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Angiogenic Signaling and Structural Abnormalities in Tumors

  • Magdalena Tertil
  • Klaudia Skrzypek
  • Agnieszka ŁobodaEmail author
Chapter

Abstract

Growing tumor needs to be supplied with oxygen and nutrients; hence, the mechanisms responsible for development of new blood vessels are crucial for tumor progression. Enhanced expression of proangiogenic factors enables development of tumor vasculature and subsequent invasion of tumor cells. The key step in these events is decreased oxygen tension within the growing tumor due to limited oxygen diffusion within the tissue. Apart from canonical hypoxic signaling, there are numerous molecular pathways that may modulate angiogenic secretome of cancer cells, such as the action of angiogenic enzymes and microRNAs. Besides tumor cells, also other cellular components of tumor microenvironment play an important role in stimulation of endothelium, out of which the key players are different populations of bone marrow-derived cells of myeloid origin.

Overstimulation of endothelial cells leads to development of abnormal vasculature that may be further disorganized by adaptation of alternative mechanisms of vascularization such as vessel co-option, intussusceptive microvascular growth or glomeruloid angiogenesis. Several tumor types are also capable of forming functional vessel-like structures lined with cancer cells by means of vasculogenic mimicry.

The understanding of the complexity and the diversity of the factors leading to tumor development as well as the unique structural adaptation of tumor microvessels to form functional vasculature may be helpful for the establishing potent antitumor therapies.

Keywords

Neovascularization Hypoxia Tumor-associated macrophages Chemokines microRNA miR-378 

Notes

Acknowledgments

AL is supported by the Foundation for Polish Science—PARENT-BRIDGE Programme cofinanced by the European Union within European Regional Development Fund (POMOST/2010-2/8) and she is the recipient of L'Oreal Poland for Women in Science Scholarship. The Faculty of Biochemistry, Biophysics, and Biotechnology of the Jagiellonian University is a beneficiary of the structural funds from the European Union and the Polish Ministry of Science and Higher Education (grants No: POIG.02.01.00-12 064/08, POIG 01.01.02-00-109/09, POIG.02.02.00-014/08 and 01.01.02-00-069/09).

References

  1. 1.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186PubMedGoogle Scholar
  2. 2.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedGoogle Scholar
  3. 3.
    Rak J, Yu JL, Klement G, Kerbel RS (2000) Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Investig Dermatol Symp Proc 5(1):24–33PubMedGoogle Scholar
  4. 4.
    Rak J, Mitsuhashi Y, Sheehan C, Tamir A, Viloria-Petit A, Filmus J, Mansour SJ, Ahn NG, Kerbel RS (2000) Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res 60(2):490–498PubMedGoogle Scholar
  5. 5.
    Okada F, Rak JW, Croix BS, Lieubeau B, Kaya M, Roncari L, Shirasawa S, Sasazuki T, Kerbel RS (1998) Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc Natl Acad Sci USA 95(7):3609–3614PubMedGoogle Scholar
  6. 6.
    Mezquita P, Parghi SS, Brandvold KA, Ruddell A (2005) Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation. Oncogene 24(5):889–901PubMedGoogle Scholar
  7. 7.
    Zhang Y, Wang L, Zhang M, Jin M, Bai C, Wang X (2012) Potential mechanism of interleukin-8 production from lung cancer cells: an involvement of EGF-EGFR-PI3K-Akt-Erk pathway. J Cell Physiol 227(1):35–43PubMedGoogle Scholar
  8. 8.
    Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578PubMedGoogle Scholar
  9. 9.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676PubMedGoogle Scholar
  10. 10.
    Nakashima T, Huang CL, Liu D, Kameyama K, Masuya D, Ueno M, Haba R, Yokomise H (2004) Expression of vascular endothelial growth factor-A and vascular endothelial growth factor-C as prognostic factors for non-small cell lung cancer. Med Sci Monit 10(6):BR157–BR165PubMedGoogle Scholar
  11. 11.
    Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC (2001) Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 19(2):432–441PubMedGoogle Scholar
  12. 12.
    Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10(3):165–177PubMedGoogle Scholar
  13. 13.
    Holopainen T, Huang H, Chen C, Kim KE, Zhang L, Zhou F, Han W, Li C, Yu J, Wu J, Koh GY, Alitalo K, He Y (2009) Angiopoietin-1 overexpression modulates vascular endothelium to facilitate tumor cell dissemination and metastasis establishment. Cancer Res 69(11):4656–4664PubMedGoogle Scholar
  14. 14.
    Saharinen P, Bry M, Alitalo K (2010) How do angiopoietins Tie in with vascular endothelial growth factors? Curr Opin Hematol 17(3):198–205PubMedGoogle Scholar
  15. 15.
    Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K (2011) VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 17(7):347–362PubMedGoogle Scholar
  16. 16.
    Nasarre P, Thomas M, Kruse K, Helfrich I, Wolter V, Deppermann C, Schadendorf D, Thurston G, Fiedler U, Augustin HG (2009) Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res 69(4):1324–1333PubMedCentralPubMedGoogle Scholar
  17. 17.
    Cao Y, Cao R, Hedlund EM (2008) Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl) 86(7):785–789Google Scholar
  18. 18.
    Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16(2):159–178PubMedGoogle Scholar
  19. 19.
    Lindner V, Majack RA, Reidy MA (1990) Basic fibroblast growth factor stimulates endothelial regrowth and proliferation in denuded arteries. J Clin Invest 85(6):2004–2008PubMedCentralPubMedGoogle Scholar
  20. 20.
    Korc M, Friesel RE (2009) The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 9(5):639–651PubMedCentralPubMedGoogle Scholar
  21. 21.
    Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8(3):235–253PubMedCentralPubMedGoogle Scholar
  22. 22.
    Zlotnik A, Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12(2):121–127PubMedGoogle Scholar
  23. 23.
    Thelen M, Stein JV (2008) How chemokines invite leukocytes to dance. Nat Immunol 9(9):953–959PubMedGoogle Scholar
  24. 24.
    Keeley EC, Mehrad B, Strieter RM (2011) Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res 317(5):685–690PubMedCentralPubMedGoogle Scholar
  25. 25.
    Strieter RM, Burdick MD, Gomperts BN, Belperio JA, Keane MP (2005) CXC chemokines in angiogenesis. Cytokine Growth Factor Rev 16(6):593–609PubMedGoogle Scholar
  26. 26.
    Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ (2000) Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96(1):34–40PubMedGoogle Scholar
  27. 27.
    Klimova T, Chandel NS (2008) Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ 15(4):660–666PubMedGoogle Scholar
  28. 28.
    Page EL, Chan DA, Giaccia AJ, Levine M, Richard DE (2008) Hypoxia-inducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion. Mol Biol Cell 19(1):86–94PubMedCentralPubMedGoogle Scholar
  29. 29.
    Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85(4):241–272PubMedGoogle Scholar
  30. 30.
    Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, Ku SK, Jung Y, Kwak MK (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res 71(6):2260–2275PubMedGoogle Scholar
  31. 31.
    Zhang X, Chen X, Song H, Chen HZ, Rovin BH (2005) Activation of the Nrf2/antioxidant response pathway increases IL-8 expression. Eur J Immunol 35(11):3258–3267PubMedGoogle Scholar
  32. 32.
    Loboda A, Stachurska A, Florczyk U, Rudnicka D, Jazwa A, Wegrzyn J, Kozakowska M, Stalinska K, Poellinger L, Levonen AL, Yla-Herttuala S, Jozkowicz A, Dulak J (2009) HIF-1 induction attenuates Nrf2-dependent IL-8 expression in human endothelial cells. Antioxid Redox Signal 11(7):1501–1517PubMedGoogle Scholar
  33. 33.
    Florczyk U, Czauderna S, Stachurska A, Tertil M, Nowak W, Kozakowska M, Poellinger L, Jozkowicz A, Loboda A, Dulak J (2011) Opposite effects of HIF-1alpha and HIF-2alpha on the regulation of IL-8 expression in endothelial cells. Free Radic Biol Med 51(10):1882–1892PubMedCentralPubMedGoogle Scholar
  34. 34.
    Singh S, Wu S, Varney M, Singh AP, Singh RK (2011) CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation. Microvasc Res 82(3):318–325PubMedCentralPubMedGoogle Scholar
  35. 35.
    Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang X, Zimmer MA, Iliopoulos O, Zukerberg LR, Kohgo Y, Lynch MP, Rueda BR, Chung DC (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11(9):992–997PubMedGoogle Scholar
  36. 36.
    Zhou S, Ye W, Zhang M, Liang J (2012) The effects of nrf2 on tumor angiogenesis: a review of the possible mechanisms of action. Crit Rev Eukaryot Gene Expr 22(2):149–160PubMedGoogle Scholar
  37. 37.
    Torisu-Itakura H, Furue M, Kuwano M, Ono M (2000) Co-expression of thymidine phosphorylase and heme oxygenase-1 in macrophages in human malignant vertical growth melanomas. Jpn J Cancer Res 91(9):906–910PubMedGoogle Scholar
  38. 38.
    Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, Kuwano M (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5(5):1107–1113PubMedGoogle Scholar
  39. 39.
    Skrzypek KTM, Golda S, Ciesla M, Weglarczyk K, Collet G, Guichard A, Kozakowska M, Boczkowski J, Was H, Gil T, Kuzdzal J, Muchova L, Vitek L, Loboda A, Jozkowicz A, Kieda C, Dulak J (2013) Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization and metastasis. Antioxid Redox Signal 19(7):644–660PubMedGoogle Scholar
  40. 40.
    Friedkin M, Roberts D (1954) The enzymatic synthesis of nucleosides. I. Thymidine phosphorylase in mammalian tissue. J Biol Chem 207(1):245–256PubMedGoogle Scholar
  41. 41.
    Miyazono K, Okabe T, Urabe A, Takaku F, Heldin CH (1987) Purification and properties of an endothelial cell growth factor from human platelets. J Biol Chem 262(9):4098–4103PubMedGoogle Scholar
  42. 42.
    Liekens S, Bilsen F, De Clercq E, Priego EM, Camarasa MJ, Perez-Perez MJ, Balzarini J (2002) Anti-angiogenic activity of a novel multi-substrate analogue inhibitor of thymidine phosphorylase. FEBS Lett 510(1–2):83–88PubMedGoogle Scholar
  43. 43.
    Miyadera K, Sumizawa T, Haraguchi M, Yoshida H, Konstanty W, Yamada Y, Akiyama S (1995) Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res 55(8):1687–1690PubMedGoogle Scholar
  44. 44.
    Uchimiya H, Furukawa T, Okamoto M, Nakajima Y, Matsushita S, Ikeda R, Gotanda T, Haraguchi M, Sumizawa T, Ono M, Kuwano M, Kanzaki T, Akiyama S (2002) Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose. Cancer Res 62(10):2834–2839PubMedGoogle Scholar
  45. 45.
    Moghaddam A, Zhang HT, Fan TP, Hu DE, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R (1995) Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci USA 92(4):998–1002PubMedGoogle Scholar
  46. 46.
    Haraguchi M, Miyadera K, Uemura K, Sumizawa T, Furukawa T, Yamada K, Akiyama S, Yamada Y (1994) Angiogenic activity of enzymes. Nature 368(6468):198PubMedGoogle Scholar
  47. 47.
    Sengupta S, Sellers LA, Matheson HB, Fan TP (2003) Thymidine phosphorylase induces angiogenesis in vivo and in vitro: an evaluation of possible mechanisms. Br J Pharmacol 139(2):219–231PubMedGoogle Scholar
  48. 48.
    Stevenson DP, Collins WP, Farzaneh F, Hata K, Miyazaki K (1998) Thymidine phosphorylase activity and prodrug effects in a three-dimensional model of angiogenesis: implications for the treatment of ovarian cancer. Am J Pathol 153(5):1573–1578PubMedGoogle Scholar
  49. 49.
    Bronckaers A, Gago F, Balzarini J, Liekens S (2009) The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med Res Rev 29(6):903–953PubMedGoogle Scholar
  50. 50.
    Akiyama S, Furukawa T, Sumizawa T, Takebayashi Y, Nakajima Y, Shimaoka S, Haraguchi M (2004) The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression. Cancer Sci 95(11):851–857PubMedGoogle Scholar
  51. 51.
    Brown NS, Jones A, Fujiyama C, Harris AL, Bicknell R (2000) Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res 60(22):6298–6302PubMedGoogle Scholar
  52. 52.
    Brown NS, Streeter EH, Jones A, Harris AL, Bicknell R (2005) Cooperative stimulation of vascular endothelial growth factor expression by hypoxia and reactive oxygen species: the effect of targeting vascular endothelial growth factor and oxidative stress in an orthotopic xenograft model of bladder carcinoma. Br J Cancer 92(9):1696–1701PubMedCentralPubMedGoogle Scholar
  53. 53.
    Volm M, Mattern J, Koomagi R (1998) Expression of platelet-derived endothelial cell growth factor in non-small cell lung carcinomas: relationship to various biological factors. Int J Oncol 13(5):975–979PubMedGoogle Scholar
  54. 54.
    Bijnsdorp IV, Capriotti F, Kruyt FA, Losekoot N, Fukushima M, Griffioen AW, Thijssen VL, Peters GJ (2011) Thymidine phosphorylase in cancer cells stimulates human endothelial cell migration and invasion by the secretion of angiogenic factors. Br J Cancer 104(7):1185–1192PubMedCentralPubMedGoogle Scholar
  55. 55.
    Tabata S, Ikeda R, Yamamoto M, Furukawa T, Kuramoto T, Takeda Y, Yamada K, Haraguchi M, Nishioka Y, Sone S, Akiyama S (2012) Thymidine phosphorylase enhances reactive oxygen species generation and interleukin-8 expression in human cancer cells. Oncol Rep 28(3):895–902PubMedGoogle Scholar
  56. 56.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99(24):15524–15529PubMedGoogle Scholar
  57. 57.
    Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1(12):882–891PubMedGoogle Scholar
  58. 58.
    Ciesla M, Skrzypek K, Kozakowska M, Loboda A, Jozkowicz A, Dulak J (2011) MicroRNAs as biomarkers of disease onset. Anal Bioanal Chem 401(7):2051–2061PubMedGoogle Scholar
  59. 59.
    Wang S, Olson EN (2009) AngiomiRs – key regulators of angiogenesis. Curr Opin Genet Dev 19(3):205–211PubMedCentralPubMedGoogle Scholar
  60. 60.
    Sun CY, She XM, Qin Y, Chu ZB, Chen L, Ai LS, Zhang L, Hu Y (2013) miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF. Carcinogenesis 34(2):426–435PubMedGoogle Scholar
  61. 61.
    He J, Jing Y, Li W, Qian X, Xu Q, Li FS, Liu LZ, Jiang BH, Jiang Y (2013) Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis. PLoS One 8(2):e56647PubMedCentralPubMedGoogle Scholar
  62. 62.
    Choi YC, Yoon S, Jeong Y, Yoon J, Baek K (2011) Regulation of vascular endothelial growth factor signaling by miR-200b. Mol Cells 32(1):77–82PubMedGoogle Scholar
  63. 63.
    Hua Z, Lv Q, Ye W, Wong CK, Cai G, Gu D, Ji Y, Zhao C, Wang J, Yang BB, Zhang Y (2006) MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS One 1:e116PubMedCentralPubMedGoogle Scholar
  64. 64.
    Lee DY, Deng Z, Wang CH, Yang BB (2007) MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc Natl Acad Sci USA 104(51):20350–20355PubMedGoogle Scholar
  65. 65.
    Pola R, Ling LE, Silver M, Corbley MJ, Kearney M, Blake Pepinsky R, Shapiro R, Taylor FR, Baker DP, Asahara T, Isner JM (2001) The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 7(6):706–711PubMedGoogle Scholar
  66. 66.
    Chen LT, Xu SD, Xu H, Zhang JF, Ning JF, Wang SF (2012) MicroRNA-378 is associated with non-small cell lung cancer brain metastasis by promoting cell migration, invasion and tumor angiogenesis. Med Oncol 29(3):1673–1680PubMedGoogle Scholar
  67. 67.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631PubMedGoogle Scholar
  68. 68.
    Coffelt SB, Lewis CE, Naldini L, Brown JM, Ferrara N, De Palma M (2010) Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am J Pathol 176(4):1564–1576PubMedGoogle Scholar
  69. 69.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555PubMedGoogle Scholar
  70. 70.
    Allavena P, Mantovani A (2012) Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 167(2):195–205PubMedCentralPubMedGoogle Scholar
  71. 71.
    Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193(6):727–740PubMedCentralPubMedGoogle Scholar
  72. 72.
    Biswas SK, Lewis CE (2010) NF-kappaB as a central regulator of macrophage function in tumors. J Leukoc Biol 88(5):877–884PubMedGoogle Scholar
  73. 73.
    Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9(5):361–371PubMedGoogle Scholar
  74. 74.
    Li N, Grivennikov SI, Karin M (2011) The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 19(4):429–431PubMedCentralPubMedGoogle Scholar
  75. 75.
    De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211–226PubMedGoogle Scholar
  76. 76.
    Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y, Lewis CE (2010) Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 70(13):5270–5280PubMedGoogle Scholar
  77. 77.
    Kostoulas G, Lang A, Nagase H, Baici A (1999) Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases. FEBS Lett 455(3):286–290PubMedGoogle Scholar
  78. 78.
    Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr + CD11b + cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421PubMedGoogle Scholar
  79. 79.
    Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13(3):206–220PubMedCentralPubMedGoogle Scholar
  80. 80.
    Bekes EM, Schweighofer B, Kupriyanova TA, Zajac E, Ardi VC, Quigley JP, Deryugina EI (2011) Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol 179(3):1455–1470PubMedGoogle Scholar
  81. 81.
    Ardi VC, Van den Steen PE, Opdenakker G, Schweighofer B, Deryugina EI, Quigley JP (2009) Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathway. J Biol Chem 284(38):25854–25866PubMedGoogle Scholar
  82. 82.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275(5302):964–967PubMedGoogle Scholar
  83. 83.
    Jung SY, Choi JH, Kwon SM, Masuda H, Asahara T, Lee YM (2012) Decursin inhibits vasculogenesis in early tumor progression by suppression of endothelial progenitor cell differentiation and function. J Cell Biochem 113(5):1478–1487PubMedGoogle Scholar
  84. 84.
    Liang PH, Tian F, Lu Y, Duan B, Stolz DB, Li LY (2011) Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors. Angiogenesis 14(1):61–68PubMedCentralPubMedGoogle Scholar
  85. 85.
    Purhonen S, Palm J, Rossi D, Kaskenpaa N, Rajantie I, Yla-Herttuala S, Alitalo K, Weissman IL, Salven P (2008) Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 105(18):6620–6625PubMedGoogle Scholar
  86. 86.
    Yoder MC (2009) Defining human endothelial progenitor cells. J Thromb Haemost 7(Suppl 1):49–52PubMedGoogle Scholar
  87. 87.
    Li Calzi S, Neu MB, Shaw LC, Kielczewski JL, Moldovan NI, Grant MB (2010) EPCs and pathological angiogenesis: when good cells go bad. Microvasc Res 79(3):207–216PubMedGoogle Scholar
  88. 88.
    Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V (2008) Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319(5860):195–198PubMedGoogle Scholar
  89. 89.
    Fleitas T, Martinez-Sales V, Gomez-Codina J, Martin M, Reynes G (2010) Circulating endothelial and endothelial progenitor cells in non-small-cell lung cancer. Clin Transl Oncol 12(8):521–525PubMedGoogle Scholar
  90. 90.
    Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EG, Walenkamp AM (2013) A review on CXCR4/CXCL12 axis in oncology: no place to hide. Eur J Cancer 49(1):219–230PubMedGoogle Scholar
  91. 91.
    Song C, Li G (2011) CXCR4 and matrix metalloproteinase-2 are involved in mesenchymal stromal cell homing and engraftment to tumors. Cytotherapy 13(5):549–561PubMedGoogle Scholar
  92. 92.
    Beckermann BM, Kallifatidis G, Groth A, Frommhold D, Apel A, Mattern J, Salnikov AV, Moldenhauer G, Wagner W, Diehlmann A, Saffrich R, Schubert M, Ho AD, Giese N, Buchler MW, Friess H, Buchler P, Herr I (2008) VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 99(4):622–631PubMedCentralPubMedGoogle Scholar
  93. 93.
    Allen M, Louise Jones J (2010) Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol 223(2):162–176PubMedGoogle Scholar
  94. 94.
    Ishikawa S, Takenaka K, Yanagihara K, Miyahara R, Kawano Y, Otake Y, Hasegawa S, Wada H, Tanaka F (2004) Matrix metalloproteinase-2 status in stromal fibroblasts, not in tumor cells, is a significant prognostic factor in non-small-cell lung cancer. Clin Cancer Res 10(19):6579–6585PubMedGoogle Scholar
  95. 95.
    Mishra P, Banerjee D, Ben-Baruch A (2011) Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy. J Leukoc Biol 89(1):31–39PubMedGoogle Scholar
  96. 96.
    Burger JA, Stewart DJ, Wald O, Peled A (2011) Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev Anticancer Ther 11(4):621–630PubMedGoogle Scholar
  97. 97.
    Wald O, Izhar U, Amir G, Kirshberg S, Shlomai Z, Zamir G, Peled A, Shapira OM (2011) Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation. J Thorac Cardiovasc Surg 141(6):1503–1512PubMedGoogle Scholar
  98. 98.
    Imai H, Sunaga N, Shimizu Y, Kakegawa S, Shimizu K, Sano T, Ishizuka T, Oyama T, Saito R, Minna JD, Mori M (2010) Clinicopathological and therapeutic significance of CXCL12 expression in lung cancer. Int J Immunopathol Pharmacol 23(1):153–164PubMedCentralPubMedGoogle Scholar
  99. 99.
    Matsumoto K, Nakamura T (2006) Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int J Cancer 119(3):477–483PubMedGoogle Scholar
  100. 100.
    Kaga T, Kawano H, Sakaguchi M, Nakazawa T, Taniyama Y, Morishita R (2012) Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor. Vascul Pharmacol 57(1):3–9PubMedGoogle Scholar
  101. 101.
    Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P, Rosen EM (1993) Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci USA 90(5):1937–1941PubMedGoogle Scholar
  102. 102.
    Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12(2):89–103PubMedGoogle Scholar
  103. 103.
    Sulpice E, Ding S, Muscatelli-Groux B, Berge M, Han ZC, Plouet J, Tobelem G, Merkulova-Rainon T (2009) Cross-talk between the VEGF-A and HGF signalling pathways in endothelial cells. Biol Cell 101(9):525–539PubMedGoogle Scholar
  104. 104.
    Zhang YW, Su Y, Volpert OV, Vande Woude GF (2003) Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci USA 100(22):12718–12723PubMedGoogle Scholar
  105. 105.
    Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R, Karczmar G, Salgia R (2007) A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res 67(8):3529–3534PubMedGoogle Scholar
  106. 106.
    Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20(9):1487–1495PubMedGoogle Scholar
  107. 107.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659PubMedGoogle Scholar
  108. 108.
    Bussolati B, Grange C, Camussi G (2011) Tumor exploits alternative strategies to achieve vascularization. FASEB J 25(9):2874–2882PubMedGoogle Scholar
  109. 109.
    Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Zembala M (2007) Tumour-derived microvesicles modulate biological activity of human monocytes. Immunol Lett 113(2):76–82PubMedGoogle Scholar
  110. 110.
    Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71(15):5346–5356PubMedGoogle Scholar
  111. 111.
    Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, Ratajczak MZ (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113(5):752–760PubMedGoogle Scholar
  112. 112.
    Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T (2013) Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem 288(15):10849–10859PubMedGoogle Scholar
  113. 113.
    Zhuang G, Wu X, Jiang Z, Kasman I, Yao J, Guan Y, Oeh J, Modrusan Z, Bais C, Sampath D, Ferrara N (2012) Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J 31(17):3513–3523PubMedGoogle Scholar
  114. 114.
    De Bock K, Cauwenberghs S, Carmeliet P (2011) Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications. Curr Opin Genet Dev 21(1):73–79PubMedGoogle Scholar
  115. 115.
    Ribatti D, Nico B, Crivellato E, Vacca A (2007) The structure of the vascular network of tumors. Cancer Lett 248(1):18–23PubMedGoogle Scholar
  116. 116.
    Less JR, Posner MC, Skalak TC, Wolmark N, Jain RK (1997) Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation 4(1):25–33PubMedGoogle Scholar
  117. 117.
    Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133(1):95–109PubMedGoogle Scholar
  118. 118.
    Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, Klagsbrun M (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64(22):8249–8255PubMedGoogle Scholar
  119. 119.
    Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48(10):2641–2658PubMedGoogle Scholar
  120. 120.
    Lunt SJ, Chaudary N, Hill RP (2009) The tumor microenvironment and metastatic disease. Clin Exp Metastasis 26(1):19–34PubMedGoogle Scholar
  121. 121.
    Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379(6560):88–91PubMedGoogle Scholar
  122. 122.
    Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8(3):180–192PubMedGoogle Scholar
  123. 123.
    Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95PubMedGoogle Scholar
  124. 124.
    Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120(1):127–141PubMedCentralPubMedGoogle Scholar
  125. 125.
    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3(4):347–361PubMedGoogle Scholar
  126. 126.
    Chang Q, Jurisica I, Do T, Hedley DW (2011) Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res 71(8):3110–3120PubMedGoogle Scholar
  127. 127.
    Wang Y, Ohh M (2010) Oxygen-mediated endocytosis in cancer. J Cell Mol Med 14(3):496–503PubMedGoogle Scholar
  128. 128.
    Jiang J, Tang YL, Liang XH (2011) EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther 11(8):714–723PubMedGoogle Scholar
  129. 129.
    Yotnda P, Wu D, Swanson AM (2010) Hypoxic tumors and their effect on immune cells and cancer therapy. Methods Mol Biol 651:1–29PubMedGoogle Scholar
  130. 130.
    Alison MR, Lim SM, Nicholson LJ (2010) Cancer stem cells: problems for therapy? J Pathol 223(2):147–161PubMedGoogle Scholar
  131. 131.
    Leite de Oliveira R, Deschoemaeker S, Henze AT, Debackere K, Finisguerra V, Takeda Y, Roncal C, Dettori D, Tack E, Jonsson Y, Veschini L, Peeters A, Anisimov A, Hofmann M, Alitalo K, Baes M, D’Hooge J, Carmeliet P, Mazzone M (2012) Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell 22(2):263–277PubMedGoogle Scholar
  132. 132.
    Dome B, Hendrix MJ, Paku S, Tovari J, Timar J (2007) Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am J Pathol 170(1):1–15PubMedGoogle Scholar
  133. 133.
    Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1(2):149–153PubMedGoogle Scholar
  134. 134.
    Pezzella F, Pastorino U, Tagliabue E, Andreola S, Sozzi G, Gasparini G, Menard S, Gatter KC, Harris AL, Fox S, Buyse M, Pilotti S, Pierotti M, Rilke F (1997) Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. Am J Pathol 151(5):1417–1423PubMedGoogle Scholar
  135. 135.
    Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422):1994–1998PubMedGoogle Scholar
  136. 136.
    Hillen F, Griffioen AW (2007) Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 26(3–4):489–502PubMedCentralPubMedGoogle Scholar
  137. 137.
    Djonov VG, Kurz H, Burri PH (2002) Optimality in the developing vascular system: branching remodeling by means of intussusception as an efficient adaptation mechanism. Dev Dyn 224(4):391–402PubMedGoogle Scholar
  138. 138.
    Kurz H, Burri PH, Djonov VG (2003) Angiogenesis and vascular remodeling by intussusception: from form to function. News Physiol Sci 18:65–70PubMedGoogle Scholar
  139. 139.
    Dome B, Timar J, Paku S (2003) A novel concept of glomeruloid body formation in experimental cerebral metastases. J Neuropathol Exp Neurol 62(6):655–661PubMedGoogle Scholar
  140. 140.
    Straume O, Akslen LA (2003) Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma. Angiogenesis 6(4):295–301PubMedGoogle Scholar
  141. 141.
    Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR, Begin LR, Foulkes WD, Akslen LA (2002) Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62(23):6808–6811PubMedGoogle Scholar
  142. 142.
    Nagy JA, Dvorak HF (2012) Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets. Clin Exp Metastasis 29(7):657–662PubMedCentralPubMedGoogle Scholar
  143. 143.
    Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF (2010) Heterogeneity of the tumor vasculature. Semin Thromb Hemost 36(3):321–331PubMedCentralPubMedGoogle Scholar
  144. 144.
    Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155(3):739–752PubMedGoogle Scholar
  145. 145.
    Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, Hendrix MJ (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181(4):1115–1125PubMedGoogle Scholar
  146. 146.
    Ruf W, Seftor EA, Petrovan RJ, Weiss RM, Gruman LM, Margaryan NV, Seftor RE, Miyagi Y, Hendrix MJ (2003) Differential role of tissue factor pathway inhibitors 1 and 2 in melanoma vasculogenic mimicry. Cancer Res 63(17):5381–5389PubMedGoogle Scholar
  147. 147.
    Hendrix MJ, Seftor RE, Seftor EA, Gruman LM, Lee LM, Nickoloff BJ, Miele L, Sheriff DD, Schatteman GC (2002) Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res 62(3):665–668PubMedGoogle Scholar
  148. 148.
    Frenkel S, Barzel I, Levy J, Lin AY, Bartsch DU, Majumdar D, Folberg R, Pe’er J (2008) Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography. Eye (Lond) 22(7):948–952Google Scholar
  149. 149.
    Hendrix MJ, Seftor EA, Hess AR, Seftor RE (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3(6):411–421PubMedGoogle Scholar
  150. 150.
    Kirschmann DA, Seftor EA, Hardy KM, Seftor RE, Hendrix MJ (2012) Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res 18(10):2726–2732PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • Magdalena Tertil
    • 1
    • 2
  • Klaudia Skrzypek
    • 1
    • 3
  • Agnieszka Łoboda
    • 1
    Email author
  1. 1.Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityKrakówPoland
  2. 2.Department of Molecular NeuropharmacologyInstitute of Pharmacology, Polish Academy of SciencesKrakówPoland
  3. 3.Department of TransplantationPolish-American Institute of Pediatrics, Jagiellonian University Medical CollegeKrakówPoland

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