar Harbor, Maine, United States) and Taconic Farms (Germantown, New York, United States), respectively. All mice were maintained in our specific-pathogen-free animal facility according to institutional guidelines, and experiments were done with mice from 4 to 12 wk of age. Reagents CD1d tetramer loaded with α-GalCer was prepared as described previously [6]. The α-GalCer compound DB01–1 was kindly provided by Steven Porcelli. The CXCL16-Fc fusion protein was a kind gift of J. Cyster. Recombinant murine CXCL16, SDF-1, and fractalkine were purchased from R & D Systems (Minneapolis, Minnesota, United States). ConA was purchased from Sigma-Aldrich (St. Louis, Missouri, United States). The following monoclonal antibodies were purchased from PharMingen (San Diego, California, United States): H57–597-PE and -APC (anti-TCRβ); PK136-PE, -biotin, and -PE (anti-NK1.1); IM7-biotin (anti-CD44); and 2.4G2 (anti-FcγRII/III). Rabbit polyclonal serum against caveolin-1 was purchased from Transduction Laboratories (Lexington, Kentucky, United States). Goat F(ab′)2 anti-human IgG Fc conjugated to Cy5, goat F(ab′)2 anti-rat IgG Fc conjugated to Cy3, and goat anti-rabbit Ig conjugated to Cy3 were purchased from Jackson ImmunoResearch (West Grove, Pennsylvania, United States). Anti-CD1d antibody (clone 1B1) was purchased from PharMingen and conjugated to Cy5 succinimide ester (Amersham Biosciences, Little Chalfont, United Kingdom) at a final ratio of 1.7 fluorophores/antibody. Cell Tracker 633 (Bodipy 630/650 MeBr) was purchased from Molecular Probes (Eugene, Oregon, United States). Production of anti-murine CXCL16 antibodies Female Wistar-Kyoto rats, 6–8 wk old, were immunized intraperitoneally with 100 μg of murine CXCL16. Immunizations were performed with 100 μg of protein emulsified in incomplete Freund's adjuvant at 2-wk intervals. After a minimum of three immunizations, the rats were boosted with 100 μg of soluble CXCL16 protein in PBS. Three days post-boost, the spleens were harvested and fused with SP2/0 myeloma cells. The fusion was screened by ELISA using plates coated with CXCL16 protein. Specificity of the hybridomas was determined by ELISA with a panel of murine chemokines including CXCL11, CCL22, CCL5, CCL27, CCL28, CCL17, CXCL10, CCL25, and CXCL9. Hybridomas producing CXCL16-specific antibodies were then subjected to three rounds of subcloning by limiting dilution. Biological activity was confirmed by FACS and inhibition of chemotaxis. Isolation and staining of lymphocytes from mouse tissues Spleen tissue was minced and mashed through a 70-μm strainer in PBS with 0.5% BSA. The resulting suspension was pelleted by centrifugation, re-suspended in PBS with 0.5% BSA, layered on Ficoll-paque (Pharmacia LKB Technology, Uppsala, Sweden), and centrifuged at 400 g for 20 min. Blood was collected in heparinized tubes by cardiac puncture of anesthetized animals. Bone marrow was obtained by flushing femurs with PBS containing 0.5% BSA using a 26 G needle. Cells in the resulting pellets were treated with tris-ammonium chloride to remove red blood cells and then washed extensively before use. Lung or liver tissue was minced and mashed through a 70-μm strainer in PBS containing 0.5% BSA. The resulting suspension was pelleted by centrifugation, re-suspended in 40% Percoll (Pharmacia LKB Technology), layered on 80% Percoll, and centrifuged at 600 g. Cells at the gradient interface were harvested and washed extensively before use. Alternatively, liver mononuclear cells were recovered by perfusion of liver of anesthetized mice as follows: the diaphragm and the sus-hepatic vein were cut and the liver reclined in a Petri dish; perfusion with cold PBS and 2 mM EDTA was through the aorta, and the effluent was collected through the severed sus-hepatic vein (approximately 5 ml). Staining of CD1d on parenchymal hepatic cells Fluorescence microscopy of fixed liver sections was performed as described above for CXCL16 analysis. For flow cytometry analysis, liver tissue was mashed with the back of a 5-ml syringe plunger, digested in PBS containing Mg and Ca by 0.2 mg/ml Collagenase D (Roche, Basel, Switzerland) and 0.02 mg/ml DNase I (Roche) for 30 min at 37 °C while agitating, filtered through a 70-μm strainer, pelleted in 40% Percoll (Pharmacia LKB Technology), cleared of red blood cells by tris-ammonium chloride solution, and washed with cold PBS. This suspension of hepatic parenchymal cells was blocked with goat and bovine serum (2% each) and anti-CD16 antibody (PharMingen) for 20 min on ice and then stained with CD31-PE or Tie2-PE (eBioscience, San Diego, California, United States), F4/80-PE (Serotec, Oxford, United Kingdom), or CD11c-PE (PharMingen) along with anti-murine CD1d-Cy5 or rat IgG2b-Cy5. After 30 min on ice, cells were washed twice and analyzed by flow cytometry. Thymocyte transfer experiment Thymocytes were isolated from 4-wk-old cxcr6+/+ , cxcr6gfp/+ , and cxcr6gfp/gfp littermates. tcrα−/− recipient mice (devoid of TCRαβ lymphocytes) were grafted IV with 30 × 106 thymocytes from a 50:50 mix of cells (cxcr6+/+ :cxcr6gfp/+ and cxcr6+/+ :cxcr6gfp/gfp ). After 2 and 3 d, recipient mice were sacrificed, and liver cell suspensions were prepared and stained with antibodies against TCRβ-APC, and NK1.1-PE or CD1d-α-GalCer-tetramer-PE. After exclusion of dead cells with PI, cells present in the TCRβ+ gate were analyzed for staining with NK1.1 or CD1d tetramer and GFP. ConA hepatitis During preliminary time-course and dose-escalation experiments using wild-type and TCRα KO 6-wk-old C57BL6 mice, a dose of 20 mg/kg ConA IP was determined to induce acute liver disease with a peak in serum transaminases AST and ALT at 12 h. Groups of 6-wk-old cxcr6+/+ , cxcr6gfp/+ , and cxcr6gfp/gfp mice were therefore treated with 20 mg/kg ConA diluted in PBS, blood was sampled by tail bleeding after 12 h, serum was aliquoted and stored at −20 °C, and transaminases were measured using a Vitros 950 (Ortho-Clinical Diagnosis, Mississauga, Ontario, Canada). In vitro survival/proliferation assay Liver leukocytes were isolated from 8- to 12-week-old cxcr6gfp/+ and cxcr6gfp/gfp littermates. Equal numbers of CD1d-α-GalCer-tetramer-PE-positive T cells, as measured by flow cytometry, were cultured in RPMI 1640 medium with 10% FCS, 1% penicillin/streptomycin, and beta-mercapto-ethanol on 96-well plates coated sequentially with 0.5 μg/well anti-CD3 antibody (2C11, PharMingen) and/or 0.5 μg/well recombinant CXCL16 diluted in PBS or with PBS alone. The number of GFPhi CD1d-α-GalCer-tetramer-PE-positive T cells, surface-stained with Annexin V (PharMingen), were determined in duplicate, at the indicated time points, by flow cytometry. The number of GFPhi CD1d-α-GalCer-tetramer-PE-positive T cells in the sample from gfp/+ mice cultivated in wells coated with CXCL16 was considered to be 100%. Confocal microscopy Livers were dissected and removed, washed in PBS, sliced, and fixed for 45min at 4 °C in 4% paraformaldehyde. Liver slices were washed with PBS and incubated overnight at 4 °C in 30% sucrose, and then washed again in PBS, placed in OCT medium, and frozen. Sections with a thickness of 7 μm were stained with rabbit polyclonal anti-caveolin-1 serum followed by goat anti-rabbit antibody conjugated to Cy3, with rat monoclonal IgG2b anti-CXCL16 followed by goat anti-rat antibody conjugated to Cy3, and with control serum and isotype control antibodies followed by the corresponding second-step reagents. Slides were mounted with Fluoprep (Biomerieux SA, Marcy l'Etoile, France) and analyzed with a confocal laser system (LSM 510, Zeiss, Jena, Germany). Intravital confocal microscopy Surgical preparation for liver imaging was based on methods described previously [38]. Mice were anesthetized using a cocktail of ketamine (50 mg/kg), xylazine (10 mg/kg), and acepromazine (1.7 mg/kg) injected intraperitoneally. Beginning 45 min later, anesthesia was maintained by half-dose boosts subcutaneously every 30 min. Hair from the left subcostal region was trimmed, and the liver was exposed through a 1.5-cm horizontal incision. The hepatoform ligament was cut and the tip of the left lobe of the liver gently extruded. The mouse was inverted onto a pre-prepared plastic or aluminum tray in which a coverslip was mounted near the center and narrow strips of paper (1.5 mm × 1.5 cm) were glued. These strips of paper provided friction that helped to immobilize the tissue being imaged. Images were acquired using an inverted epifluorescence Zeiss LSM 510 confocal laser system equipped with a 10×/0.3 Plan Neofluar objective, or Fluar 40×/1.3 objective. A warming fan blowing into an enclosure around the whole microscope was used to keep the area warm, and the microscope objective was thermostatically controlled to maintain 37 °C. Videos were acquired by consecutive frames using appropriate combinations of 488-nm, 546-nm, and 633-nm laser lines and GFP, Cy3, and Cy5 filter sets. Imaging speed varied between videos with a range from 1 to 30 s per time point. During all of our intravital imaging experiments, we were keenly aware of the possibility of local photo-toxicity causing time-dependent artifacts in our data. However, we were unable to detect, either by eye or by quantitative analysis, any indication of such a phenomenon. In vivo activation and imaging of NKT cells Animals were imaged as described above. Antibodies and antigens were injected in 50 μl of PBS solution containing 100 μg of 70-kDa dextran conjugated to tetramethylrhodamine (Molecular Probes) to confirm intravenous delivery and healthy blood flow in the region being imaged. We injected 5 μg of anti-CD3ɛ (2C11 clone, PharMingen), 250 μg of Alexa-633-conjugated ConA (Molecular Probes), or 0.05–5 μg of α-GalCer (DB01–1 compound, kind gift of S. Porcelli). Initial experiments utilized 5 μg of α-GalCer, but as little as 50 ng was sufficient to trigger identical amounts of NKT stopping. Doses of either 200 or 50 ng of α-GalCer were used in the GK1.5/CD1d blocking experiments shown here. The percentages of immobile cells before and 40 min after injection of antigen were assessed by manual observation: 6 min of video was analyzed, and cells that moved less than one cell-body-length (10 μm) were considered immobile. Analysis of intravital imaging videos Quantitative analysis was performed only on videos in which there was no detectable whole-liver movement. Cells were tracked using Volocity software version 2.0 (Improvision, Lexington, Massachusetts, United States). Because the software lost some cells due to cells moving out of focus or coming close to one another, the resulting data were an array of cell paths ranging from single frames to the full length of the video (typically 10–15 min). No effort was made to reassemble these partial tracks, but there appeared to be no significant difference in the distribution of track lengths between cxcr6gfp/+ and cxcr6gfp/gfp mice. In total, 640 tracks were analyzed from four videos of cxcr6gfp/+ mice, and 574 tracks were analyzed from four videos of cxcr6gfp/gfp mice. Values such as cell velocity, overall displacement, and displacement-to-path-length ratio were calculated for each track by manipulation of Volocity output in spreadsheets. To safeguard against possible flaws or biases in the Volocity software, data were analyzed according to various subsets to look for unexpected trends (such as shorter average path lengths in particular videos) that might cause the data to be biased. Furthermore, all Volocity-based conclusions, such as velocity and directedness, we confirmed by manual observation of a limited number of cells. To calculate the visitation rate, we calculated the density of GFP+ cells in cxcr6gfp/+ from the intravital videos used in Figure 3B and 3C (see Videos S2 and S3). Using intravital images to compare the density of GFP+ cells was deemed to be inaccurate because of the relatively low number of events counted and was likely to cause a bias in the choice of fields for collecting videos. Thus, the density of cells in cxcr6gfp/gfp mice was calculated from the density for cxcr6gfp/+ mice and the relative frequency of cells in cxcr6gfp/+ and cxcr6gfp/gfp mice as quantified by flow cytometry (see Figure 2). Using the hepatocyte nuclear exclusion of mitochondrial autofluorescence clearly visible in the higher magnification images of Figure 3A, we calculated hepatocytes to be 28 μm long along the sinusoids, at a density of 1,142/mm2. Utilizing the velocity data and assuming that a CD1d-reactive T cell can contact only one hepatocyte at a time, we estimated the number of hepatocyte areas visited by CD1d-reactive T cells per minute in the cxcr6gfp/+ mice and in the cxcr6-null mice. Supporting Information Video S1 NKT Cells Patrol Hepatic Sinusoids High magnification (40×) intravital video of GFP+ cells crawling along the hepatic sinusoids of a cxcr6gfp/+ animal. Video is 300-fold compressed in time. (6.1 MB AVI). Click here for additional data file. Video S2 NKT Cells Patrol Similarly in cxcr6gfp/+ and cxcr6gfp/gfp Animals I Low magnification (10×) intravital video of cxcr6gfp/+ liver showing the typical pattern of crawling observed in each genotype. Video is 300-fold compressed in time. (9.2 MB AVI). Click here for additional data file. Video S3 NKT Cells Patrol Similarly in cxcr6gfp/+ and cxcr6gfp/gfp Animals II Low magnification (10×) intravital video of cxcr6gfp/gfp liver showing the typical pattern of crawling observed in each genotype. Video is 300-fold compressed in time. (2.3 MB AVI). Click here for additional data file. Video S4 Various Examples of Crawling Patterns of Hepatic NKT Cells Assortment of clips from various videos displaying examples of NKT cells passing each other in single sinusoids, or turning around within a single sinusoid. These examples suggest that NKT cells are not responding to spatial molecular gradients and are capable of crawling both with and against the direction of blood flow. All clips were 300-fold compressed in time. (7.9 MB AVI). Click here for additional data file. Video S5 Real-Time Imaging of Blood Flow Low-magnification (10×) intravital video of the liver of a wild-type C57BL/6 animal during which fluorescent dextran was injected intravenously (red). Video is shown with no compression in time (i.e., at real time). (779 KB AVI). Click here for additional data file. Video S6 NKT Cells Stop Patrolling upon Stimulation by ConA Low-magnification (10×) intravital video of the liver of a cxcr6gfp/+ animal during which 250 μg of ConA was injected intravenously. Video is 300-fold compressed in time. (4.5 MB AVI). Click here for additional data file. Video S7 NKT Cells Stop Patrolling upon Stimulation by α-GalCer Low-magnification (10×) intravital video of the liver of a cxcr6gfp/gfp animal during which 5 μg of α-GalCer was injected intravenously. Video is 300-fold compressed in time. (7.5 MB AVI). Click here for additional data file. Video S8 Recruitment of Blood-Borne NKT Cell to Hepatic Sinusoidal Endothelium Low-magnification (10×) intravital video of the liver of a cxcr6gfp/gfp animal taken at a high frame rate (1 frame/s). The arrival, initial rolling, and subsequent attachment and crawling of a single NKT is shown. (5.4 MB AVI). Click here for additional data file. Accession Numbers The LocusLink (http://www.ncbi.nlm.nih.gov/LocusLink) accession number for the CXCR6/Bonzo/STRL33 chemokine receptor is 80901and for its CXCL16 ligand is 66102.
- Record: found
- Abstract: found
- Article: not found
International union of pharmacology. XXII. Nomenclature for chemokine receptors.
P Murphy, M Baggiolini, I Charo … (2000)
Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.
- Record: found
- Abstract: found
- Article: not found
Role of chemokines in tumor growth.
Dayanidhi Raman, Paige Baugher, Yee Mon Thu … (2007)
Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma-associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed.
Author and article information
Contributors
: Role: Editor
Journal
Journal ID (nlm-ta): PLoS One
Journal ID (publisher-id): plos
Journal ID (pmc): plosone
Title:
PLoS ONE
Publisher:
Public Library of Science
(San Francisco, USA
)
ISSN
(Electronic):
1932-6203
Publication date Collection: 2009
Publication date
(Electronic):
19
August
2009
Volume: 4
Issue: 8
Electronic Location Identifier: e6695
Affiliations
[1
]Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases
(NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of
America
[2
]SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland, United
States of America
[3
]Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research
(CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda,
Maryland, United States of America
Author notes
* E-mail:
meravd@
123456hadassah.org.il
(MDY);
jfarber@
123456niaid.nih.gov
(JMF)
Article
Publisher ID: 09-PONE-RA-09600R1DOI: 10.1371/journal.pone.0006695
PMC ID: 2723911
PubMed ID: 19690611
SO-VID: c16b8930-cbcd-4da3-9e70-48352dc59b5f
Copyright © This is an open-access article distributed under the terms of the Creative Commons
Public Domain declaration which stipulates that, once placed in the public domain,
this work may be freely reproduced, distributed, transmitted, modified, built upon,
or otherwise used by anyone for any lawful purpose.
History
Date
received
: 6
April
2009
Date
accepted
: 21
July
2009
Page count
Pages: 12
Categories
Subject:
Research Article
Subject:
Immunology
Subject:
Oncology
Subject:
Oncology/Prostate Cancer
ScienceOpen disciplines: Uncategorized
Data availability:
ScienceOpen disciplines: Uncategorized