Isotypic neutralizing antibodies against mouse GCP-2/CXCL6 inhibit melanoma growth and metastasis.

The chemokine granulocyte chemotactic protein (GCP)-2/CXCL6 promotes tumor growth as angiogenesis inducer and neutrophil chemoattractant. The neutralizing capacity and specificity of monoclonal mouse anti-murine (mu)GCP-2/CXCL6 antibodies were evidenced by granulocyte chemotaxis and signaling assays. The half-life of the non-antigenic antibody in the blood circulation was approximately 15 days. The titers remained constant upon weekly injection. Tumor growth and lymphogenic metastases of human melanoma over-expressing muGCP-2 were reduced in mice treated with anti-muGCP-2. Moreover, the drop in muGCP-2 antibody titer correlated with the melanoma tumor size. Taken together, we show that functional blocking of GCP-2 inhibits tumor growth and metastases.

[1]  H. Herschman,et al.  Glucocorticoid-attenuated Response Genes Encode Intercellular Mediators, Including a New C-X-C Chemokine (*) , 1995, The Journal of Biological Chemistry.

[2]  Rakesh K. Singh,et al.  Distinct expression of CXCL8 and its receptors CXCR1 and CXCR2 and their association with vessel density and aggressiveness in malignant melanoma. , 2006, American journal of clinical pathology.

[3]  Y. Iwashita,et al.  Increased mRNA expression of chemokines in hepatocellular carcinoma with tumor‐infiltrating lymphocytes , 2006, Journal of gastroenterology and hepatology.

[4]  D. Trisciuoglio,et al.  Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression. , 2009, European journal of cancer.

[5]  C. Wolf‐Peeters,et al.  Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells. In vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8. , 1993, Journal of immunology.

[6]  D. Schadendorf,et al.  Expression of interleukin‐8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma , 1999, The Journal of pathology.

[7]  W. Wood,et al.  Chemokine binding and activities mediated by the mouse IL-8 receptor. , 1995, Journal of immunology.

[8]  M. Smyth,et al.  The role of natural killer cells in tumor control—effectors and regulators of adaptive immunity , 2005, Springer Seminars in Immunopathology.

[9]  I. Stříž,et al.  CXC and CC chemokines induced in human renal epithelial cells by inflammatory cytokines , 2009, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[10]  D. Jonas,et al.  Prostate tumor CXC-chemokine profile correlates with cell adhesion to endothelium and extracellular matrix. , 2006, Life sciences.

[11]  Ann Richmond,et al.  Role of chemokines in tumor growth. , 2007, Cancer letters.

[12]  G. Opdenakker,et al.  GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors. , 2005, Experimental cell research.

[13]  M. Iannettoni,et al.  Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. , 1998, The Journal of clinical investigation.

[14]  P. Proost,et al.  NH2- and COOH-terminal truncations of murine granulocyte chemotactic protein-2 augment the in vitro and in vivo neutrophil chemotactic potency. , 1999, Journal of immunology.

[15]  G. Opdenakker,et al.  The CXC Chemokine GCP-2/CXCL6 Is Predominantly Induced in Mesenchymal Cells by Interleukin-1β and Is Down-Regulated by Interferon-γ: Comparison with Interleukin-8/CXCL8 , 2003, Laboratory Investigation.

[16]  A. Sadanandam,et al.  Small interfering RNA‐mediated CXCR1 or CXCR2 knock‐down inhibits melanoma tumor growth and invasion , 2010, International journal of cancer.

[17]  F. Wamunyokoli,et al.  A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer. , 2006, Cancer research.

[18]  Cornelis J H van de Velde,et al.  Disrupted Expression of CXCL5 in Colorectal Cancer Is Associated with Rapid Tumor Formation in Rats and Poor Prognosis in Patients , 2008, Clinical Cancer Research.

[19]  D. Lev,et al.  Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. , 2003, Molecular cancer therapeutics.

[20]  Paul Rutgeerts,et al.  CXCR1‐binding chemokines in inflammatory bowel diseases: down‐regulated IL‐8/CXCL8 production by leukocytes in Crohn's disease and selective GCP‐2/CXCL6 expression in inflamed intestinal tissue , 2004, European journal of immunology.

[21]  U. V. von Andrian,et al.  Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. , 2004, Annual review of immunology.

[22]  G. Opdenakker,et al.  Murine CXCR1 Is a Functional Receptor for GCP-2/CXCL6 and Interleukin-8/CXCL8* , 2007, Journal of Biological Chemistry.

[23]  G. Opdenakker,et al.  Identification of mouse granulocyte chemotactic protein-2 from fibroblasts and epithelial cells. Functional comparison with natural KC and macrophage inflammatory protein-2. , 1996, Journal of immunology.

[24]  R. Strieter,et al.  THE ROLE OF CXC CHEMOKINES AS REGULATORS OF ANGIOGENESIS , 1995, Shock.

[25]  R. Fillmore,et al.  Differential regulation of ENA-78 and GCP-2 gene expression in human corneal keratocytes and epithelial cells. , 2003, Investigative ophthalmology & visual science.

[26]  B. Moser,et al.  Chemokines: role in inflammation and immune surveillance , 2004, Annals of the rheumatic diseases.

[27]  Ji Ming Wang,et al.  Granulocyte chemotactic protein‐2 and related CXC chemokines: from gene regulation to receptor usage , 1997, Journal of leukocyte biology.

[28]  P. Allavena,et al.  Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors. , 2004, Seminars in cancer biology.

[29]  J. Simon,et al.  Ultraviolet‐B irradiation enhances melanoma cell motility via induction of autocrine interleukin 8 secretion , 2007, Experimental dermatology.

[30]  P. Herdewijn,et al.  Characterization of synthetic human granulocyte chemotactic protein 2: usage of chemokine receptors CXCR1 and CXCR2 and in vivo inflammatory properties. , 1997, Biochemistry.

[31]  B. Mian,et al.  Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. , 2002, The American journal of pathology.

[32]  G. Opdenakker,et al.  Chemokines synergize in the recruitment of circulating neutrophils into inflamed tissue , 2005, European journal of immunology.

[33]  C. Uyttenhove,et al.  Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis , 2006, European journal of immunology.

[34]  C. Uyttenhove,et al.  Development of an anti‐IL‐12 p40 auto‐vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection , 2004, European journal of immunology.

[35]  R. Okayasu,et al.  Extremely low dose ionizing radiation up-regulates CXC chemokines in normal human fibroblasts. , 2005, Cancer research.

[36]  J. Van Damme,et al.  The role of CXC chemokines and their receptors in cancer. , 2008, Cancer letters.

[37]  D. Ota,et al.  Angiogenic Effects of Interleukin 8 (CXCL8) in Human Intestinal Microvascular Endothelial Cells Are Mediated by CXCR2* , 2003, The Journal of Biological Chemistry.

[38]  E. Rofstad,et al.  The tumor bed effect: increased metastatic dissemination from hypoxia-induced up-regulation of metastasis-promoting gene products. , 2005, Cancer research.

[39]  S. Vacher,et al.  CXC chemokines located in the 4q21 region are up-regulated in breast cancer. , 2007, Endocrine-related cancer.

[40]  E. De Clercq,et al.  CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3. , 1999, Journal of immunology.

[41]  A. Zlotnik,et al.  Chemokines: a new classification system and their role in immunity. , 2000, Immunity.

[42]  P. Proost,et al.  Synergy between proinflammatory ligands of G protein‐coupled receptors in neutrophil activation and migration , 2004, Journal of leukocyte biology.

[43]  Jeffrey W. Clark,et al.  Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. , 2009, Cancer research.

[44]  P. Woll,et al.  Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer , 2006, British Journal of Cancer.

[45]  Simon A. Jones,et al.  Granulocyte chemotactic protein 2 acts via both IL‐ 8 receptors, CXCR1 and CXCR2 , 1998, European journal of immunology.

[46]  A. Richmond,et al.  Chemokines and chemokine receptors: new insights into cancer-related inflammation. , 2010, Trends in molecular medicine.

[47]  B. Dave,et al.  Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype , 2004, Clinical & Experimental Metastasis.

[48]  Jun Zhang,et al.  Cloning and characterization of mouse homolog of the CXC chemokine receptor CXCR1. , 2005, Cytokine.

[49]  M. Haine,et al.  Van Damme A. , 1986 .

[50]  A. Giwercman,et al.  Constitutive expression of the antibacterial CXC chemokine GCP-2/CXCL6 by epithelial cells of the male reproductive tract. , 2008, Journal of reproductive immunology.

[51]  A. Griffioen,et al.  Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. , 2000, Pharmacological reviews.

[52]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[53]  C. Wolf‐Peeters,et al.  Tumor angiogenesis induced by granulocyte chemotactic protein-2 as a countercurrent principle. , 2001, The American journal of pathology.