Skip to main content
SpringerLink
Log in

Benefits and Pitfalls of Tumor Vessel Normalization

  • Living reference work entry
  • First Online:
Tumor Angiogenesis

  • 173 Accesses

Abstract

Tumor vasculature has been intensively studied not only to understand its role in tumor progression and metastasis but also to discover regulatory pro- and anti-angiogenic molecules and cells. Until now, numerous anti-angiogenic agents have been developed, with more than ten agents currently being administered or tested to treat patients with various types of cancers. Despite high hopes for success, recent clinical trials have shown that these anti-angiogenic agents are not as effective as other drugs with different targets in terms of increasing patient survival when used as a single agent. These unsuccessful trials have led researchers to reevaluate the nature of tumor vasculature and the dynamic consequences that arise from anti-angiogenic treatments. Subsequently, a new hypothesis was introduced, where tumor vessels were sought to be tamed and harnessed to our advantage rather than simply attempting to eliminate them, which, by itself, has shown only marginal survival benefit. Thus, a new avenue of research was revealed, and the concept “tumor vessel normalization” has gained considerable attention ever since. However, our knowledge in this field is still rather rudimentary, and much still needs to be accomplished in order to overcome the pitfalls and relish the benefits of normalizing tumor vessels for anticancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D, Mcdonald DM (2006) Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol 290:H547–H559

    Article  PubMed  CAS  Google Scholar 

  • Bagri A, Berry L, Gunter B, Singh M, Kasman I, Damico LA, Xiang H, Schmidt M, Fuh G, Hollister B, Rosen O, Plowman GD (2010) Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin Cancer Res 16:3887–3900

    Article  PubMed  CAS  Google Scholar 

  • Barker HE, Paget JT, Khan AA, Harrington KJ (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15:409–425

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Batchelor TT, Sorensen AG, Di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Batchelor TT, Duda DG, Di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK (2010) 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK (2013) Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A 110:19059–19064

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–192

    Article  PubMed  CAS  Google Scholar 

  • Bullitt E, Ewend MG, Aylward S, Lin W, Gerig G, Joshi S, Jung I, Muller K, Smith JK (2004) Abnormal vessel tortuosity as a marker of treatment response of malignant gliomas: preliminary report. Technol Cancer Res Treat 3:577–584

    Article  PubMed  Google Scholar 

  • Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquiere B, Rehman J, Lambrechts D, MALIK AB, Dewerchin M, Carmeliet P (2016) Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30:968–985

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Jain RK (2011a) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carmeliet P, Jain RK (2011b) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417–427

    Article  PubMed  CAS  Google Scholar 

  • Carrer A, Moimas S, Zacchigna S, Pattarini L, Zentilin L, Ruozi G, Mano M, Sinigaglia M, Maione F, Serini G, Giraudo E, Bussolino F, Giacca M (2012) Neuropilin-1 identifies a subset of bone marrow Gr1- monocytes that can induce tumor vessel normalization and inhibit tumor growth. Cancer Res 72:6371–6381

    Article  PubMed  CAS  Google Scholar 

  • Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hammerling GJ (2015) Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol 16:609–617

    Article  PubMed  CAS  Google Scholar 

  • Cho CH, Kammerer RA, Lee HJ, Steinmetz MO, Ryu YS, Lee SH, Yasunaga K, Kim KT, Kim I, Choi HH, Kim W, Kim SH, Park SK, Lee GM, Koh GY (2004) COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity. Proc Natl Acad Sci U S A 101:5547–5552

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10:505–514

    Article  PubMed  CAS  Google Scholar 

  • Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP (2008) Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7:71–78

    Article  PubMed  CAS  Google Scholar 

  • Cully M (2017) Cancer: tumour vessel normalization takes centre stage. Nat Rev Drug Discov 16:87

    Article  PubMed  CAS  Google Scholar 

  • Daly C, Wong V, Burova E, Wei Y, Zabski S, Griffiths J, Lai KM, Lin HC, Ioffe E, Yancopoulos GD, Rudge JS (2004) Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 18:1060–1071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Daly C, Eichten A, Castanaro C, Pasnikowski E, Adler A, Lalani AS, Papadopoulos N, Kyle AH, Minchinton AI, Yancopoulos GD, Thurston G (2013) Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res 73:108–118

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • De Bock K, Georgiadou M, Carmeliet P (2013) Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18:634–647

    Article  PubMed  CAS  Google Scholar 

  • De Palma M, Biziato D, Petrova TV (2017) Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 17:457–474

    Article  PubMed  CAS  Google Scholar 

  • Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hagedorn NL, Mccarville MB, Stewart CF, Davidoff AM (2007) 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

    Article  PubMed  CAS  Google Scholar 

  • Duda DG, Cohen KS, DI Tomaso E, Au P, Klein RJ, Scadden DT, Willett CG, Jain RK (2006) Differential CD146 expression on circulating versus tissue endothelial cells in rectal cancer patients: implications for circulating endothelial and progenitor cells as biomarkers for antiangiogenic therapy. J Clin Oncol 24:1449–1453

    Article  PubMed  CAS  Google Scholar 

  • Duda DG, Willett CG, Ancukiewicz M, DI Tomaso E, Shah M, Czito BG, Bentley R, Poleski M, Lauwers GY, Carroll M, Tyler D, Mantyh C, Shellito P, Clark JW, Jain RK (2010) 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eales KL, Hollinshead KE, Tennant DA (2016) Hypoxia and metabolic adaptation of cancer cells. Oncogenesis 5:e190

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Emblem KE, Farrar CT, Gerstner ER, Batchelor TT, Borra RJ, Rosen BR, Sorensen AG, Jain RK (2014) Vessel caliber – a potential MRI biomarker of tumour response in clinical trials. Nat Rev Clin Oncol 11:566–584

    Article  PubMed  PubMed Central  Google Scholar 

  • Falcon BL, Hashizume H, Koumoutsakos P, Chou J, Bready JV, Coxon A, Oliner JD, Mcdonald DM (2009) Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol 175:2159–2170

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fenton BM, Paoni SF, Ding I (2004) Effect of VEGF receptor-2 antibody on vascular function and oxygenation in spontaneous and transplanted tumors. Radiother Oncol 72:221–230

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd, Eastern Cooperative Oncology Group Study, E (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544

    Article  PubMed  CAS  Google Scholar 

  • Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJJR, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga J-Y, Gupta V, Costa R, Srock S, De Ducla S, Freudensprung U, Mustacchi G (2014) Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol 15:1351–1360

    Article  PubMed  CAS  Google Scholar 

  • Goel S, Wong AH, Jain RK (2012) Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med 2:a006486

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goel S, Gupta N, Walcott BP, Snuderl M, Kesler CT, Kirkpatrick ND, Heishi T, Huang Y, Martin JD, Ager E, Samuel R, Wang S, Yazbek J, Vakoc BJ, Peterson RT, Padera TP, Duda DG, Fukumura D, Jain RK (2013) Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J Natl Cancer Inst 105:1188–1201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, Ganss R (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–414

    Article  PubMed  CAS  Google Scholar 

  • Han S, Lee SJ, Kim KE, Lee HS, Oh N, Park I, Ko E, Oh SJ, Lee YS, Kim D, Lee S, Lee DH, Lee KH, Chae SY, Lee JH, Kim SJ, Kim HC, Kim S, Kim SH, Kim C, Nakaoka Y, He Y, Augustin HG, Hu J, Song PH, Kim YI, Kim P, Kim I, Koh GY (2016) Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med 8:335ra55

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Agudo E, Mondejar T, Soto-Montenegro ML, Megias D, Mouron S, Sanchez J, Hidalgo M, Lopez-Casas PP, Mulero F, Desco M, Quintela-Fandino M (2016) Monitoring vascular normalization induced by antiangiogenic treatment with (18)F-fluoromisonidazole-PET. Mol Oncol 10:704–718

    Article  PubMed  CAS  Google Scholar 

  • 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 69:4656–4664

    Article  PubMed  CAS  Google Scholar 

  • Hormigo A, Gutin PH, Rafii S (2007) Tracking normalization of brain tumor vasculature by magnetic imaging and proangiogenic biomarkers. Cancer Cell 11:6–8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang FJ, You WK, Bonaldo P, Seyfried TN, Pasquale EB, Stallcup WB (2010) Pericyte deficiencies lead to aberrant tumor vascularization in the brain of the NG2 null mouse. Dev Biol 344:1035–1046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D'Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, Wherry EJ (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60–65

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  • Hwang JA, Lee EH, Kim HW, Park JB, Jeon BH, Cho CH (2009) COMP-Ang1 potentiates the antitumor activity of 5-fluorouracil by improving tissue perfusion in murine Lewis lung carcinoma. Mol Cancer Res 7:1920–1927

    Article  PubMed  CAS  Google Scholar 

  • Ishibashi S, Ohashi Y, Suzuki T, Miyazaki S, Moriya T, Satomi S, Sasano H (2006) Tumor-associated tissue eosinophilia in human esophageal squamous cell carcinoma. Anticancer Res 26:1419–1424

    PubMed  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2008) Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer 8:309–316

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31:2205–2218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605–622

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jain RK, Duda DG, Clark JW, Loeffler JS (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3:24–40

    Article  PubMed  CAS  Google Scholar 

  • Jayson GC, Parker GJ, Mullamitha S, Valle JW, Saunders M, Broughton L, Lawrance J, Carrington B, Roberts C, Issa B, Buckley DL, Cheung S, Davies K, Watson Y, Zinkewich-PEOTTI K, Rolfe L, Jackson A (2005) Blockade of platelet-derived growth factor receptor-beta 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

    Article  PubMed  CAS  Google Scholar 

  • Kamoun WS, Ley CD, Farrar CT, Duyverman AM, Lahdenranta J, Lacorre DA, Batchelor TT, DI Tomaso E, Duda DG, Munn LL, Fukumura D, Sorensen AG, Jain RK (2009) 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739

    Article  PubMed  CAS  Google Scholar 

  • Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  PubMed  CAS  Google Scholar 

  • Kim C, Yang H, Fukushima Y, Saw PE, Lee J, Park JS, Park I, Jung J, Kataoka H, Lee D, Heo WD, Kim I, Jon S, Adams RH, Nishikawa S, Uemura A, Koh GY (2014) Vascular RhoJ is an effective and selective target for tumor angiogenesis and vascular disruption. Cancer Cell 25:102–117

    Article  PubMed  CAS  Google Scholar 

  • Koh GY (2013) Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med 19:31–39

    Article  PubMed  CAS  Google Scholar 

  • Koh YJ, Kim HZ, Hwang SI, Lee JE, Oh N, Jung K, Kim M, Kim KE, Kim H, Lim NK, Jeon CJ, Lee GM, Jeon BH, Nam DH, Sung HK, Nagy A, Yoo OJ, Koh GY (2010) Double antiangiogenic protein, DAAP, targeting VEGF-A and angiopoietins in tumor angiogenesis, metastasis, and vascular leakage. Cancer Cell 18:171–184

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Liao S, Huang Y, Samuel R, Shi T, Naxerova K, Huang P, Kamoun W, Jain RK, Fukumura D, Xu L (2011) PDGF-D improves drug delivery and efficacy via vascular normalization, but promotes lymphatic metastasis by activating CXCR4 in breast cancer. Clin Cancer Res 17:3638–3648

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma J, Pulfer S, Li S, Chu J, Reed K, Gallo JM (2001) Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470. Cancer Res 61:5491–5498

    PubMed  CAS  Google Scholar 

  • Maes H, Kuchnio A, Peric A, Moens S, Nys K, De Bock K, Quaegebeur A, Schoors S, Georgiadou M, Wouters J, Vinckier S, Vankelecom H, Garmyn M, Vion AC, Radtke F, Boulanger C, Gerhardt H, Dejana E, Dewerchin M, Ghesquiere B, Annaert W, Agostinis P, Carmeliet P (2014) Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26:190–206

    Article  PubMed  CAS  Google Scholar 

  • Majmundar AJ, WONG WJ, Simon MC (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40:294–309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, Politi LS, Gentner B, Brown JL, Naldini L, De Palma M (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19:512–526

    Article  PubMed  CAS  Google Scholar 

  • Mazzone M, Dettori D, Leite De Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz De Almodovar C, De Smet F, Vinckier S, Aragones J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136:839–851

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mcgee MC, Hamner JB, Williams RF, Rosati SF, Sims TL, Ng CY, Gaber MW, Calabrese C, Wu J, Nathwani AC, Duntsch C, Merchant TE, Davidoff AM (2010) Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation. Int J Radiat Oncol Biol Phys 76:1537–1545

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Murata R, Nishimura Y, Hiraoka M (1997) An antiangiogenic agent (TNP-470) inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma. Int J Radiation Oncol Biol Phys 37:1107–1113

    Article  CAS  Google Scholar 

  • Myers AL, Williams RF, Ng CY, Hartwich JE, Davidoff AM (2010) Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. J Pediatr Surg 45:1080–1085

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagy JA, Dvorak AM, Dvorak HF (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2:251–275

    Article  PubMed  CAS  Google Scholar 

  • 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 69:1324–1333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nguyen DX, Massague J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8:341–352

    Article  PubMed  CAS  Google Scholar 

  • Nielsen HJR, Hansen U, Christensen IJ, Reimert CM, Brunner N, Moesgaard F (1999) Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. J Pathol 189:487–495

    Article  PubMed  CAS  Google Scholar 

  • Nisancioglu MH, Mahoney WM Jr, Kimmel DD, Schwartz SM, Betsholtz C, Genove G (2008) Generation and characterization of rgs5 mutant mice. Mol Cell Biol 28:2324–2331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Park JS, Kim IK, Han S, Park I, Kim C, Bae J, Oh SJ, Lee S, Kim JH, Woo DC, He Y, Augustin HG, Kim I, Lee D, Koh GY (2016) Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30:953–967

    Article  PubMed  CAS  Google Scholar 

  • Park DY, Lee J, Kim J, Kim K, Hong S, Han S, kubota Y, Augustin HG, Ding L, Kim JW, Kim H, He Y, Adams RH, Koh GY (2017) Plastic roles of pericytes in the blood-retinal barrier. Nat Commun 8:15296

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887

    Article  PubMed  CAS  Google Scholar 

  • Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, shentu Y, Rangwala R, Brahmer JR, Investigators K (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833

    Article  PubMed  CAS  Google Scholar 

  • Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86:236–242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reymond N, D’agua BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870

    Article  PubMed  CAS  Google Scholar 

  • Rivera LB, Bergers G (2015) CANCER. Tumor angiogenesis, from foe to friend. Science 349:694–695

    Article  PubMed  CAS  Google Scholar 

  • Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Akerud P, De Mol M, Salomaki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19:31–44

    Article  PubMed  CAS  Google Scholar 

  • Saharinen P, Eklund L, Alitalo K (2017) Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov 16:635–661

    Article  PubMed  CAS  Google Scholar 

  • Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  PubMed  CAS  Google Scholar 

  • Schadler KL, Thomas NJ, Galie PA, Bhang DH, Roby KC, Addai P, Till JE, Sturgeon K, Zaslavsky A, Chen CS, Ryeom S (2016) Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7:65429–65440

    Article  PubMed  PubMed Central  Google Scholar 

  • Schmittnaegel M, Rigamonti N, Kadioglu E, Cassara A, Wyser Rmili C, Kiialainen A, Kienast Y, Mueller HJ, Ooi CH, Laoui D, De Palma M (2017) Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med 9:eaak9670

    Article  PubMed  CAS  Google Scholar 

  • Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70:6171–6180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sorensen AG, Batchelor TT, Wen PY, Zhang WT, Jain RK (2008) Response criteria for glioma. Nat Clin Pract Oncol 5:634–644

    Article  PubMed  PubMed Central  Google Scholar 

  • Sorensen AG, Batchelor TT, Zhang WT, chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, Di Tomaso E, Duda DG, Jain RK (2009) 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, Wang M, Wen PY, Ivy P, Batchelor TT, Jain RK (2012) Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 72:402–407

    Article  PubMed  CAS  Google Scholar 

  • Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS (2008) Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456:814–818

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taal W, Oosterkamp HM, Walenkamp AME, Dubbink HJ, Beerepoot LV, Hanse MCJ, Buter J, Honkoop AH, Boerman D, De Vos FYF, Dinjens WNM, enting RH, Taphoorn MJB, Van den Berkmortel FWPJ, Jansen RLH, Brandsma D, Bromberg JEC, Van Heuvel I, Vernhout RM, Van der Holt B, VAN den Bent MJ (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15:943–953

    Article  PubMed  CAS  Google Scholar 

  • Tailor TD, Hanna G, Yarmolenko PS, Dreher MR, Betof AS, Nixon AB, Spasojevic I, Dewhirst MW (2010) Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 9:1798–1808

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tian L, Goldstein A, wang H, Ching Lo H, Sun Kim I, Welte T, Sheng K, Dobrolecki LE, Zhang X, Putluri N, Phung TL, Mani SA, STOSSI F, Sreekumar A, Mancini MA, Decker WK, Zong C, Lewis MT, Zhang XH (2017) Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544:250–254

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) 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

    Article  PubMed  CAS  Google Scholar 

  • Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Viallard C, Larrivee B (2017) Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis

    Article  PubMed  CAS  Google Scholar 

  • Wagemakers M, Sie M, Hoving EW, Molema G, De Bont ES, Den Dunnen WF (2010) Tumor vessel biology in pediatric intracranial ependymoma. J Neurosurg Pediatr 5:335–341

    Article  PubMed  Google Scholar 

  • Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, De Bruijn EA, Van Oosterom AT (2003) Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979–1986

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Willett CG, Boucher Y, Di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Willett CG, Boucher Y, Duda DG, Di Tomaso E, munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, Sahani DV, Kalva SP, Cohen KS, Scadden DT, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Shellito PC, Mino-Kenudson M, Lauwers GY (2005) 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

    Article  PubMed  Google Scholar 

  • Willett CG, Duda DG, Di Tomaso E, Boucher Y, ancukiewicz M, Sahani DV, Lahdenranta J, chung DC, Fischman AJ, lauwers GY, Shellito P, CZITO BG, Wong TZ, Paulson E, Poleski M, Vujaskovic Z, Bentley R, Chen HX, Clark JW, Jain RK (2009) 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, Di Tomaso E, Munn LL, Jain RK (2004) 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

    PubMed  CAS  Google Scholar 

  • Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, Tachibana T, Imamura M (2005) 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

    Article  PubMed  Google Scholar 

  • Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK (1996) 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 U S A 93:14765–14770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang H, Ren Y, Tang X, Wang K, Liu Y, Zhang L, LI X, Liu P, Zhao C, He J (2015) Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis. Sci Rep 5:8888

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao Y, Ting K, Li J, Cogger VC, Chen J, Johansson-Percival A, Ngiow SF, Holst J, Grau GER, Goel S, Moller T, Dejana E, Mccaughan GW, Smyth MJ, Ganss R, Vadas MA, Gamble JR (2017) Targeting vascular endothelial-cadherin in tumor-associated blood vessels promotes T cell-mediated immunotherapy. Cancer Res 77:4434–4447

    Article  PubMed  CAS  Google Scholar 

  • Zhu AX, Sahani DV, Duda DG, Di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP, Jain RK (2009) Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 27:3027–3035

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ziyad S, Iruela-Arispe ML (2011) Molecular mechanisms of tumor angiogenesis. Genes Cancer 2:1085–1096

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

We apologize for not being able to cite all of the original research articles and related references due to space limitations. Work in the authors’ laboratory is supported by funds from the Institute for Basic Science funded by the Ministry of Science, ICT and Future Planning, Korea (IBS-R025-D1).

Author information

Author notes

  1. Jin-Sung Park, Intae Park and Gou Young Koh have been contributed equally.

Authors and Affiliations

  1. Center for Vascular Research, Institute for Basic Science (IBS) and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea

    Jin-Sung Park, Intae Park & Gou Young Koh

Authors
  1. Jin-Sung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Intae Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gou Young Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gou Young Koh .

Editor information

Editors and Affiliations

  1. Tumor Biology Center, Freiburg, Baden-Württemberg, Germany

    Dieter Marmé

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Park, JS., Park, I., Koh, G.Y. (2018). Benefits and Pitfalls of Tumor Vessel Normalization. In: Marmé, D. (eds) Tumor Angiogenesis. Springer, Cham. https://doi.org/10.1007/978-3-319-31215-6_46-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-31215-6_46-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-31215-6

  • Online ISBN: 978-3-319-31215-6

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation