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Down-modulation of TNFSF15 in ovarian cancer by VEGF and MCP-1 is a pre-requisite for tumor neovascularization

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Abstract

Persistent inflammation and neovascularization are critical to cancer development. In addition to upregulation of positive control mechanisms such as overexpression of angiogenic and inflammatory factors in the cancer microenvironment, loss of otherwise normally functioning negative control mechanisms is likely to be an important attribute. Insights into the down-modulation of such negative control mechanisms remain largely unclear, however. We show here that tumor necrosis factor superfamily-15 (TNFSF15), an endogenous inhibitor of neovascularization, is a critical component of the negative control mechanism that operates in normal ovary but is missing in ovarian cancer. We show in clinical settings that TNFSF15 is present prominently in the vasculature of normal ovary but diminishes in ovarian cancer as the disease progresses. Vascular endothelial growth factor (VEGF) produced by cancer cells and monocyte chemotactic protein-1 (MCP-1) produced mainly by tumor-infiltrating macrophages and regulatory T cells effectively inhibits TNFSF15 production by endothelial cells in vitro. Using a mouse syngeneic tumor model, we demonstrate that silencing TNFSF15 by topical shRNA treatments prior to and following mouse ovarian cancer ID8 cell inoculation greatly facilitates angiogenesis and tumor growth, whereas systemic application of recombinant TNFSF15 inhibits angiogenesis and tumor growth. Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization.

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Acknowledgments

This study is supported in part by grants from Ministry of Science and Technology of China (2009CB918901 to L.Y.L), National Institute of Health of the United States (R01CA113875 to L.Y.L), and Natural Science Foundation of China (30670801 to W.M.D).

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Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology, Tianjin, China

    Weimin Deng, Yangyang Zheng, Zhisong Zhang & Lu-Yuan Li

  2. Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China

    Weimin Deng, Xin Gu, Yi Lu, Chao Gu & Zhi Yao

  3. Key Laboratory of Ministry of Education, Tianjin, China

    Weimin Deng, Yi Lu, Chao Gu, Yangyang Zheng & Zhi Yao

  4. Nankai University School of Pharmaceutical Science, Tianjin, China

    Yangyang Zheng, Zhisong Zhang & Lu-Yuan Li

  5. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Yi Lu, Li Chen & Lu-Yuan Li

  6. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Yi Lu, Li Chen & Lu-Yuan Li

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  1. Weimin Deng
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  2. Xin Gu
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Correspondence to Zhi Yao or Lu-Yuan Li.

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10456_2011_9244_MOESM1_ESM.jpg

Figure S1. Changes in the production of all 60 cytokines on the panel. White bar, 10% DMEM. Gray bar, OVCAR3 CM. Stripe bar, CM from untreated CD4+ CD25+ TReg. Black bar, CM from OVCAR3 CM-treated CD4+ CD25+ TReg. 1. Angiogenin; 2.BDNF; 3.BLC; 4.BMP-4; 5. BMP-6; 6. CK β 8-1; 7. CNTF; 8. EGF; 9. Eotaxin; 10.Eotaxin-2; 11.Eotaxin-3; 12. FGF-6; 13. FGF-7; 14. Fit-3 Ligand; 15. Fractalkine; 16. GCP-2; 17. GDNF; 18. GM-CSF; 19. I-309; 20. IFN-γ; 21. IGFBP-1; 22. IGFBP-2; 23. IGFBP-4; 24.IGF-I; 25.IL-10; 26.IL-13; 27.IL-15; 28.IL-16; 29.IL- 1α; 30.IL-1β; 31.IL-1ra; 32.IL-2; 33.IL-3; 34.IL-4; 35.IL-5; 36.IL-6; 37.IL-7; 38.Leptin; 39.LIGHT; 40.MCP-1; 41. MCP-2; 42. MCP-3; 43. MCP-4; 44. M-CSF; 45. MDC; 46. MIG; 47. MIP-1δ; 48. MIP-3α; 49. NAP-2; 50. NT-3; 51. PARC; 52. PDGF-BB; 53. RANTES; 54. SCF; 55. SDF-1; 56. TARC; 57. TGF-β1; 58. TGF-β 3; 59. TNF-α; 60. TNF-β. (JPEG 269 kb)

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Deng, W., Gu, X., Lu, Y. et al. Down-modulation of TNFSF15 in ovarian cancer by VEGF and MCP-1 is a pre-requisite for tumor neovascularization. Angiogenesis 15, 71–85 (2012). https://doi.org/10.1007/s10456-011-9244-y

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