Overexpression of chemokine ligand 7 is associated with the progression of canine transmissible venereal tumor

BMC Veterinary Research

Chen-Si Lin¹  Rea-Min Chu³  Albert Taiching Liao¹  Chung-Hsi Chou¹  Yu-Shan Wang²  Hsin-Chien Chiang³ 

[1] School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan;Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan;Animal Cancer Center, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan

关键词: CTVT;    TGF-β;    IL-6;    CXCR2;    CXCL7;   

Others  :  1119671
DOI  :  10.1186/1746-6148-8-216

 received in 2012-03-12, accepted in 2012-10-18,  发布年份 2012

【 摘 要 】

Background

Chemokines play multiple roles in the development and progression in a variety of tumors. Chemokine (C-X-C motif) ligand 7 (CXCL7) has been found associated with pro-inflammatory responses, but its role in cancer growth remains unclear. Our previous study showed that R phase tumor infiltrating lymphocytes (TILs) produced large amounts of interleukin (IL)-6 which antagonized transforming growth factor (TGF)-β derived from CTVT to diminish the immune-suppressive microenvironment. Now we intend to determine the expression pattern of CXCL7 and the role of IL-6/TGF-β in CXCL7 induction during spontaneous progressive (P) and regressive (R) phases in canine transmissible venereal tumor (CTVT).

Results

We have demonstrated that CXCL7 expressed at high level in P phase and down-regulated in R phase by western blot and real-time PCR. This suggested that CXCL7 expression was negatively correlated with the tumor growth. Co-culturing TILs with CTVT cells was found to reduce CXCL7 expression, while adding IL-6 blocking antibody reversed it. Moreover, in P phase CTVT, while IL-1β and TGF-β had no obvious effect on CXCL7 expression, IL-6 was found significantly to reduce CXCL7 expression in a dose-dependent manner. The mRNA expression results of CXCL7 receptor, CXCR2, further confirmed the effects of IL-6 concentration on the CXCL7 expression.

Conclusion

CXCL7 overexpression might be associated with the progressive growth of CTVT. The results shown here also suggest the role of CXCL7 in cancer development and the potential as the anti-cancer therapeutic target.

【 授权许可】

   
2012 Chiang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Murgia C, Pritchard J, Kim SY, Fassati A, Weiss RA: Clonal Origin and Evolution of a Transmissible Cancer. Cell 2006, 126:477-487.
• [2]Chu RM, Lin CY, Liu CC, Yang SY, Hsiao YW, Hung SW, Pao HN, Liao KW: Proliferation characteristics of canine transmissible venereal tumor. Anticancer Res 2001, 21(6A):4017-4024.
• [3]Cohen D: The canine transmissible venereal tumor: a unique result of tumor progression. Adv Cancer Res 1985, 43:75-112.
• [4]Hsiao YW, Liao KW, Hung SW, Chu RM: Effect of tumor infiltrating lymphocytes on the expression of MHC molecules in canine transmissible venereal tumor cells. Vet Immunol Immunopathol 2002, 87(1–2):19-27.
• [5]Hsiao YW, Liao KW, Hung SW, Chu RM: Tumor-Infiltrating Lymphocyte Secretion of IL-6 Antagonizes Tumor-Derived TGF-beta1 and Restores the Lymphokine-Activated Killing Activity. J Immunol 2004, 172(3):1508-1514.
• [6]Baggiolini M: Activation and recruitment of neutrophil leukocytes. Clin Exp Immunol 1995, 101(Suppl 1):5-6.
• [7]Feniger-Barish R, Ran M, Zaslaver A, Ben-Baruch A: Differential modes of regulation of cxc chemokine-induced internalization and recycling of human CXCR1 and CXCR2. Cytokine 1999, 11(12):996-1009.
• [8]Ludwig A, Petersen F, Zahn S, Gotze O, Schroder JM, Flad HD, Brandt E: The CXC-chemokine neutrophil-activating peptide-2 induces two distinct optima of neutrophil chemotaxis by differential interaction with interleukin-8 receptors CXCR-1 and CXCR-2. Blood 1997, 90(11):4588-4597.
• [9]Walz A, Baggiolini M: A novel cleavage product of beta-thromboglobulin formed in cultures of stimulated mononuclear cells activates human neutrophils. Biochem Biophys Res Commun 1989, 159(3):969-975.
• [10]Detmers PA, Powell DE, Walz A, Clark-Lewis I, Baggiolini M, Cohn ZA: Differential effects of neutrophil-activating peptide 1/IL-8 and its homologues on leukocyte adhesion and phagocytosis. J Immunol 1991, 147(12):4211-4217.
• [11]Bieche I, Chavey C, Andrieu C, Busson M, Vacher S, Le Corre L, Guinebretiere JM, Burlinchon S, Lidereau R, Lazennec G: CXC chemokines located in the 4q21 region are up-regulated in breast cancer. Endocr Relat Cancer 2007, 14(4):1039-1052.
• [12]Park JY, Park KH, Bang S, Kim MH, Lee JE, Gang J, Koh SS, Song SY: CXCL5 overexpression is associated with late stage gastric cancer. J Cancer Res Clin Oncol 2007, 133(11):835-840.
• [13]Begley LA, Kasina S, Mehra R, Adsule S, Admon AJ, Lonigro RJ, Chinnaiyan AM, Macoska JA: CXCL5 promotes prostate cancer progression. Neoplasia 2008, 10(3):244-254.
• [14]O'Hayre M, Salanga CL, Handel TM, Allen SJ: Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J 2008, 409(3):635-649.
• [15]Busillo JM, Benovic JL: Regulation of CXCR4 signaling. Biochim Biophys Acta 2007, 1768(4):952-963.
• [16]Wang YS, Liao KW, Chen MF, Huang YC, Chu RM, Chi KH: Canine CXCL7 and its functional expression in dendritic cells undergoing maturation. Vet Immunol Immunopathol 2010, 135(1–2):128-136.
• [17]Liu CC, Wang YS, Lin CY, Chuang TF, Liao KW, Chi KH, Chen MF, Chiang HC, Chu RM: Transient downregulation of monocyte-derived dendritic-cell differentiation, function, and survival during tumoral progression and regression in an in vivo canine model of transmissible venereal tumor. Cancer Immunol Immunother 2008, 57(4):479-491.
• [18]Hsiao YW, Liao KW, Chung TF, Liu CH, Hsu CD, Chu RM: Interactions of host IL-6 and IFN-gamma and cancer-derived TGF-beta1 on MHC molecule expression during tumor spontaneous regression. Cancer Immunol Immunother 2008, 57(7):1091-1104.
• [19]Liao KW, Hung SW, Hsiao YW, Bennett M, Chu RM: Canine transmissible venereal tumor cell depletion of B lymphocytes: molecule(s) specifically toxic for B cells. Vet Immunol Immunopathol 2003, 92(3–4):149-162.
• [20]Kruidenier L, MacDonald TT, Collins JE, Pender SLF, Sanderson IR: Myofibroblast Matrix Metalloproteinases Activate the Neutrophil Chemoattractant CXCL7 From Intestinal Epithelial Cells. Gastroenterology 2006, 130(1):127-136.
• [21]Arenberg DA, Kunkel SL, Polverini PJ, Glass M, Burdick MD, Strieter RM: Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 1996, 97(12):2792-2802.
• [22]Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Morris SB, Xue YY, Burdick MD, Glass MC, Iannettoni MD, Strieter RM: Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest 1998, 102(3):465-472.
• [23]Caruso RA, Bellocco R, Pagano M, Bertoli G, Rigoli L, Inferrera C: Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy. Mod Pathol 2002, 15(8):831-837.
• [24]Di Carlo E, Forni G, Lollini P, Colombo MP, Modesti A, Musiani P: The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 2001, 97(2):339-345.
• [25]Welch DR, Schissel DJ, Howrey RP, Aeed PA: Tumor-elicited polymorphonuclear cells, in contrast to “normal” circulating polymorphonuclear cells, stimulate invasive and metastatic potentials of rat mammary adenocarcinoma cells. Proc Natl Acad Sci U S A 1989, 86(15):5859-5863.
• [26]McLoughlin RM, Hurst SM, Nowell MA, Harris DA, Horiuchi S, Morgan LW, Wilkinson TS, Yamamoto N, Topley N, Jones SA: Differential Regulation of Neutrophil-Activating Chemokines by IL-6 and Its Soluble Receptor Isoforms. J Immunol 2004, 172(9):5676-5683.
• [27]Hirano T, Akira S, Taga T, Kishimoto T: Biological and clinical aspects of interleukin 6. Immunol Today 1990, 11(12):443-449.
• [28]Akira S, Hirano T, Taga T, Kishimoto T: Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 1990, 4(11):2860-2867.
• [29]Rabinowich H, Sedlmayr P, Herberman RB, Whiteside TL: Response of human NK cells to IL-6 alterations of the cell surface phenotype, adhesion to fibronectin and laminin, and tumor necrosis factor-alpha/beta secretion. J Immunol 1993, 150(11):4844-4855.
• [30]Hurst SM, Wilkinson TS, McLoughlin RM, Jones S, Horiuchi S, Yamamoto N, Rose-John S, Fuller GM, Topley N, Jones SA: Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 2001, 14(6):705-714.
• [31]Maxwell PJ, Gallagher R, Seaton A, Wilson C, Scullin P, Pettigrew J, Stratford IJ, Williams KJ, Johnston PG, Waugh DJJ: HIF-1 and NF-[kappa]B-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene 2007, 26(52):7333-7345.
• [32]Loetscher P, Seitz M, Baggiolini M, Moser B: Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. J Exp Med 1996, 184(2):569-577.
• [33]Wang YS, Chi KH, Chu RM: Cytokine profiles of canine monocyte-derived dendritic cells as a function of lipopolysaccharide- or tumor necrosis factor-alpha-induced maturation. Vet Immunol Immunopathol 2007, 118(3–4):186-198.
• [34]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25(4):402-408.