Advertisement

Angiogenesis – Vessels Recruitment by Tumor Cells

  • Ana MagalhãesEmail author
  • Sergio Dias
Chapter
Part of the Learning Materials in Biosciences book series (LMB)

Abstract

In this chapter you will learn that tumor blood vessels play important roles in tumor progression and that targeting the tumor vasculature is an alternative cancer therapy. Blood vessels are formed by endothelial cells organized in a monolayer, attached to a basement membrane and covered by pericytes. In general, endothelial cells are adherent to each other through molecular complexes that form the adherens and tight junctions. Such adhesion complexes guarantee the barrier function of the endothelial monolayer, crucial for the regulated transport of molecules and cells between the blood and the tissue and vice-versa. Blood vessels are essential for cell survival as they bring oxygen and nutrients to cells and also participate in the transport of waste products away from tissues. In that sense, as tumors grow, through the rapid proliferation of tumor cells, they require the formation of a new vasculature that irrigates the cells. Without a new vasculature, tumor cells are too far away from a vascular bed, which results in hypoxia and nutrient starvation. These are believed to be the main triggers of new blood vessel formation. The formation of a new blood vessel from a pre-existing one is called angiogenesis and is the main type of blood vessel formation that takes place in tumors. However, other ways to ensure blood deliver to tumor cells have been described. Angiogenesis also occurs in physiological conditions such as during development and wound closure and several cellular and molecular mechanisms that govern it have been elucidated. The most common experimental models used to study physiological angiogenesis are the mouse retina, the transparent zebrafish and human endothelial cells cultured in in vitro systems. The vascular Endothelial Growth Factor (VEGF) is the main signaling molecule that regulates angiogenesis, although several other pro- and anti-angiogenic stimuli exist. In tumors, due to an imbalance of such stimuli, angiogenesis is abnormal, resulting in a disorganized and leaky vascular network. The abnormal nature of the tumor vasculature plays critical roles in cancer progression, in particular its inadequate ability to ensure the barrier function of the vessels has several pathological consequences and is an obstacle to the delivery of therapeutic drugs to tumors. Abnormally permeable blood vessels allow the uncontrolled movement of molecules, extracellular vesicles and cells, in and out of the tumor. This is the starting point for cancer to become a systemic disease. Through leaky blood vessels, tumors send signals to distant tissues, recruit and control immune response and invade the blood through a process called intravasation. Targeting blood vascular formation in tumors or its interaction with tumor and immune cells, or instead, normalize the otherwise abnormal tumor vessels, are alternatives for anti-cancer therapies.

References

  1. 1.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186.  https://doi.org/10.1056/NEJM197111182852108 CrossRefPubMedGoogle Scholar
  2. 2.
    Ribatti D (2008) Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis 11:3–10.  https://doi.org/10.1007/s10456-008-9092-6 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Carmeliet P, Jain RK (473, 2011) Molecular mechanisms and clinical applications of angiogenesis. Nature:298–307, doi:nature10144 [pii].  https://doi.org/10.1038/nature10144
  4. 4.
    Missiaen R, Morales-Rodriguez F, Eelen G, Carmeliet P (2017) Targeting endothelial metabolism for anti-angiogenesis therapy: a pharmacological perspective. Vascul Pharmacol 90:8–18, doi:S1537-1891(16)30376-7 [pii].  https://doi.org/10.1016/j.vph.2017.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417–427, doi:nrd3455 [pii].  https://doi.org/10.1038/nrd3455 CrossRefGoogle Scholar
  6. 6.
    Goel S et al (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91:1071–1121, doi:91/3/1071 [pii].  https://doi.org/10.1152/physrev.00038.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Butler JM, Kobayashi H, Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10:138–146, doi:nrc2791 [pii].  https://doi.org/10.1038/nrc2791 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hendry SA et al (2016) The role of the tumor vasculature in the host immune response: implications for therapeutic strategies targeting the tumor microenvironment. Front Immunol 7:621.  https://doi.org/10.3389/fimmu.2016.00621 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Eilken HM, Adams RH (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22:617–625, doi:S0955-0674(10)00133-X [pii].  https://doi.org/10.1016/j.ceb.2010.08.010 CrossRefGoogle Scholar
  10. 10.
    Ferrara N (2009) VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw 20:158–163, doi:ecn.2009.0170 [pii].  https://doi.org/10.1684/ecn.2009.0170 CrossRefGoogle Scholar
  11. 11.
    Nagy JA, Dvorak AM, Dvorak HF (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2:251–275.  https://doi.org/10.1146/annurev.pathol.2.010506.134925 CrossRefGoogle Scholar
  12. 12.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309CrossRefGoogle Scholar
  13. 13.
    Keck PJ et al (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312CrossRefGoogle Scholar
  14. 14.
    Senger DR et al (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985CrossRefGoogle Scholar
  15. 15.
    Terman BI et al (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586, doi:0006-291X(92)90483-2 [pii]CrossRefGoogle Scholar
  16. 16.
    Millauer B et al (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846, doi:0092-8674(93)90573-9 [pii]CrossRefGoogle Scholar
  17. 17.
    Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16:196–208, doi:S1534-5807(09)00043-4 [pii].  https://doi.org/10.1016/j.devcel.2009.01.015 CrossRefGoogle Scholar
  18. 18.
    Lohela M, Bry M, Tammela T, Alitalo K (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21:154–165, doi:S0955-0674(09)00013-1 [pii].  https://doi.org/10.1016/j.ceb.2008.12.012 CrossRefGoogle Scholar
  19. 19.
    Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476, doi:S0092-8674(10)00115-7 [pii].  https://doi.org/10.1016/j.cell.2010.01.045 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tammela T et al (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–660, doi:nature07083 [pii].  https://doi.org/10.1038/nature07083 CrossRefGoogle Scholar
  21. 21.
    Siekmann AF, Lawson ND (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445:781–784, doi:nature05577 [pii].  https://doi.org/10.1038/nature05577 CrossRefGoogle Scholar
  22. 22.
    Adams RH, Eichmann A (2010) Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol 2:a001875, doi:cshperspect.a001875 [pii].  https://doi.org/10.1101/cshperspect.a001875 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jones CA et al (2008) Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat Med 14:448–453, doi:nm1742 [pii].  https://doi.org/10.1038/nm1742 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Koch AW et al (2011) Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev Cell 20:33–46, doi:S1534-5807(10)00551-4 [pii].  https://doi.org/10.1016/j.devcel.2010.12.001 CrossRefGoogle Scholar
  25. 25.
    Larrivee B et al (2007) Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes Dev 21:2433–2447, doi:21/19/2433 [pii].  https://doi.org/10.1101/gad.437807 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wang B et al (2003) Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell 4:19–29, doi:S1535610803001648 [pii]CrossRefGoogle Scholar
  27. 27.
    Neufeld G, Sabag AD, Rabinovicz N, Kessler O (2012) Semaphorins in angiogenesis and tumor progression. Cold Spring Harb Perspect Med 2:a006718.  https://doi.org/10.1101/cshperspect.a006718. a006718 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Pan Q et al (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11:53–67, doi:S1535-6108(06)00367-9 [pii].  https://doi.org/10.1016/j.ccr.2006.10.018 CrossRefGoogle Scholar
  29. 29.
    Kessler O et al (2004) Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 64:1008–1015CrossRefGoogle Scholar
  30. 30.
    Sierra JR et al (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685, doi:jem.20072602 [pii].  https://doi.org/10.1084/jem.20072602 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS (2004) Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64:5212–5224.  https://doi.org/10.1158/0008-5472.CAN-04-0126. 64/15/5212 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52, doi:S0092-8674(08)00386-3 [pii].  https://doi.org/10.1016/j.cell.2008.03.011 CrossRefPubMedGoogle Scholar
  33. 33.
    Sawamiphak S et al (2010) Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465:487–491, doi:nature08995 [pii].  https://doi.org/10.1038/nature08995 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wang Y et al (2010) Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465:483–486, doi:nature09002 [pii].  https://doi.org/10.1038/nature09002 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fantin A et al (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116:829–840, doi:blood-2009-12-257832 [pii].  https://doi.org/10.1182/blood-2009-12-257832 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lammert E, Axnick J (2012) Vascular lumen formation. Cold Spring Harb Perspect Med 2:a006619.  https://doi.org/10.1101/cshperspect.a006619. a006619 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gebala V, Collins R, Geudens I, Phng LK, Gerhardt H (2016) Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo. Nat Cell Biol 18:443–450, doi:ncb3320 [pii].  https://doi.org/10.1038/ncb3320 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nicoli S et al (2010) MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 464:1196–1200, doi:nature08889 [pii].  https://doi.org/10.1038/nature08889 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gaengel K, Genove G, Armulik A, Betsholtz C (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638, doi:ATVBAHA.107.161521 [pii].  https://doi.org/10.1161/ATVBAHA.107.161521 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    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 10:165–177, doi:nrm2639 [pii].  https://doi.org/10.1038/nrm2639 CrossRefGoogle Scholar
  41. 41.
    Huang H, Bhat A, Woodnutt G, Lappe R (2010) Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer 10:575–585, doi:nrc2894 [pii].  https://doi.org/10.1038/nrc2894 CrossRefGoogle Scholar
  42. 42.
    Gridley T (2010) Notch signaling in the vasculature. Curr Top Dev Biol 92:277–309, doi:S0070-2153(10)92009-7 [pii].  https://doi.org/10.1016/S0070-2153(10)92009-7 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Pitulescu ME, Adams RH (2010) Eph/ephrin molecules--a hub for signaling and endocytosis. Genes Dev 24:2480–2492, doi:24/22/2480 [pii].  https://doi.org/10.1101/gad.1973910 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Korn C, Augustin HG (2015) Mechanisms of vessel pruning and regression. Dev Cell 34:5–17, doi:S1534-5807(15)00393-7 [pii].  https://doi.org/10.1016/j.devcel.2015.06.004 CrossRefGoogle Scholar
  45. 45.
    Ando J, Yamamoto K (2009) Vascular mechanobiology: endothelial cell responses to fluid shear stress. Circ J 73:1983–1992, doi:JST.JSTAGE/circj/CJ-09-0583 [pii]CrossRefGoogle Scholar
  46. 46.
    Kurz H, Burri PH, Djonov VG (2003) Angiogenesis and vascular remodeling by intussusception: from form to function. News Physiol Sci 18:65–70Google Scholar
  47. 47.
    Lyden D et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201.  https://doi.org/10.1038/nm1101-1194. nm1101-1194 [pii]CrossRefGoogle Scholar
  48. 48.
    Maniotis AJ et al (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155:739–752, doi:S0002-9440(10)65173-5 [pii].  https://doi.org/10.1016/S0002-9440(10)65173-5 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Seftor RE et al (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181:1115–1125, doi:S0002-9440(12)00578-0 [pii].  https://doi.org/10.1016/j.ajpath.2012.07.013 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Donnem T et al (2013) Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med 2:427–436.  https://doi.org/10.1002/cam4.105 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    De Bock K, Cauwenberghs S, Carmeliet P (2011) Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications. Curr Opin Genet Dev 21:73–79, doi:S0959-437X(10)00175-9 [pii].  https://doi.org/10.1016/j.gde.2010.10.008 CrossRefGoogle Scholar
  52. 52.
    Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31:2205–2218, doi:JCO.2012.46.3653 [pii].  https://doi.org/10.1200/JCO.2012.46.3653 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62, doi:307/5706/58 [pii].  https://doi.org/10.1126/science.1104819 CrossRefPubMedGoogle Scholar
  54. 54.
    Dejana E, Tournier-Lasserve E, Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16:209–221, doi:S1534–5807(09)00032-X [pii].  https://doi.org/10.1016/j.devcel.2009.01.004 CrossRefGoogle Scholar
  55. 55.
    Giannotta M, Trani M, Dejana E (2013) VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26:441–454, doi:S1534-5807(13)00507-8 [pii].  https://doi.org/10.1016/j.devcel.2013.08.020 CrossRefGoogle Scholar
  56. 56.
    Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8:1223–1234, doi:ncb1486 [pii].  https://doi.org/10.1038/ncb1486 CrossRefGoogle Scholar
  57. 57.
    Weis S, Cui J, Barnes L, Cheresh D (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167:223–229, doi:jcb.200408130 [pii].  https://doi.org/10.1083/jcb.200408130 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Ngok SP et al (2012) VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx. J Cell Biol 199:1103–1115, doi:jcb.201207009 [pii].  https://doi.org/10.1083/jcb.201207009 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Li X et al (2016) VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nat Commun 7:11017, doi:ncomms11017 [pii].  https://doi.org/10.1038/ncomms11017 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Reymond N, d'Agua BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870, doi:nrc3628 [pii].  https://doi.org/10.1038/nrc3628 CrossRefGoogle Scholar
  61. 61.
    Deryugina EI, Quigley JP (2008) Chick embryo chorioallantoic membrane model systems to study and visualize human tumor cell metastasis. Histochem Cell Biol 130:1119–1130.  https://doi.org/10.1007/s00418-008-0536-2 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Stoletov K, Montel V, Lester RD, Gonias SL, Klemke R (2007) High-resolution imaging of the dynamic tumor cell vascular interface in transparent zebrafish. Proc Natl Acad Sci U S A 104:17406–17411, doi:0703446104 [pii].  https://doi.org/10.1073/pnas.0703446104 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Deryugina EI, Kiosses WB (2017) Intratumoral cancer cell intravasation can occur independent of invasion into the adjacent stroma. Cell Rep 19:601–616, doi:S2211-1247(17)30425-4 [pii].  https://doi.org/10.1016/j.celrep.2017.03.064 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Harney AS et al (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation simulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5:932–943, doi:2159-8290.CD-15-0012 [pii].  https://doi.org/10.1158/2159-8290.CD-15-0012 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Wyckoff JB et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656, doi:67/6/2649 [pii].  https://doi.org/10.1158/0008-5472.CAN-06-1823 CrossRefGoogle Scholar
  66. 66.
    Anderberg C et al (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210:563–579, doi:jem.20120662 [pii].  https://doi.org/10.1084/jem.20120662 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Wieland E et al (2017) Endothelial notch1 activity facilitates metastasis. Cancer Cell 31:355–367, doi:S1535-6108(17)30007-7 [pii].  https://doi.org/10.1016/j.ccell.2017.01.007 CrossRefGoogle Scholar
  68. 68.
    Sonoshita M et al (2011) Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19:125–137, doi:S1535-6108(10)00473-3 [pii].  https://doi.org/10.1016/j.ccr.2010.11.008 CrossRefGoogle Scholar
  69. 69.
    Zang G et al (2015) Vascular dysfunction and increased metastasis of B16F10 melanomas in Shb deficient mice as compared with their wild type counterparts. BMC Cancer 15:234.  https://doi.org/10.1186/s12885-015-1269-y CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Ohga N et al (2012) Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high- and low-metastatic tumors. Am J Pathol 180:1294–1307, doi:S0002-9440(11)01107-2 [pii].  https://doi.org/10.1016/j.ajpath.2011.11.035 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Maishi N et al (2016) Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan. Sci Rep 6:28039, doi:srep28039 [pii].  https://doi.org/10.1038/srep28039 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7:678–689, doi:nri2156 [pii].  https://doi.org/10.1038/nri2156 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Griffioen AW et al (1998) The angiogenic factor bFGF impairs leukocyte adhesion and rolling under flow conditions. Angiogenesis 2:235–243, doi:191805 [pii].  https://doi.org/10.1023/A:1009237324501 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Griffioen AW, Damen CA, Blijham GH, Groenewegen G (1996) Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88:667–673PubMedPubMedCentralGoogle Scholar
  75. 75.
    Zhang H, Issekutz AC (2002) Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor: reversal by the anti-angiogenic agent SU6668. Am J Pathol 160:2219–2230, doi:S0002-9440(10)61169-8 [pii].  https://doi.org/10.1016/S0002-9440(10)61169-8 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Dirkx AE et al (2003) Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res 63:2322–2329PubMedPubMedCentralGoogle Scholar
  77. 77.
    Tromp SC et al (2000) Tumor angiogenesis factors reduce leukocyte adhesion in vivo. Int Immunol 12:671–676CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Karikoski M et al (2014) Clever-1/stabilin-1 controls cancer growth and metastasis. Clin Cancer Res 20:6452–6464, doi:1078-0432.CCR-14-1236 [pii].  https://doi.org/10.1158/1078-0432.CCR-14-1236 CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Motz GT et al (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20:607–615, doi:nm.3541 [pii].  https://doi.org/10.1038/nm.3541 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Instituto de Medicina Molecular – João Lobo AntunesLisbonPortugal
  2. 2.Faculdade de Medicina da Universidade de LisboaLisbonPortugal

Personalised recommendations