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Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases

Abstract

Despite having an abundant number of vessels, tumours are usually hypoxic and nutrient-deprived because their vessels malfunction. Such abnormal milieu can fuel disease progression and resistance to treatment. Traditional anti-angiogenesis strategies attempt to reduce the tumour vascular supply, but their success is restricted by insufficient efficacy or development of resistance. Preclinical and initial clinical evidence reveal that normalization of the vascular abnormalities is emerging as a complementary therapeutic paradigm for cancer and other vascular disorders, which affect more than half a billion people worldwide. Here, we discuss the mechanisms, benefits, limitations and possible clinical translation of vessel normalization for cancer and other angiogenic disorders.

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Figure 1: Tumour vessels are structurally and functionally abnormal.
Figure 2: Molecular changes leading to abnormal vessels.
Figure 3: Potential targets and strategies for vascular normalization.

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References

  1. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273–286 (2007).

    Article  CAS  Google Scholar 

  2. Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nature Med. 7, 987–989 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Baluk, P., Hashizume, H. & McDonald, D. M. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 15, 102–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Nagy, J. A., Chang, S. H., Shih, S. C., Dvorak, A. M. & Dvorak, H. F. Heterogeneity of the tumor vasculature. Semin. Thromb. Hemost. 36, 321–331 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  PubMed  Google Scholar 

  8. Crawford, Y. & Ferrara, N. VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res. 335, 261–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Ferrara, N. Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 21, 21–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592–603 (2008).

    Article  CAS  Google Scholar 

  12. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Padera, T. P. et al. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Ther. 7, 2272–2279 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Miles, D. et al. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J. Clin. Oncol. 29, 83–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Yuan, F. et al. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc. Natl Acad. Sci. USA 93, 14765–14770 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

    CAS  PubMed  Google Scholar 

  18. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Jain, R. K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 95, 10820–10825 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jain, R. K. Determinants of tumor blood flow: a review. Cancer Res. 48, 2641–2658 (1988).

    CAS  PubMed  Google Scholar 

  25. Pettersson, A. et al. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab. Invest. 80, 99–115 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Fukumura, D., Duda, D. G., Munn, L. L. & Jain, R. K. Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation 17, 206–225 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jain, R. K. & Styllanopoulos, T. Delivering nanomedicine to solid tumors. Nature Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  Google Scholar 

  28. Baluk, P., Morikawa, S., Haskell, A., Mancuso, M. & McDonald, D. M. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 163, 1801–1815 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Morikawa, S. et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 160, 985–1000 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ozawa, M. G. et al. Angiogenesis with pericyte abnormalities in a transgenic model of prostate carcinoma. Cancer 104, 2104–2115 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Van de Veire, S. et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141, 178–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Hagendoorn, J. et al. Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res. 66, 3360–3364 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, P. et al. In vivo wide-area cellular imaging by side-view endomicroscopy. Nature Methods 7, 303–305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Less, J. R., Posner, M. C., Skalak, T. C., Wolmark, N. & Jain, R. K. Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation 4, 25–33 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Rocha, S. F. & Adams, R. H. Molecular differentiation and specialization of vascular beds. Angiogenesis 12, 139–147 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Potenta, S., Zeisberg, E. & Kalluri, R. The role of endothelial-to-mesenchymal transition in cancer progression. Br. J. Cancer 99, 1375–1379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Langenkamp, E. & Molema, G. Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer. Cell Tissue Res. 335, 205–222 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Yang, Z. F. & Poon, R. T. Vascular changes in hepatocellular carcinoma. Anat. Rec. (Hoboken) 291, 721–734 (2008).

    Article  CAS  Google Scholar 

  42. Zhu, A. X., Duda, D. G., Sahani, D. V. & Jain, R. K. HCC and angiogenesis: possible targets and future directions. Nature Rev. Clin. Oncol. 8 Mar 2011 (doi:10.1038/nrclinonc.2011.30).

  43. Pries, A. R., Hopfner, M., le Noble, F., Dewhirst, M. W. & Secomb, T. W. The shunt problem: control of functional shunting in normal and tumour vasculature. Nature Rev. Cancer 10, 587–593 (2010).

    Article  CAS  Google Scholar 

  44. Diaz-Flores, L. et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol. Histopathol. 24, 909–969 (2009).

    CAS  PubMed  Google Scholar 

  45. Raza, A., Franklin, M. J. & Dudek, A. Z. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am. J. Hematol. 85, 593–598 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Gerhardt, H. & Semb, H. Pericytes: gatekeepers in tumour cell metastasis? J. Mol. Med. 86, 135–144 (2008).

    Article  PubMed  Google Scholar 

  47. Eble, J. A. & Niland, S. The extracellular matrix of blood vessels. Curr. Pharm. Des. 15, 1385–1400 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Boucher, Y. & Jain, R. K. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52, 5110–5114 (1992).

    CAS  PubMed  Google Scholar 

  49. Moeller, B. J., Richardson, R. A. & Dewhirst, M. W. Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev. 26, 241–248 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Padera, T. P. et al. Pathology: cancer cells compress intratumour vessels. Nature 427, 695 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Dewhirst, M. W. Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat. Res. 172, 653–665 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rey, S. & Semenza, G. L. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc. Res. 86, 236–242 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cardone, R. A., Casavola, V. & Reshkin, S. J. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nature Rev. Cancer 5, 786–795 (2005).

    Article  CAS  Google Scholar 

  54. Hunt, T. K., Aslam, R., Hussain, Z. & Beckert, S. Lactate, with oxygen, incites angiogenesis. Adv. Exp. Med. Biol. 614, 73–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nature Med. 16, 116–122 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Sullivan, R. & Graham, C. H. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 26, 319–331 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Lunt, S. J., Chaudary, N. & Hill, R. P. The tumor microenvironment and metastatic disease. Clin. Exp. Metastasis 26, 19–34 (2009).

    Article  PubMed  Google Scholar 

  58. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nature Rev. Immunol. 9, 609–617 (2009).

    Article  CAS  Google Scholar 

  61. Chung, A. S., Lee, J. & Ferrara, N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nature Rev. Cancer 10, 505–514 (2010).

    Article  CAS  Google Scholar 

  62. Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol. 2, 251–275 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Jain, R. K. Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nature Rev. Cancer 8, 309–316 (2008).

    Article  CAS  Google Scholar 

  64. Baffert, F. et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am. J. Physiol. Heart Circ. Physiol. 290, H547–H559 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Kamoun, W. S. et al. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J. Clin. Oncol. 27, 2542–2552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Greenberg, J. I. et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456, 809–813 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Abramovitch, R., Dafni, H., Smouha, E., Benjamin, L. E. & Neeman, M. In vivo prediction of vascular susceptibility to vascular endothelial growth factor withdrawal: magnetic resonance imaging of C6 rat glioma in nude mice. Cancer Res. 59, 5012–5016 (1999).

    CAS  PubMed  Google Scholar 

  68. Hedlund, E. M., Hosaka, K., Zhong, Z., Cao, R. & Cao, Y. Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature. Proc. Natl Acad. Sci. USA 106, 17505–17510 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Fischer, C., Mazzone, M., Jonckx, B. & Carmeliet, P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nature Rev. Cancer 8, 942–956 (2008).

    Article  CAS  Google Scholar 

  70. Vosseler, S., Mirancea, N., Bohlen, P., Mueller, M. M. & Fusenig, N. E. Angiogenesis inhibition by vascular endothelial growth factor receptor-2 blockade reduces stromal matrix metalloproteinase expression, normalizes stromal tissue, and reverts epithelial tumor phenotype in surface heterotransplants. Cancer Res. 65, 1294–1305 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Dickson, P. V. et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin. Cancer Res. 13, 3942–3950 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Tailor, T. D. et al. Effect of pazopanib on tumor microenvironment and liposome delivery. Mol. Cancer Ther. 9, 1798–1808 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Myers, A. L., Williams, R. F., Ng, C. Y., Hartwich, J. E. & Davidoff, A. M. Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. J. Pediatr. Surg. 45, 1080–1085 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Franco, M. et al. Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res. 66, 3639–3648 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Aragones, J., Fraisl, P., Baes, M. & Carmeliet, P. Oxygen sensors at the crossroad of metabolism. Cell. Metab. 9, 11–22 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. De Bock, K., De Smet, F., Leite De Oliveira, R., Anthonis, K. & Carmeliet, P. Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells. J. Mol. Med. 87, 561–569 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685–693 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Hellberg, C., Ostman, A. & Heldin, C. H. PDGF and vessel maturation. Recent Results Cancer Res. 180, 103–114 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Abramsson, A., Lindblom, P. & Betsholtz, C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J. Clin. Invest. 112, 1142–1151 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Huang, F. J. et al. Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the NG2 null mouse. Dev. Biol. 344, 1035–1046 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yonenaga, Y. et al. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology 69, 159–166 (2005).

    Article  PubMed  Google Scholar 

  84. Jayson, G. C. et al. Blockade of platelet-derived growth factor receptor-β by CDP860, a humanized, PEGylated di-Fab′, leads to fluid accumulation and is associated with increased tumor vascularized volume. J. Clin. Oncol. 23, 973–981 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Liu, J. et al. PDGF-D improves drug delivery and efficacy via vascular normalization, but promotes lymphatic metastasis by activating CXCR4 in breast cancer. Clin. Cancer Res. 1 Apr 2011 (doi:10.1158/1078-0432.CCR-10-2456).

  86. Nisancioglu, M. H. et al. Generation and characterization of Rgs5 mutant mice. Mol. Cell Biol. 28, 2324–2331 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Augustin, H. G., Koh, G. Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nature Rev. Mol. Cell Biol. 10, 165–177 (2009).

    Article  CAS  Google Scholar 

  88. Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511–2514 (1999).

    Article  CAS  PubMed  Google Scholar 

  89. Stoeltzing, O. et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 63, 3370–3377 (2003).

    CAS  PubMed  Google Scholar 

  90. Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nature Cell Biol. 10, 527–537 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Chae, S. S. et al. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin. Cancer Res. 16, 3618–3627 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Falcon, B. L. et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol. 175, 2159–2170 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Nasarre, P. et al. 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, 1324–1333 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Koh, Y. J. et al. Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage. Cancer Cell 18, 171–184 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Kashiwagi, S. et al. Perivascular nitric oxide gradients normalize tumor vasculature. Nature Med. 14, 255–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575–583 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Bais, C. et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141, 166–177 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Gullino, P. M. Consideration on blood supply and fluid exchange in tumors. Prog. Clin. Biol. Res. 107, 1–20 (1982).

    CAS  PubMed  Google Scholar 

  101. Bullitt, E. et al. Abnormal vessel tortuosity as a marker of treatment response of malignant gliomas: preliminary report. Technol. Cancer Res. Treat. 3, 577–584 (2004).

    Article  PubMed  Google Scholar 

  102. Wagemakers, M. et al. Tumor vessel biology in pediatric intracranial ependymoma. J. Neurosurg. Pediatr. 5, 335–341 (2010).

    Article  PubMed  Google Scholar 

  103. Willett, C. G. et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J. Clin. Oncol. 27, 3020–3026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Willett, C. G. et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J. Clin. Oncol. 23, 8136–8139 (2005).

    Article  PubMed  Google Scholar 

  105. Batchelor, T. T. et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28, 2817–2823 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sorensen, A. G. et al. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res. 69, 5296–5300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sorensen, A. G., Batchelor, T. T., Wen, P. Y., Zhang, W. T. & Jain, R. K. Response criteria for glioma. Nature Clin. Pract. Oncol. 5, 634–644 (2008).

    Article  Google Scholar 

  108. Claes, A. et al. Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol. Cancer Ther. 7, 71–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Zhu, A. X. et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J. Clin. Oncol. 27, 3027–3035 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Duda, D. G. et al. Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer. Oncologist 15, 577–583 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wildiers, H. et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br. J. Cancer 88, 1979–1986 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Van Steenkiste, C. et al. Role of placental growth factor in mesenteric neoangiogenesis in a mouse model of portal hypertension. Gastroenterology 137, 2112–2124 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Plotkin, S. R. et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N. Engl. J. Med. 361, 358–367 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Jain, R. K., Finn, A. V., Kolodgie, F. D., Gold, H. K. & Virmani, R. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nature Clin. Pract. Cardiovasc. Med. 4, 491–502 (2007).

    Article  CAS  Google Scholar 

  116. Gupta, R., Tongers, J. & Losordo, D. W. Human studies of angiogenic gene therapy. Circ. Res. 105, 724–736 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stantz, K. M., Cao, M., Cao, N., Liang, Y. & Miller, K. D. Monitoring the longitudinal intra-tumor physiological impulse response to VEGFR2 blockade in breast tumors using DCE-CT. Mol. Imaging Biol. 19 Oct 2010 (doi:10.1007/s11307-010-044-7).

  118. O'Connor, J. P. et al. Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. Clin. Cancer Res. 15, 6674–6682 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ansiaux, R. et al. Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin. Cancer Res. 11, 743–750 (2005).

    CAS  PubMed  Google Scholar 

  120. Zhou, Q., Guo, P. & Gallo, J. M. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin. Cancer Res. 14, 1540–1549 (2008).

    Article  PubMed  Google Scholar 

  121. Dings, R. P. et al. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin. Cancer Res. 13, 3395–3402 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Eichhorn, M. E. et al. Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment. Cancer Biol. Ther. 7, 1006–1013 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Maione, F. et al. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Invest. 119, 3356–3372 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. McGee, M. C. et al. Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation. Int. J. Radiat. Oncol. Biol. Phys. 76, 1537–1545 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kamoun, W. S. et al. Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks. Nature Methods 7, 655–660 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Heishi, T. et al. Restoration of peri-vascular nitric oxide gradient radio-sensitizes murine breast cancers via vascular normalization. American Association for Cancer Research [online], (2011).

    Google Scholar 

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Acknowledgements

We would like to thank D. G. Duda, S. Goel, E. Dejana, H. Augustin and L. Claesson-Welsch for their insightful comments and L. Notebaert for help with the illustrations. The work of P.C. is supported by grant IUAP06/30 from the Federal Government Belgium; by long-term structural Methusalem funding by the Flemish Government; by grant GOA2006/11 from the Concerted Research Activities (Belgium); and by a grant from The Research Foundation — Flanders (FWO; FWO G.0673.08). The research of R.K.J. is supported by US National Institutes of Health grants P01-CA80124, R01-CA85140, R01-CA115767 and R01-CA126642; by Federal Share/NCI Proton Beam Program Income; and by a National Foundation for Cancer Research and Department of Defense Breast Cancer Research Innovator Award (W81XWH-10-1-0016).

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Correspondence to Peter Carmeliet or Rakesh K. Jain.

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P.C. is a named inventor on patent applications claiming subject matter that is partially based on the results described in this paper, which may result in royalty payments. He is a consultant to and has received speaker fees from Hoffman-La Roche, and is a consultant for, received research grants and holds stocks from Thrombogenics. He is a member of the Science Advisory Board.

R.K.J. has received research grants from Dyax, MedImmune and Roche; has served as a consultant for AstraZeneca, Astellas, Dyax, Genzyme, Noxxon and SynDevRx; has received an honoraium for a lecture given at MPM Capital; is on the scientific advisory boards of Enlight and SynDevRx; and is on the board of trustees for H&Q Capital Management.

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Carmeliet, P., Jain, R. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10, 417–427 (2011). https://doi.org/10.1038/nrd3455

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