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Bulletin of Mathematical Biology

, Volume 70, Issue 1, pp 89–117 | Cite as

Modeling the VEGF–Bcl-2–CXCL8 Pathway in Intratumoral Agiogenesis

  • Harsh V. Jain
  • Jacques E. Nör
  • Trachette L. JacksonEmail author
Original Article

Abstract

Recent experiments show that vascular endothelial growth factor (VEGF) is the crucial mediator of downstream events that ultimately lead to enhanced endothelial cell survival and increased vascular density within many tumors. The newly discovered pathway involves up-regulation of the anti-apoptotic protein Bcl-2, which in turn leads to increased production of interleukin-8 (CXCL8). The VEGF–Bcl-2–CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies including short interfering RNA (siRNA) that silence the CXCL8 gene and small molecule inhibitors of Bcl-2. In this paper, we present and validate a mathematical model designed to predict the effect of the therapeutic blockage of VEGF, CXCL8, and Bcl-2 at different stages of tumor progression. In agreement with experimental observations, the model predicts that curtailing the production of CXCL8 early in development can result in a delay in tumor growth and vascular development; however, it has little effect when applied at late stages of tumor progression. Numerical simulations also show that blocking Bcl-2 up-regulation, either at early stages or after the tumor has fully developed, ensures that both microvascular and tumor cell density stabilize at low values representing growth control. These results provide insight into those aspects of the VEGF–Bcl-2–CXCL8 pathway, which independently and in combination, are crucial mediators of tumor growth and vascular development. Continued quantitative modeling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines to alter tumor progression.

Keywords

Mathematical model Anti-angiogenic therapy Angiogenesis Bcl-2 CXCL8 

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References

  1. Anderson, A.R., Chaplain, M.A., 1998. Continuous and discrete mathematical models of tumor-induced angiogenesis. Bull. Math. Biol. 60(5), 857–899. zbMATHCrossRefGoogle Scholar
  2. Ausprunk, D.H., Folkman, J., 1977. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc. Res. 14(1), 53–65. CrossRefGoogle Scholar
  3. Bach, F., Uddin, F.J., Burke, D., 2007. Angiopoietins in malignancy. Eur. J. Surg. Oncol. 33(1), 7–15. CrossRefGoogle Scholar
  4. Baxter, L.T., Jain, R.K., 1991. Transport of fluid and macromolecules in tumors. III. Role of binding and metabolism. Microvasc. Res. 41(1), 5–23. CrossRefGoogle Scholar
  5. Bernatchez, P.N., Soker, S., Sirois, M.G., 1999. Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependant. J. Biol. Chem. 274(43), 31047–31054. CrossRefGoogle Scholar
  6. Cao, Y., 2004. Antiangiogenic cancer therapy. Semin. Cancer Biol. 14(2), 139–145. CrossRefGoogle Scholar
  7. Chaplain, M.A., Anderson, A.R., 1996. Mathematical modelling, simulation and prediction of tumour-induced angiogenesis. Invasion Metastasis 16(4-5), 222–234. Google Scholar
  8. Daugulis, P., Arakelyan, L., Ginosar, Y., Agur, Z., 2004. Hopf point analysis for angiogenesis models. Discret. Contin. Dyn. Syst. Ser. B 4(1), 29–38. zbMATHMathSciNetGoogle Scholar
  9. Dong, Z., Song, W., Sun, Q., Zeitlin, B.D., Karl, E., Spencer, D.M., Jain, H.V., Jackson, T., Núñez, G., Nör, J.E., 2007. Endothelial cell apoptosis and microvessel disruption. Exp. Cell Res., accepted. Google Scholar
  10. Dvorak, H.F., Brown, L.F., Detmar, M., Dvorak, A.M., 1995. Vascular permeability factor/vascular endothelial growth factor, vascular hyperpermeability, and angiogenesis. Am. J. Pathol. 146(5), 1029–1039. Google Scholar
  11. Ferrara, N., 1999. Molecular and biological properties of vascular endothelial growth factor. J. Mol. Med. 77(7), 527–543. CrossRefGoogle Scholar
  12. Ferrara, N., 2002. VEGF and the quest for tumour angiogenesis factors. Nat. Rev. Cancer 2, 795–803. Google Scholar
  13. Ferrara, N., Gerber, H.P., LeCouter, J., 2003. The biology of VEGF and its receptors. Nat. Med. 9(6), 669–676. CrossRefGoogle Scholar
  14. Folkman, J., 1971. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285(21), 1182–1186. CrossRefGoogle Scholar
  15. Gammack, D., Byrne, H.M., 2001. Estimating the selective advantage of mutant p53 tumour cells to repeated rounds of hypoxia. Bull. Math. Biol. 63(1), 135–166. CrossRefGoogle Scholar
  16. Garber, K., 2002. Angiogenesis inhibitors suffer new setback. Nat. Biotechnol. 20, 1067–1068. CrossRefGoogle Scholar
  17. Gille, H., Kowalski, J., Li, B., LeCouter, J., Moffat, B., Zioncheck, T.F., Pelletier, N., Ferrara, N., 2001. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J. Biol. Chem. 276(5), 3222–3230. CrossRefGoogle Scholar
  18. Guglielmi, N., Hairer, E., 2001. Implementing Radau IIA methods for stiff delay differential equations. Computing 67(1), 1–12. zbMATHCrossRefMathSciNetGoogle Scholar
  19. Holmes, M.J., Sleeman, B.D., 2000. A mathematical model of tumour angiogenesis incorporating cellular traction and viscoelastic effects. J. Theor. Biol. 202(2), 95–112. CrossRefGoogle Scholar
  20. Holmes, W.E., Lee, J., Kuang, W.J., Rice, G.C., Wood, W.I., 1991. Structure and functional expression of a human interleukin-8 receptor. Science 253(5025), 1278–1280. CrossRefGoogle Scholar
  21. Horuk, R., 1994. The interleukin-8-receptor family: from chemokines to malaria. Immunol. Today 15(4), 169–174. CrossRefGoogle Scholar
  22. Karl, E., Warner, K., Zeitlin, B., Kaneko, T., Wurtzel, L., Jin, T., Chang, J., Wang, S., Wang, C.Y., Strieter, R.M., Nunez, G., Polverini, P.J., Nör, J.E., 2005. Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer Res. 65(12), 5063–5069. CrossRefGoogle Scholar
  23. Ke, L.D., Shi, Y.X., Im, S.A., Chen, X., Yung, W.K., 2000. The relevance of cell proliferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines. Clin. Cancer Res. 6(6), 2562–2572. Google Scholar
  24. Kim, K.J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H.S., Ferrara, N., 1993. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423), 841–844. CrossRefGoogle Scholar
  25. Klintworth, G.K., 1973. The hamster cheek pouch: an experimental model of corneal vascularization. Am. J. Pathol. 73(3), 691–710. Google Scholar
  26. Koch, A.E., Polverini, P.J., Kunkel, S.L., Harlow, L.A., DiPietro, L.A., Elner, V.M., Elner, S.G., Strieter, R.M., 1992. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089), 1798–1801. CrossRefGoogle Scholar
  27. Kuang, Y., Nagy, J.D., Elser, J.J., 2004. Biological stoichiometry of tumor dynamics. Discret. Contin. Dyn. Syst. Ser. B 4(1), 221–240. zbMATHMathSciNetGoogle Scholar
  28. Leung, D.W., Cachianes, G., Kuang, W.J., Goeddel, D.V., Ferrara, N., 1989. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935), 1306–1309. CrossRefGoogle Scholar
  29. Levine, H.A., Sleeman, B.D., Nilsen-Hamilton, M., 2000. A mathematical model for the roles of pericytes and macrophages in the initiation of angiogenesis. I. The role of protease inhibitors in preventing angiogenesis. Math. Biosci. 168(1), 77–115. zbMATHCrossRefMathSciNetGoogle Scholar
  30. Levine, H.A., Pamuk, S., Sleeman, B.D., Nilsen-Hamilton, M., 2001. Mathematical modeling of capillary formation and development in tumor angiogenesis: penetration into the stroma. Bull. Math. Biol. 63(5), 801–863. CrossRefGoogle Scholar
  31. Levine, H.A., Tucker, A.L., Nilsen-Hamilton, M., 2002. A mathematical model for the role of cell signal transduction in the initiation and inhibition of angiogenesis. Growth Factors 20(4), 155–175. CrossRefGoogle Scholar
  32. Mac Gabhann, F., Popel, A.S., 2004. Model of competitive binding of vascular endothelial growth factor and placental growth factor to VEGF receptors on endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 286(1), H153–H164. CrossRefGoogle Scholar
  33. McMahon, G., 2000. VEGF receptor signalling in tumor angiogenesis. Oncologist 5, 3–10. CrossRefGoogle Scholar
  34. Maher, J.J., 1995. Rat hepatocytes and Kupffer cells interact to produce interleukin-8 (CINC) in the setting of ethanol. Am. J. Physiol. 269(4 Pt 1), G518–G523. Google Scholar
  35. Mukaida, N., 2003. Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. Am. J. Physiol. Lung Cell. Mol. Physiol. 284(4), L566–L577. Google Scholar
  36. Nagy, J.D., 2004. Competition and natural selection in a mathematical model of cancer. Bull. Math. Biol. 66(4), 663–687. CrossRefMathSciNetGoogle Scholar
  37. Nguyen, M., Shing, Y., Folkman, J., 1994. Quantitation of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane. Microvasc. Res. 47(1), 31–40. CrossRefGoogle Scholar
  38. Nör, J.E., Christensen, J., Mooney, D.J., Polverini, P.J., 1999. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am. J. Pathol. 154(2), 375–384. Google Scholar
  39. Nör, J.E., Christensen, J., Liu, J., Peters, M., Mooney, D.J., Strieter, R.M., Polverini, P.J., 2001a. Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res. 61(5), 2183–2188. Google Scholar
  40. Nör, J.E., Peters, M.C., Christensen, J.B., Sutorik, M.M., Linn, S., Khan, M.K., Addison, C.L., Mooney, D.J., Polverini, P.J., 2001b. Engineering and characterization of functional human microvessels in immunodeficient mice. Lab. Invest. 81(4), 453–463. Google Scholar
  41. Norrby, K., 1998. Microvascular density in terms of number and length of microvessel segments per unit tissue volume in mammalian angiogenesis. Microvasc. Res. 55(1), 43–53. CrossRefGoogle Scholar
  42. Ohta, M., Kitadai, Y., Tanaka, S., Yoshihara, M., Yasui, W., Mukaida, N., Haruma, K., Chayama, K., 2002. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas. Int. J. Cancer 102(3), 220–224. CrossRefGoogle Scholar
  43. Oikawa, T., Sasaki, M., Inose, M., 1997. Effect of cytogenin, a novel microbial product, on embryonic and tumor cell induced angiogenic responses in vivo. Anticancer Res. 17(3C), 1881–1886. Google Scholar
  44. Patan, S., 2000. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J. Neurooncol. 50(1–2), 1–15. Google Scholar
  45. Pepper, M.S., Ferrara, N., Orci, L., Montesano, R., 1992. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem. Biophys. Res. Commun. 189(2), 824–831. CrossRefGoogle Scholar
  46. Pettet, G.J., Byrne, H.M., McElwain, D.L., Norbury, J., 1996a. A model of wound-healing angiogenesis in soft tissue. Math. Biosci. 136(1), 35–63. zbMATHCrossRefGoogle Scholar
  47. Pettet, G., Chaplain, M.A., McElwain, D.L., Byrne, H.M., 1996b. On the role of angiogenesis in wound healing. Proc. Biol. Sci. 263(1376), 1487–1493. CrossRefGoogle Scholar
  48. Plank, M.J., Sleeman, B.D., 2003. A reinforced random walk model of tumour angiogenesis and anti-angiogenic strategies. Math. Med. Biol. 20(2), 135–181. zbMATHCrossRefGoogle Scholar
  49. Plank, M.J., Sleeman, B.D., Jones, P.F., 2004. A mathematical model of tumour angiogenesis, regulated by vascular endothelial growth factor and the angiopoietins. J. Theor. Biol. 229(4), 435–454. CrossRefMathSciNetGoogle Scholar
  50. Pradeep, C.R., Sunila, E.S., Kuttan, G., 2005. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr. Cancer Ther. 4(4), 315–321. CrossRefGoogle Scholar
  51. Ribatti, D., Vacca, A., Roncali, L., Dammacco, F., 1996. The chick embryo chorioallantoic membrane as a model for in vivo research on angiogenesis. Int. J. Dev. Biol. 40(6), 1189–1197. Google Scholar
  52. Ruhrberg, C., Gerhardt, H., Golding, M., Watson, R., Ioannidou, S., Fujisawa, H., Betsholtz, C., Shima, D.T., 2002. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16(20), 2684–2698. CrossRefGoogle Scholar
  53. Salcedo, R., Ponce, M.L., Young, H.A., Wasserman, K., Ward, J.M., Kleinman, H.K., Oppenheim, J.J., Murphy, W.J., 2000. Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96(1), 34–40. Google Scholar
  54. Samanta, A.K., Oppenheim, J.J., Matsushima, K., 1989. Identification and characterization of specific receptors for monocyte-derived neutrophil chemotactic factor (MDNCF) on human neutrophils. J. Exp. Med. 169(3), 1185–1189. CrossRefGoogle Scholar
  55. Serini, G., Ambrosi, D., Giraudo, E., Gamba, A., Preziosi, L., Bussolino, F., 2003. Modeling the early stages of vascular network assembly. EMBO J. 22(8), 1771–1779. CrossRefGoogle Scholar
  56. Shweiki, D., Neeman, M., Itin, A., Keshet, E., 1995. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: Implications for tumor angiogenesis. Proc. Natl. Acad. Sci. USA 92(3), 768–772. CrossRefGoogle Scholar
  57. Siemeister, G., Schirner, M., Reusch, P., Barleon, B., Marme, D., Martiny-Baron, G., 1998. An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells. Proc. Natl. Acad. Sci. USA 95(8), 4625–4629. CrossRefGoogle Scholar
  58. Smith, D.R., Polverini, P.J., Kunkel, S.L., Orringer, M.B., Whyte, R.I., Burdick, M.D., Wilke, C.A., Strieter, R.M., 1994. Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J. Exp. Med. 179(5), 1409–1415. CrossRefGoogle Scholar
  59. Spyridopoulos, I., Brogi, E., Kearney, M., Sullivan, A.B., Cetrulo, C., Isner, J.M., Losordo, D.W., 1997. Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: balance between growth and death signals. J. Mol. Cell. Cardiol. 29(5), 1321–1330. CrossRefGoogle Scholar
  60. Stewart, M., Turley, H., Cook, N., Pezzella, F., Pillai, G., Ogilvie, D., Cartlidge, S., Paterson, D., Copley, C., Kendrew, J., Barnes, C., Harris, A.L., Gatter, K.C., 2003. The angiogenic receptor KDR is widely distributed in human tissues and tumours and relocates intracellularly on phosphorylation. An immunohistochemical study. Histopathology 43(1), 33–39. CrossRefGoogle Scholar
  61. Strieter, R.M., Kunkel, S.L., Elner, V.M., Martonyi, C.L., Koch, A.E., Polverini, P.J., Elner, S.G., 1992. Interleukin-8. A corneal factor that induces neovascularization. Am. J. Pathol. 141(6), 1279–1284. Google Scholar
  62. Tee, D., DiStefano, J., 2004. Simulation of tumor-induced angiogenesis and its response to anti-angiogenic drug treatment: mode of drug delivery and clearance rate dependencies. J. Cancer Res. Clinical Oncol. 130(1), 15–24. CrossRefGoogle Scholar
  63. Terranova, V.P., DiFlorio, R., Lyall, R.M., Hic, S., Friesel, R., Maciag, T., 1985. Human endothelial cells are chemotactic to endothelial cell growth factor and heparin. J. Cell. Biol. 101(6), 2330–2334. CrossRefGoogle Scholar
  64. Trettel, F., Di Bartolomeo, S., Lauro, C., Catalano, M., Ciotti, M.T., Limatola, C., 2003. Ligand-independent CXCR2 dimerization. J. Biol. Chem. 278(42), 40980–40988. CrossRefGoogle Scholar
  65. Ueno, H., Li, J.J., Masuda, S., Qi, Z., Yamamoto, H., Takeshita, A., 1997. Adenovirus-mediated expression of the secreted form of basic fibroblast growth factor (FGF-2) induces cellular proliferation and angiogenesis in vivo. Arterioscler. Thromb. Vasc. Biol. 17(11), 2453–2460. Google Scholar
  66. Wang, D., Lehman, R.E., Donner, D.B., Matli, M.R., Warren, R.S., Welton, M.L., 2002. Expression and endocytosis of VEGF and its receptors in human colonic vascular endothelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282(6), G1088–G1096. Google Scholar
  67. Ward, J.P., King, J.R., 1999. Mathematical modelling of avascular-tumour growth. II: Modelling growth saturation. IMA J. Math. Appl. Med. Biol. 16(2), 171–211. zbMATHCrossRefGoogle Scholar
  68. Wilson, S., Wilkinson, G., Milligan, G., 2005. The CXCR1 and CXCR2 receptors form constitutive homo- and heterodimers selectively and with equal apparent affinities. J. Biol. Chem. 280(31), 28663–28674. CrossRefGoogle Scholar
  69. Yonekura, K., Basaki, Y., Chikahisa, L., 1999. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin. Cancer Res. 5(8), 2185–2191. Google Scholar

Copyright information

© Society for Mathematical Biology 2007

Authors and Affiliations

  • Harsh V. Jain
    • 1
  • Jacques E. Nör
    • 2
  • Trachette L. Jackson
    • 1
    Email author
  1. 1.Department of MathematicsUniversity of MichiganAnn ArborUSA
  2. 2.Departments of CariologyRestorative Sciences, and Endontics, University of MichiganAnn ArborUSA

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