Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

Journal of Angiogenesis Research

Jessica J Kandel³  Darrell J Yamashiro¹  Kathleen O'Toole⁴  Paolo Guarnieri²  Tessa B Johung³  Yan-Jung Chang³  Jianzhong Huang³  Sonia L Hernandez¹  Mary Jo Haley³  Jeffrey W Gander³  Jason C Fisher⁵ 

[1] Department of Pediatrics, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA;Center for Computational Biology and Bioinformatics, College of Physicians and Surgeons of Columbia University, 1130 St. Nicholas Ave, New York, New York 10032, USA;Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA;Department of Pathology, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., New York, New York 10032, USA;Department of Surgery, Cincinnati Children's Hospital and Medical Center, 3333 Burnet Ave, Cincinnati, 45229-3039, USA

关键词: macrophage;    inflammation;    VEGF;    metastasis;    angiogenesis;    COX-2;   

Others  :  802272
DOI  :  10.1186/2045-824X-3-22

 received in 2011-04-13, accepted in 2011-10-06,  发布年份 2011

【 摘 要 】

Vascular endothelial growth factor (VEGF) blockade is an effective therapy for human cancer, yet virtually all neoplasms resume primary tumor growth or metastasize during therapy. Mechanisms of progression have been proposed to include genes that control vascular remodeling and are elicited by hypoperfusion, such as the inducible enzyme cyclooxygenase-2 (COX-2). We have previously shown that COX-2 inhibition by the celecoxib analog SC236 attenuates perivascular stromal cell recruitment and tumor growth. We therefore examined the effect of combined SC236 and VEGF blockade, using the metastasizing orthotopic SKNEP1 model of pediatric cancer. Combined treatment perturbed tumor vessel remodeling and macrophage recruitment, but did not further limit primary tumor growth as compared to VEGF blockade alone. However, combining SC236 and VEGF inhibition significantly reduced the incidence of lung metastasis, suggesting a distinct effect on prometastatic mechanisms. We found that SC236 limited tumor cell viability and migration in vitro, with effects enhanced by hypoxia, but did not change tumor proliferation or matrix metalloproteinase expression in vivo. Gene set expression analysis (GSEA) indicated that the addition of SC236 to VEGF inhibition significantly reduced expression of gene sets linked to macrophage mobilization. Perivascular recruitment of macrophages induced by VEGF blockade was disrupted in tumors treated with combined VEGF- and COX-2-inhibition. Collectively, these findings suggest that during VEGF blockade COX-2 may restrict metastasis by limiting both prometastatic behaviors in individual tumor cells and mobilization of macrophages to the tumor vasculature.

【 授权许可】

   
2011 Fisher et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Ebos JM, Lee CR, Kerbel RS: Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 2009, 15:5020-5025.
• [2]Gaur P, Bose D, Samuel S, Ellis LM: Targeting tumor angiogenesis. Semin Oncol 2009, 36:S12-19.
• [3]Rowe DH, Huang J, Kayton ML, Thompson R, Troxel A, O'Toole KM, Yamashiro D, Stolar CJ, Kandel JJ: Anti-VEGF antibody suppresses primary tumor growth and metastasis in an experimental model of Wilms' tumor. J Pediatr Surg 2000, 35:30-32; discussion 32-33.
• [4]Huang J, Frischer JS, Serur A, Kadenhe A, Yokoi A, McCrudden KW, New T, O'Toole K, Zabski S, Rudge JS, et al.: Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci USA 2003, 100:7785-7790.
• [5]Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS: Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009, 15:232-239.
• [6]Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009, 15:220-231.
• [7]Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M, Ponomarev V, Gerald WL, Blasberg R, Massague J: Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 2005, 115:44-55.
• [8]Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, Kreike B, Zhang Y, Wang Y, Ishwaran H, et al.: Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci USA 2007, 104:6740-6745.
• [9]Mantovani A: Cancer: Inflaming metastasis. Nature 2009, 457:36-37.
• [10]Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y: The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 2008, 10:1349-1355.
• [11]Roy LD, Pathangey LB, Tinder TL, Schettini JL, Gruber HE, Mukherjee P: Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. Breast Cancer Res 2009, 11:R56. BioMed Central Full Text
• [12]Nakao S, Kuwano T, Tsutsumi-Miyahara C, Ueda S, Kimura YN, Hamano S, Sonoda KH, Saijo Y, Nukiwa T, Strieter RM, et al.: Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth. J Clin Invest 2005, 115:2979-2991.
• [13]Roche-Nagle G, Connolly EM, Eng M, Bouchier-Hayes DJ, Harmey JH: Antimetastatic activity of a cyclooxygenase-2 inhibitor. Br J Cancer 2004, 91:359-365.
• [14]Lee A, Frischer J, Serur A, Huang J, Bae JO, Kornfield ZN, Eljuga L, Shawber CJ, Feirt N, Mansukhani M, et al.: Inhibition of cyclooxygenase-2 disrupts tumor vascular mural cell recruitment and survival signaling. Cancer Res 2006, 66:4378-4384.
• [15]Huang J, Soffer SZ, Kim ES, McCrudden KW, New T, Manley CA, Middlesworth W, O'Toole K, Yamashiro DJ, Kandel JJ: Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res 2004, 2:36-42.
• [16]Benjamin LE, Hemo I, Keshet E: A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998, 125:1591-1598.
• [17]Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D: Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003, 111:1287-1295.
• [18]Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P: Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004, 18:338-340.
• [19]Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002., 3RESEARCH0034
• [20]Team R-DC, (Ed.): R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing 2009.
• [21]Borenstein M, Hedges LV, Higgins JPT, Rothstein HR: An Introduction to Meta-Analysis. Chichester: John Wiley & Sons Ltd 2009.
• [22]Huang J, Frischer JS, New T, Kim ES, Serur A, Lee A, Kadenhe-Chiwishe A, Pollyea DA, Yokoi A, Holash J, et al.: TNP-470 promotes initial vascular sprouting in xenograft tumors. Mol Cancer Ther 2004, 3:335-343.
• [23]Hulit J, Suyama K, Chung S, Keren R, Agiostratidou G, Shan W, Dong X, Williams TM, Lisanti MP, Knudsen K, Hazan RB: N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res 2007, 67:3106-3116.
• [24]Fayard B, Bianchi F, Dey J, Moreno E, Djaffer S, Hynes NE, Monard D: The serine protease inhibitor protease nexin-1 controls mammary cancer metastasis through LRP-1-mediated MMP-9 expression. Cancer Res 2009, 69:5690-5698.
• [25]Larkins TL, Nowell M, Singh S, Sanford GL: Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. BMC Cancer 2006, 6:181. BioMed Central Full Text
• [26]Calvo A, Catena R, Noble MS, Carbott D, Gil-Bazo I, Gonzalez-Moreno O, Huh JI, Sharp R, Qiu TH, Anver MR, et al.: Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis. Oncogene 2008, 27:5373-5384.
• [27]Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA: IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241-255.
• [28]Shreedhar V, Giese T, Sung VW, Ullrich SE: A cytokine cascade including prostaglandin E2, IL-4, and IL-10 is responsible for UV-induced systemic immune suppression. J Immunol 1998, 160:3783-3789.
• [29]Huang J, Soffer SZ, Kim ES, McCrudden KW, Huang J, New T, Manley CA, Middlesworth W, O'Toole K, Yamashiro DJ, Kandel JJ: Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res 2004, 2:36-42.