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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 34-40
CHEMOKINES
From the Laboratory of Molecular Immunoregulation, Laboratory of
Experimental Immunology, Division of Basic Sciences; Intramural
Research Support Program, SAIC; Veterinary and Tumor Pathology Section,
Office of Laboratory Animal Resources, Frederick Cancer Research and
Development Center, Frederick, MD; and Cell Biology Section, National
Institute of Dental and Craniofacial Research, Bethesda, MD.
Although several CXC chemokines have been shown to induce
angiogenesis and play roles in tumor growth, to date, no member of the
CC chemokine family has been reported to play a direct role in
angiogenesis. Here we report that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), induced chemotaxis of human endothelial cells at nanomolar concentrations. This chemotactic
response was inhibited by a monoclonal antibody to MCP-1. MCP-1 also
induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic membrane and the matrigel plug assays. As expected, the
angiogenic response induced by MCP-1 was accompanied by an inflammatory
response. With the use of a rat aortic sprouting assay in the absence
of leukocytic infiltrates, we ruled out the possibility that the
angiogenic effect of MCP-1 depended on leukocyte products. Moreover,
the direct effect of MCP-1 on angiogenesis was consistent with the
expression of CCR2, the receptor for MCP-1, on endothelial cells.
Assessment of supernatant from a human breast carcinoma cell line
demonstrated the production of MCP-1. Treatment of immunodeficient mice
bearing human breast carcinoma cells with a neutralizing antibody to
MCP-1 resulted in significant increases in survival and inhibition of
the growth of lung micrometastases. Taken together, our data indicate
that MCP-1 can act as a direct mediator of angiogenesis. As a chemokine
that is abundantly produced by some tumors, it can also directly
contribute to tumor progression. Therefore, therapy employing
antagonists of MCP-1 in combination with other inhibitors of
angiogenesis may achieve more comprehensive inhibition of tumor growth.
(Blood. 2000;96:34-40)
Several members of the CXC chemokine subfamily that
contain an ELR motif, including interleukin-8 (IL-8) NAP-2, ENA-78, and GRO MCP-1 is encoded by a single gene, which is well conserved in several
species, including human, mouse, and rat.10,11 Human MCP-1
is active in all these species; therefore, human MCP-1 can be tested in
cross-species bioassays. Although MCP-1 exerts chemotactic activity for
several cell types, including monocytes, T lymphocytes, basophils, and NK cells,12-17 it is not known if it is
chemotactic for endothelial cells. Moreover, the expression of CCR2 on
endothelial cells, the only seven-transmembrane G protein-coupled
receptor for MCP-1, has not yet been reported.
MCP-1 is abundantly produced in a variety of inflammatory diseases,
such as atherosclerosis and rheumatoid arthritis.18,19 The
MCP-1 gene is also expressed during early stages of melanoma, and it is
also produced in metastatic lesions.20,21 The expression of
the MCP-1 gene in tumor parenchyma has been correlated with the degree
of invasiveness of human breast carcinomas.21 Moreover, the
concentration of MCP-1 in the urine was shown to be correlated with the
degree of tumor malignancy.22 Because MCP-1 is abundantly produced by tumors, we tested whether MCP-1 contributes directly toward
tumor angiogenesis by a mechanism independent of monocyte recruitment.
In contrast to a recent report23 implicating that the
angiogenic effects of MCP-1 were due to monocytic infiltrates, we have
found that MCP-1 is a direct mediator of angiogenesis, as measured by
its ability to induce in vitro endothelial cell migration, endothelial
cell sprouting from aortal rings in the absence of an inflammatory
response, and in vivo angiogenesis in the matrigel plug assay.
Furthermore, blocking of MCP-1 activity in immunodeficient mice bearing
human breast carcinomas resulted in significant prolongation of the
survival of tumor-bearing mice. These results demonstrate that MCP-1
can exert direct effects promoting angiogenesis.
Chemokines and antibodies
Cell culture
Flow cytometric analysis Indirect immunofluorescence was performed on HMECs and HUVECs by exposing cells to saturating amounts of mouse antibodies to human CCR2. Fluorescein-conjugated F(ab)2 fragments of goat anti-mouse (Sigma) diluted 1:50 was used as the secondary antibody. After staining, cells were analyzed using a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).Endothelial cell migration assay HMEC and HUVEC chemotaxis was performed using micro-Boyden chambers as described.6 Briefly, polycarbonate filters of 5 µm pore size (Nucleopore, NeuroProbe, Cabin John, MD) were coated with fibronectin (10 µg/mL; Sigma) overnight at 4°C. Binding buffer containing 1.0% bovine serum albumin in RPMI 1640 with or without various amounts of MCP-1 was placed in the lower compartment of the chamber, and 0.5 × 106 cells/mL resuspended in binding medium were then added to the upper compartment. The chambers were incubated for 4 hours at 37°C. After the filters were removed, the upper surface was scraped, fixed with methanol, and stained with Leukostat (Fisher Scientific, Pittsburgh, PA). Membranes were analyzed using the BIOQUANT program (R & M Biometrics, Inc, Nashville, TN), and the results were expressed as the mean number of migrated cells/10 fields at 10× magnification. For inhibitory assays, MCP-1 antibody was added together with MCP-1 in the lower compartment of the chamber. Each sample was tested in triplicate. Chemotaxis and inhibition of chemotaxis experiments were performed 5 times.Rat aortic ring assay Rat aortic rings were prepared as previously described.6 The thoracic and abdominal aorta was obtained from 100- to 150-g male Sprague-Dawley rats (Taconic, Germantown, NY). Excess perivascular tissue was removed, transverse sections (1 to 2 mm) were made, and the resulting aortic rings were then washed in medium 199 (Gibco BRL, Life Technology, Grand Island, NY). The rings were then embedded in matrigel (Beckton Dickinson, Bedford, MA) in 8-well chamber slides (Nalge Nunc International, Milwaukee, WI) so that the lumen was parallel to the base of the slide. After the matrigel gelled, serum-free medium (endothelial basal medium supplemented with antibiotics) with or without different concentrations of MCP-1 (1-100 ng/mL) was added to each well, and the slides were incubated at 37°C, with 5% CO2, for 3 days (n = 6 per dose). ECGS was used as the positive control at concentrations of 200 µg/mL. After the incubation period, the rings were fixed, stained, and photographed. The ring assay was repeated 2 times.Chick chorioallantoic membrane (CAM) assay Ovalbumin (4 mL) was removed from 3-day-old embryonated eggs (Truslow Farms, Charlestown, MD). Thereafter, windows were opened for each egg and coated with tape, and eggs were incubated at 37°C. On day 10, five µL of distilled water containing different amounts of MCP-1 were applied in the center of quartered 13-mm diameter plastic coverslips (Thermanox, Nalge NUNC International) and let dry for 10 minutes. Each coverslip was placed on the chorioallantoic membrane of the chick, and the eggs were incubated at 37°C for 3 days. The assay was scored and photographed on the 13th embryonic day. EGF and water were used as positive and negative controls, respectively. Twenty eggs were used in total for each data point. A positive score for angiogenesis was made when vessels appeared to radiate from the spot in the coverslip to which the stimulant was applied. The scores are reported as a percentage of positive CAMs at each dilution.In vivo matrigel plug angiogenesis assay Matrigel (9 mg/mL; 0.3 mL/mouse) alone or mixed with different concentrations of MCP-1 was injected subcutaneously into the flank of C57BL/6 mice. For angiogenesis inhibition, the mice were injected intraperitoneally with antibody to MCP-1 or control rabbit IgG (35 µg/mouse) on days 1, 3, and 6. On day 7, mice were sacrified, and plugs were removed and fixed in 3.7% formaldehyde/phosphate-buffered saline (PBS), paraffin embedded, and Giemsa-stained slides were photographed. The experiment was repeated 2 times with 8 mice per group in each experiment.In vivo tumor studies CB-17 severed combine immune deficient (SCID) mice were used at 6 to 8 weeks of age and purchased from the animal production area (NCI-FCRDC, Frederick, MD). Animal housing and management were in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences, Institute of Laboratory Animal Resources, National Research Council, 1996), and the protocol used was approved by the NCI-FCRDC Animal Care and Use Committee. For survival experiments, SCID mice were injected intravenously with 20 µL of anti-ASGM1 (Wako Chemicals, Richmond, VA) on day 0, and 3 × 105 MDA231 human breast carcinoma cells were injected intravenously on day 1. Antibody to MCP-1 (Ab 279) (25 µg/mouse, 1 mg/kg) and control rabbit IgG were given intraperitoneally to the mice on days 4, 8, 12, 16, 20, 24, and 28. Survival was monitored daily, and moribund mice were euthanized. For experimental metastasis experiments, mice from both groups were sacrificed on the 35th day after intravenous injection of the tumor cells. Lungs were extracted and fixed in formalin. At this point few, if any, macrometastases were detected, and micrometastases were quantitated. Histological sections were stained with hematoxylin and eosin, and tumor micrometastasis was quantitated using the Bioquant Program, counting the total tissue area per field 40× field (D1). The micrometastasis present within the same field were gated, and the area within the gates was measured (D2). The metastatic index was calculated by the ratio D2/D1. A minimum of 20 fields was analyzed per slide, and 8 mice were used per group in each experiment. The experiment was repeated 2 times. The survival experiment was repeated 3 times with 10 mice per group in each experiment.Cell proliferation assay MDA-31 was resuspended at 1 × 106 cells/mL of proliferation medium (RPMI, 1% FCS, 2 mmol/L glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin). Cell suspensions (100 µL/well) were placed in 96-well plates and stimulated with different concentrations of MCP-1 in the presence or absence of antibody to MCP-1 (10 µg/mL). Plates were incubated at 37°C in 5% CO2 for 24, 48, or 72 hours. To determine cell proliferation, cells were loaded with 3H-thymidine (0.5-1 µCi/well) 10 hours before uptake determination. After the incubation plates were kept at 70°C overnight, the plates were thawed at room
temperature and harvested, and 3H-thymidine incorporation
was counted with the use of a beta counter.
MCP-1 is chemotactic for human microvascular and umbilical vein endothelial cells Given earlier observations regarding the ability of ELR+ CXC chemokines and SDF-1 to induce neovessel formation, which was consistent with their ability to induce migration of endothelial cells,
we first evaluated the capacity of human endothelial cells from either
HUVECs or HMECs to respond to MCP-1 by in vitro chemotaxis assay. We
observed a dose-dependent chemotactic response for both cell types
toward MCP-1. The maximal chemotactic response for each cell type was
observed at 1 ng/mL of MCP-1 (Figure 1A).
To assess the specificity of the chemotactic response of endothelial cells toward MCP-1, we used a blocking polyclonal antibody to human
MCP-1. This antibody specifically inhibited the chemotactic response of
HUVECs and HMECs to MCP-1 when used at 10 µg/mL (Figure 1B). These
data demonstrate that endothelial cells migrate to very low doses of
MCP-1.
HMECs and HUVECs express CCR2 The chemotactic response of HUVECs and HMECs to MCP-1 prompted us to investigate the expression of CCR2, the receptor for MCP-1, on endothelial cells. By using immunofluorescence, we found CCR2 on the cell surface of both HMECs and HUVECs (Figure 2). The mean fluorescence intensity was 62 (±14) for HMECs versus 37 (±9) for HUVECs, indicating that CCR2 is more abundantly expressed on the cell surface of HMECs than on HUVECs. The expression of CCR2 on HMECs was threefold lower than levels found on human monocytes (data not shown).
MCP-1 induces angiogenesis in vivo To evaluate whether MCP-1 could exhibit angiogenic activities in vivo, we tested different concentrations of MCP-1, ranging from 1 to 1000 ng/mL, using the CAM assay. As shown in Figure 3, MCP-1 at concentrations of 10 ng/mL (Figure 3C) and 100 ng/mL (Figure 3D) induced the typical radial formation of vessels characteristic of other well-known angiogenic factors, such as epidermal growth factor (EGF). The scores of the angiogenic response of MCP-1 were 80% and 50% positive CAMs when used at 10 ng/mL and 100 ng/mL, respectively. The negative control showed less than 15% positivity. No significant angiogenic responses were observed above the negative control level when MCP-1 was used at 1 ng/mL or at 1000 ng/mL (Figure 3E). An inflammatory response, as indicated by an area with increased opacity on the coverslip, however, was also observed in association with the angiogenesis induced by MCP-1. These data demonstrate that MCP-1 has angiogenic effects in vivo.
Antibody to MCP-1 inhibits the angiogenic effect of MCP-1 in the in vivo matrigel plug assay We also evaluated the effect of MCP-1 using the in vivo matrigel plug assay. Mice were injected with matrigel alone or with MCP-1 containing matrigel subcutaneously in the flank. Histologic sections of the matrigel plugs indicated a significant angiogenic effect induced by MCP-1 when used at concentrations of 10 or 100 ng/mL in contrast to matrigel alone (Figure 4, and data not shown). We next studied if the angiogenic effect of MCP-1 could be inhibited specifically by an antibody to MCP-1. As shown in Figure 4C, anti-MCP-1 significantly inhibited the angiogenesis induced by 100 ng/mL of MCP-1 to a level similar to that observed in the control matrigel plugs lacking MCP-1. Moreover, injections of the control antibody did not inhibit this angiogenic effect (Figure 4D). However, as observed using the CAM assay, an inflammatory reaction was also observed in the matrigel plugs that contained MCP-1, which consisted predominantly of monocytes with few neutrophils. This inflammatory response was also inhibited by the MCP-1 antibody but not by rabbit IgG control antibody. These data demonstrate that MCP-1 is angiogenic, but it is not clear if this effect is direct or via the inflammatory cells.
MCP-1-induced rat aortic endothelial cell sprouting Because in our in vivo angiogenesis assays, as well as in the CAM and the matigel plug assays MCP-1 angiogenic effects were accompanied by monocytic infiltration, we sought to investigate the possibility that the observed angiogenesis was leukocyte dependent. We, therefore, tested the effect of MCP-1 using the ex vivo rat aortic ring sprouting assay, which allows the detection of angiogenesis in the absence of an inflammatory response. Transverse sections of rat aorta tissue embedded in collagen were cultured with MCP-1 as described in the "Materials and methods" section, and thereafter examined for the degree of sprouting vessels. Cell culture medium and ECGS medium were used as negative and positive controls, respectively. As shown in Figure 5 and Table 1, MCP-1 stimulated numerous capillary sprouts at concentrations between 5 ng/mL (nmol/L) and 50 ng/mL. Thus, MCP-1 can induce endothelial cell sprouting at nanomolar concentrations from rat aortic rings in the absence of inflammatory infiltrates, indicating a direct effect in promoting angiogenesis.
Blocking MCP-1 enhances the survival of SCID mice bearing MDA-231 human breast carcinoma cells On the basis of the fact that MCP-1 is abundantly produced by tumor cells, we wanted to evaluate the contribution of MCP-1 toward tumor growth. We, therefore, selected a human breast carcinoma cell line MDA-231 to study the effect of a MCP-1 antibody on tumor growth. The MDA-231 cell line produced approximately 6500 pg of MCP-1/mL, when cells were grown at a concentration of 0.5 × 106 cells/mL of RPMI for 24 hours as determined by enzyme-linked immunosorbent assay (data not shown). MDA-231 cells were then injected intravenously into SCID mice, as described in the "Materials and methods" section. As shown in Figure 6, administration of MCP-1 antibody significantly increased the survival of SCID mice bearing MDA-231 carcinoma tumors in contrast to mice treated with control antibody (P < .024). Neither administration of exogenous MCP-1 nor antibodies to MCP-1 had an effect on the growth of MDA-231 cells in vitro (Table 2). Analysis of the metastatic lesions in the lungs revealed that the experimental micrometastases therein were significantly smaller and lower in number when treated with the MCP-1 antibody than in the control antibody group (Figure 7). As shown in Figure 8, grading analysis of the lung metastasis by calculating the total area invaded by the tumor in each mouse indicated that the group of mice treated with control antibody exhibited about 2.5 times more metastases than the group of mice treated with anti-MCP-1. The metastatic index of control-treated mice was 0.146 (SEM ± 0.027), whereas the metastatic index of anti-MCP-1-treated mice was 0.057 (SEM ± 0.011; P < .005). These data demonstrate that the size and number of metastatic lesions formed in the presence of antibody to MCP-1 are reduced, and increases in survival were observed, indicating that MCP-1 has a role in tumor progression.
Here we report that MCP-1, a CC chemokine, can directly mediate angiogenesis. By using endothelial cells of different origins, including HUVECs and HMECs, we demonstrated that MCP-1 induced endothelial cell migration in a dose-responsive manner. This chemotactic response was inhibited by a neutralizing antibody to MCP-1. The ability of HUVECs and HMECs to respond to MCP-1 was further supported by the detection of CCR2 on the endothelial cell surface. The expression of CCR2 by endothelial cells and their responsiveness toward MCP-1 prompted us to analyze the effect of MCP-1 toward angiogenesis. The angiogenic effect of MCP-1 was clearly evident in both the in vivo matrigel plug assay and CAM assays and was appropriately inhibited by a neutralizing antibody to MCP-1. The associated inflammatory responses and previously established observations that mononuclear cell products can also act as angiogenic mediators25-27 led to the use of the rat aortic ring assay, which allowed us to evaluate angiogenic effects in the absence of an inflammatory response. MCP-1 induced rat aortic endothelial cell sprouting in a dose-responsive manner. Thus, MCP-1 can act as a direct mediator of angiogenesis.
The authors thank Dr Carlos Martinez (Centro National de Biotecnologia, Madrid, Spain) for kindly providing the antibody to CCR2. We also thank Dr Robert Wiltrout for critically reviewing the manuscript and for helpful suggestions and Dr Lloyd Kincer of Bioquant Inc for assistance regarding the method used for the measurement of micrometastases.
Submitted November 19, 1999; accepted February 14, 2000.
Supported by the National Cancer Institute; R.S. was supported by Abgenix, Inc. By acceptance of this article, the publisher or recipient acknowledges the right of the U.S. Government to retain a non-exclusive, royalty-free license in and to any copyright covering the article.
Reprints: William J. Murphy, LLB, DBS, NCI-Frederick Cancer Research and Development Center, Bldg 567, Rm 209, Frederick, MD 21702-1201; e-mail: murphyw{at}ncifcrf.gov.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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M. Itaya, E. Sakurai, M. Nozaki, K. Yamada, S. Yamasaki, K. Asai, and Y. Ogura Upregulation of VEGF in Murine Retina via Monocyte Recruitment after Retinal Scatter Laser Photocoagulation Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5677 - 5683. [Abstract] [Full Text] [PDF]
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P. Sartipy and D. J. Loskutoff Monocyte chemoattractant protein 1 in obesity and insulin resistance PNAS, June 10, 2003; 100(12): 7265 - 7270. [Abstract] [Full Text] [PDF]
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J. Hernandez-Rodriguez, M. Segarra, C. Vilardell, M. Sanchez, A. Garcia-Martinez, M.-J. Esteban, J. M. Grau, A. Urbano-Marquez, D. Colomer, H. K. Kleinman, et al. Elevated Production of Interleukin-6 Is Associated With a Lower Incidence of Disease-Related Ischemic Events in Patients With Giant-Cell Arteritis: Angiogenic Activity of Interleukin-6 as a Potential Protective Mechanism Circulation, May 20, 2003; 107(19): 2428 - 2434. [Abstract] [Full Text] [PDF]
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P. G. Lloyd, B. M. Prior, H. T. Yang, and R. L. Terjung Angiogenic growth factor expression in rat skeletal muscle in response to exercise training Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1668 - H1678. [Abstract] [Full Text] [PDF]
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G. T. Higgins, J. H. Wang, P. Dockery, P. E. Cleary, and H. P. Redmond Induction of Angiogenic Cytokine Expression in Cultured RPE by Ingestion of Oxidized Photoreceptor Outer Segments Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1775 - 1782. [Abstract] [Full Text] [PDF]
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P. Lu, Y. Nakamoto, Y. Nemoto-Sasaki, C. Fujii, H. Wang, M. Hashii, Y. Ohmoto, S. Kaneko, K. Kobayashi, and N. Mukaida Potential Interaction between CCR1 and Its Ligand, CCL3, Induced by Endogenously Produced Interleukin-1 in Human Hepatomas Am. J. Pathol., April 1, 2003; 162(4): 1249 - 1258. [Abstract] [Full Text] [PDF]
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A. Li, S. Dubey, M. L. Varney, B. J. Dave, and R. K. Singh IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis J. Immunol., March 15, 2003; 170(6): 3369 - 3376. [Abstract] [Full Text] [PDF]
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J. Guo, M. Van Eck, J. Twisk, N. Maeda, G. M. Benson, P. H.E. Groot, and T. J.C. Van Berkel Transplantation of Monocyte CC-Chemokine Receptor 2-Deficient Bone Marrow Into ApoE3-Leiden Mice Inhibits Atherogenesis Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 447 - 453. [Abstract] [Full Text] [PDF]
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S. Yoshida, A. Yoshida, T. Ishibashi, S. G. Elner, and V. M. Elner Role of MCP-1 and MIP-1{alpha} in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization J. Leukoc. Biol., January 1, 2003; 73(1): 137 - 144. [Abstract] [Full Text] [PDF]
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C. Lubeseder-Martellato, E. Guenzi, A. Jorg, K. Topolt, E. Naschberger, E. Kremmer, C. Zietz, E. Tschachler, P. Hutzler, M. Schwemmle, et al. Guanylate-Binding Protein-1 Expression Is Selectively Induced by Inflammatory Cytokines and Is an Activation Marker of Endothelial Cells during Inflammatory Diseases Am. J. Pathol., November 1, 2002; 161(5): 1749 - 1759. [Abstract] [Full Text] [PDF]
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M. C. Cid, J. Hernandez-Rodriguez, M.-J. Esteban, M. Cebrian, Y. S. Gho, C. Font, A. Urbano-Marquez, J. M. Grau, and H. K. Kleinman Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis Circulation, September 24, 2002; 106(13): 1664 - 1671. [Abstract] [Full Text] [PDF]
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R. Salcedo, M. Martins-Green, B. Gertz, J. J. Oppenheim, and W. J. Murphy Combined Administration of Antibodies to Human Interleukin 8 and Epidermal Growth Factor Receptor Results in Increased Antimetastatic Effects on Human Breast Carcinoma Xenografts Clin. Cancer Res., August 1, 2002; 8(8): 2655 - 2665. [Abstract] [Full Text] [PDF]
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 W. I. de Boer Cytokines and Therapy in COPD* : A Promising Combination? Chest, May 1, 2002; 121(5_suppl): 209S - 218S. [Abstract] [Full Text] [PDF]
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E. Azenshtein, G. Luboshits, S. Shina, E. Neumark, D. Shahbazian, M. Weil, N. Wigler, I. Keydar, and A. Ben-Baruch The CC Chemokine RANTES in Breast Carcinoma Progression: Regulation of Expression and Potential Mechanisms of Promalignant Activity Cancer Res., February 1, 2002; 62(4): 1093 - 1102. [Abstract] [Full Text] [PDF]
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 D. H. Townson, C. L. O'Connor, and J. K. Pru Expression of Monocyte Chemoattractant Protein-1 and Distribution of Immune Cell Populations in the Bovine Corpus Luteum Throughout the Estrous Cycle Biol Reprod, February 1, 2002; 66(2): 361 - 366. [Abstract] [Full Text] [PDF]
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 K. A. Dzenko, A. V. Andjelkovic, W. A. Kuziel, and J. S. Pachter The Chemokine Receptor CCR2 Mediates the Binding and Internalization of Monocyte Chemoattractant Protein-1 along Brain Microvessels J. Neurosci., December 1, 2001; 21(23): 9214 - 9223. [Abstract] [Full Text] [PDF]
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T. O. Nossuli, N. G. Frangogiannis, P. Knuefermann, V. Lakshminarayanan, O. Dewald, A. J. Evans, J. Peschon, D. L. Mann, L. H. Michael, and M. L. Entman Brief murine myocardial I/R induces chemokines in a TNF-alpha -independent manner: role of oxygen radicals Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2549 - H2558. [Abstract] [Full Text] [PDF]
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Y. Yu, J. Varughese, L. F. Brown, J. B. Mulliken, and J. Bischoff Increased Tie2 Expression, Enhanced Response to Angiopoietin-1, and Dysregulated Angiopoietin-2 Expression in Hemangioma-Derived Endothelial Cells Am. J. Pathol., December 1, 2001; 159(6): 2271 - 2280. [Abstract] [Full Text] [PDF]
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R. T. Palframan, S. Jung, G. Cheng, W. Weninger, Y. Luo, M. Dorf, D. R. Littman, B. J. Rollins, H. Zweerink, A. Rot, et al. Inflammatory Chemokine Transport and Presentation in HEV: A Remote Control Mechanism for Monocyte Recruitment to Lymph Nodes in Inflamed Tissues J. Exp. Med., November 5, 2001; 194(9): 1361 - 1374. [Abstract] [Full Text] [PDF]
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R. Salcedo, H. A. Young, M. L. Ponce, J. M. Ward, H. K. Kleinman, W. J. Murphy, and J. J. Oppenheim Eotaxin (CCL11) Induces In Vivo Angiogenic Responses by Human CCR3+ Endothelial Cells J. Immunol., June 15, 2001; 166(12): 7571 - 7578. [Abstract] [Full Text] [PDF]
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M. Nesbit, H. Schaider, T. H. Miller, and M. Herlyn Low-Level Monocyte Chemoattractant Protein-1 Stimulation of Monocytes Leads to Tumor Formation in Nontumorigenic Melanoma Cells J. Immunol., June 1, 2001; 166(11): 6483 - 6490. [Abstract] [Full Text] [PDF]
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R. Gillitzer and M. Goebeler Chemokines in cutaneous wound healing J. Leukoc. Biol., April 1, 2001; 69(4): 513 - 521. [Abstract] [Full Text]
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G. Bernardini, G. Spinetti, D. Ribatti, G. Camarda, L. Morbidelli, M. Ziche, A. Santoni, M. C. Capogrossi, and M. Napolitano I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo Blood, December 15, 2000; 96(13): 4039 - 4045. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
CXC chemokines IP-10 and MIG are reported to be
angiostatic, demonstrating the diverse roles chemokines can play in
this process.
, a well-known angiogenic factor, that was shown to inhibit blood vessel formation in
the CAM assay and cornea vascularization induced by bFGF when used at
high concentrations.