The growth and dissemination of tumors rely on an altered vascular network, which supports their survival and expansion and provides accessibility to the vasculature and a route of transport for metastasizing tumor cells. The remodeling of vascular structures through generation of new vessels (for example, via tumor angiogenesis) is a well studied, even if still quite poorly understood, process in human cancer. Antiangiogenic therapies have provided insight into the contribution of angiogenesis to the biology of human tumors, yet have also revealed the ease with which resistance to antiangiogenic drugs can develop, presumably involving alterations to vascular signaling mechanisms. Furthermore, cellular and/or molecular changes to pre-existing vessels could represent subtle pre-metastatic alterations to the vasculature, which are important for cancer progression. These changes, and associated molecular markers, may forecast the behavior of individual tumors and contribute to the early detection, diagnosis and prognosis of cancer. This review, which primarily focuses on the blood vasculature, explores current knowledge of how tumor vessels can be remodeled, and the cellular and molecular events responsible for this process.
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endothelial progenitor cell
high endothelial venule
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Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.
Hanahan D, Coussens LM . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309–322.
Adams RH, Alitalo K . Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007; 8: 464–478.
Kushner EJ, Bautch VL . Building blood vessels in development and disease. Curr Opin Hematol 2013; 20: 231–236.
Alitalo K . The lymphatic vasculature in disease. Nat Med 2011; 17: 1371–1380.
Achen MG, McColl BK, Stacker SA . Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 2005; 7: 121–127.
Achen MG, Mann GB, Stacker SA . Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer 2006; 94: 1355–1360.
Nagy JA, Dvorak HF . Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets. Clin Exp Metastasis 2012; 29: 657–662.
Qian CN . Hijacking the vasculature in ccRCC-co-option, remodelling and angiogenesis. Nat Rev Urol 2013; 10: 300–304.
Gimbrone MA Jr, Aster RH, Cotran RS, Corkery J, Jandl JH, Folkman J . Preservation of vascular integrity in organs perfused in vitro with a platelet-rich medium. Nature 1969; 222: 33–36.
Algire GH, Chalkley HW . Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 1945; 6: 73–85.
Greene JH . heterologous transplantation of mammalian tumors. I. The transfer of rabbit tumors to alien species. J Exp Med 1941; 73: 461–477.
Gimbrone MA Jr, Leapman SB, Cotran RS, Folkman J . Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972; 136: 261–276.
Folkman J, Cole P, Zimmerman S . Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg 1966; 164: 491–502.
Folkman J, Watson K, Ingber D, Hanahan D . Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature (London) 1989; 339: 58–61.
Srivastava A, Laidler P, Davies RP, Horgan K, Hughes LE . The prognostic significance of tumor vascularity in intermediate- thickness (0.76-4.0 mm thick) skin melanoma. A quantitative histologic study. Am J Pathol 1988; 133: 419–423.
Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.
Ahn GO, Brown JM . Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis 2009; 12: 159–164.
Weis SM, Cheresh DA . Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 2011; 17: 1359–1370.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N . Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–1309.
Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989; 246: 1309–1312.
Armulik A, Abramsson A, Betsholtz C . Endothelial/pericyte interactions. Circ Res 2005; 97: 512–523.
Aird WC . Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2012; 2: a006429.
Carmeliet P, Jain RK . Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10: 417–427.
Nagy JA, Feng D, Vasile E, Wong WH, Shih SC, Dvorak AM et al. Permeability properties of tumor surrogate blood vessels induced by VEGF-A. Lab Invest 2006; 86: 767–780.
Stubbs M, McSheehy PM, Griffiths JR, Bashford CL . Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 2000; 6: 15–19.
Hockel M, Vaupel P . Biological consequences of tumor hypoxia. Semin Oncol 2001; 28: 36–41.
GL Semenza . HIF-1 O(2) and the 3 PHDs. How animal cells signal hypoxia to the nucleus. Cell 2001; 107: 1–3.
Cardone RA, Casavola V, Reshkin SJ . The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 2005; 5: 786–795.
Sullivan R, Graham CH . Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 2007; 26: 319–331.
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996; 379: 88–91.
Moeller BJ, Richardson RA, Dewhirst MW . Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 2007; 26: 241–248.
Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF . Heterogeneity of the tumor vasculature. Semin Thromb Hemost 2010; 36: 321–331.
Yu JL, Rak JW, Klement G, Kerbel RS . Vascular endothelial growth factor isoform expression as a determinant of blood vessel patterning in human melanoma xenografts. Cancer Res 2002; 62: 1838–1846.
Tammela T, He Y, Lyytikka J, Jeltsch M, Markkanen J, Pajusola K et al. Distinct architecture of lymphatic vessels induced by chimeric vascular endothelial growth factor-C/vascular endothelial growth factor heparin-binding domain fusion proteins. Circ Res 2007; 100: 1468–1475.
Keskitalo S, Tammela T, Lyytikka J, Karpanen T, Jeltsch M, Markkanen J et al. Enhanced capillary formation stimulated by a chimeric vascular endothelial growth factor/vascular endothelial growth factor-C silk domain fusion protein. Circ Res 2007; 100: 1460–1467.
Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J . Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 2004; 94: 664–670.
Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 2007; 204: 1431–1440.
Woolard J, Bevan HS, Harper SJ, Bates DO . Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation 2009; 16: 572–592.
Konerding MA, Fait E, Dimitropoulou C, Malkusch W, Ferri C, Giavazzi R et al. Impact of fibroblast growth factor-2 on tumor microvascular architecture. A tridimensional morphometric study. Am J Pathol 1998; 152: 1607–1616.
Konerding MA, Malkusch W, Klapthor B, van Ackern C, Fait E, Hill SA et al. Evidence for characteristic vascular patterns in solid tumours: quantitative studies using corrosion casts. Br J Cancer 1999; 80: 724–732.
Herve MA, Buteau-Lozano H, Vassy R, Bieche I, Velasco G, Pla M et al. Overexpression of vascular endothelial growth factor 189 in breast cancer cells leads to delayed tumor uptake with dilated intratumoral vessels. Am J Pathol 2008; 172: 167–178.
Schiffer D, Bosone I, Dutto A, Di Vito N, Chio A . The prognostic role of vessel productive changes and vessel density in oligodendroglioma. J Neurooncol 1999; 44: 99–107.
Cassoni P, Gaetano L, Senetta R, Bussolati B, Molinaro L, Bussolati G . Histology far away from Flatland: 3D roller-coasting into grade-dependent angiogenetic patterns in oligodendrogliomas. J Cell Mol Med 2008; 12: 564–568.
Qin L, Bromberg-White JL, Qian CN . Opportunities and challenges in tumor angiogenesis research: back and forth between bench and bed. Adv Cancer Res 2012; 113: 191–239.
Paku S, Paweletz N . First steps of tumor-related angiogenesis. Lab Invest 1991; 65: 334–346.
Pettersson A, Nagy JA, Brown LF, Sundberg C, Morgan E, Jungles S et al. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 2000; 80: 99–115.
Dvorak AM, Kohn S, Morgan ES, Fox P, Nagy JA, Dvorak HF . The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J Leukoc Biol 1996; 59: 100–115.
Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ et al. Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am J Pathol 2001; 158: 1145–1160.
Goffin JR, Straume O, Chappuis PO, Brunet JS, Begin LR, Hamel N et al. Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer. Br J Cancer 2003; 89: 1031–1034.
Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR et al. Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 2002; 62: 6808–6811.
Birner P, Piribauer M, Fischer I, Gatterbauer B, Marosi C, Ambros PF et al. Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypes. Brain Pathol 2003; 13: 133–143.
Griffioen AW . Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother 2008; 57: 1553–1558.
Dirkx AE, oude Egbrink MG, Castermans K, van der Schaft DW, Thijssen VL, Dings RP et al. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors. FASEB J 2006; 20: 621–630.
Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 2011; 71: 5678–5687.
de Chaisemartin L, Goc J, Damotte D, Validire P, Magdeleinat P, Alifano M et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res 2011; 71: 6391–6399.
Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008; 26: 4410–4417.
Cipponi A, Mercier M, Seremet T, Baurain JF, Theate I, van den Oord J et al. Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res 2012; 72: 3997–4007.
Hindley JP, Jones E, Smart K, Bridgeman H, Lauder SN, Ondondo B et al. T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Cancer Res 2012; 72: 5473–5482.
Schrama D, thor Straten P, Fischer WH, McLellan AD, Brocker EB, Reisfeld RA et al. Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 2001; 14: 111–121.
Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 2004; 5: 141–149.
Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G . Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 2011; 71: 5601–5605.
Achen MG, Stacker SA . Molecular control of lymphatic metastasis. Ann NY Acad Sci 2008; 1131: 225–234.
Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nature Med 2001; 7: 186–191.
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7: 192–198.
Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001; 20: 672–682.
Sleeman JP, Nazarenko I, Thiele W . Do all roads lead to Rome? Routes to metastasis development. Int J Cancer 2011; 128: 2511–2526.
Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K et al. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 2012; 21: 181–195.
Bussolati B, Deregibus MC, Camussi G . Characterization of molecular and functional alterations of tumor endothelial cells to design anti-angiogenic strategies. Curr Vasc Pharmacol 2010; 8: 220–232.
Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C St, Croix B . Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 2007; 11: 539–554.
Joyce JA, Laakkonen P, Bernasconi M, Bergers G, Ruoslahti E, Hanahan D . Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 2003; 4: 393–403.
Hoffman JA, Giraudo E, Singh M, Zhang L, Inoue M, Porkka K et al. Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 2003; 4: 383–391.
Laakkonen P, Porkka K, Hoffman JA, Ruoslahti E . A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 2002; 8: 751–755.
Clasper S, Royston D, Baban D, Cao Y, Ewers S, Butz S et al. A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. Cancer Res 2008; 68: 7293–7303.
Zhang L, Giraudo E, Hoffman JA, Hanahan D, Ruoslahti E . Lymphatic zip codes in premalignant lesions and tumors. Cancer Res 2006; 66: 5696–5706.
Raza A, Franklin MJ, Dudek AZ . Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 2010; 85: 593–598.
Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 2008; 453: 410–414.
Liu P, Zhang C, Chen J, Zhang R, Ren J, Huang Y et al. Combinational therapy of interferon-alpha and chemotherapy normalizes tumor vasculature by regulating pericytes including the novel marker RGS5 in melanoma. J Immunother 2011; 34: 320–326.
Gerhardt H, Semb H . Pericytes: gatekeepers in tumour cell metastasis? J Mol Med (Berl) 2008; 86: 135–144.
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D . Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111: 1287–1295.
Bergers G, Hanahan D . Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592–603.
Murdoch C, Muthana M, Coffelt SB, Lewis CE . The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008; 8: 618–631.
Pollard JW . Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4: 71–78.
Wels J, Kaplan RN, Rafii S, Lyden D . Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 2008; 22: 559–574.
Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001; 7: 1194–1201.
Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006; 313: 1785–1787.
Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G . PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 2005; 7: 870–879.
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449: 557–563.
Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004; 6: 409–421.
Gabrilovich DI, Nagaraj S . Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9: 162–174.
De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE . Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 2007; 28: 519–524.
De Palma M, Venneri MA, Galli R, Sergi LS, Politi LS, Sampaolesi M et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005; 8: 211–226.
Carmeliet P, Jain RK . Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298–307.
McAllister SS, Weinberg RA . Tumor-host interactions: a far-reaching relationship. J Clin Oncol 2010; 28: 4022–4028.
Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85: 221–228.
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–967.
De Palma M, Venneri MA, Roca C, Naldini L . Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 2003; 9: 789–795.
Coussens LM, Zitvogel L, Palucka AK . Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 2013; 339: 286–291.
Bertolini F, Shaked Y, Mancuso P, Kerbel RS . The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 2006; 6: 835–845.
Yoder MC, Ingram DA . Endothelial progenitor cell: ongoing controversy for defining these cells and their role in neoangiogenesis in the murine system. Curr Opin Hematol 2009; 16: 269–273.
Patenaude A, Parker J, Karsan A . Involvement of endothelial progenitor cells in tumor vascularization. Microvasc Res 2010; 79: 217–223.
Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 2005; 7: 101–111.
Purhonen S, Palm J, Rossi D, Kaskenpaa N, Rajantie I, Yla-Herttuala S et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 2008; 105: 6620–6625.
Nolan DJ, Ciarrocchi A, Mellick AS, Jaggi JS, Bambino K, Gupta S et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev 2007; 21: 1546–1558.
Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V . Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 2008; 319: 195–198.
Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008; 14: 263–273.
Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM . Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002; 109: 337–346.
Aranguren XL, McCue JD, Hendrickx B, Zhu XH, Du F, Chen E et al. Multipotent adult progenitor cells sustain function of ischemic limbs in mice. J Clin Invest 2008; 118: 505–514.
Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 2005; 11: 261–262.
Rafii S, Lyden D . Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003; 9: 702–712.
Duda DG, Cohen KS, Scadden DT, Jain RK . A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood. Nat Protoc 2007; 2: 805–810.
Mancuso P, Antoniotti P, Quarna J, Calleri A, Rabascio C, Tacchetti C et al. Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses. Clin Cancer Res 2009; 15: 267–273.
Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155: 739–752.
Rybak SM, Sanovich E, Hollingshead MG, Borgel SD, Newton DL, Melillo G et al. ‘Vasocrine’ formation of tumor cell-lined vascular spaces: implications for rational design of antiangiogenic therapies. Cancer Res 2003; 63: 2812–2819.
Bruno S, Bussolati B, Grange C, Collino F, Graziano ME, Ferrando U et al. CD133+ renal progenitor cells contribute to tumor angiogenesis. Am J Pathol 2006; 169: 2223–2235.
Bussolati B, Grange C, Sapino A, Camussi G . Endothelial cell differentiation of human breast tumour stem/progenitor cells. J Cell Mol Med 2009; 13: 309–319.
Pezzolo A, Parodi F, Corrias MV, Cinti R, Gambini C, Pistoia V . Tumor origin of endothelial cells in human neuroblastoma. J Clin Oncol 2007; 25: 376–383.
Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010; 468: 829–833.
Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010; 468: 824–828.
Shen R, Ye Y, Chen L, Yan Q, Barsky SH, Gao JX . Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS One 2008; 3: e1652.
Alvero AB, Fu HH, Holmberg J, Visintin I, Mor L, Marquina CC et al. Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells 2009; 27: 2405–2413.
Bussolati B, Bruno S, Grange C, Ferrando U, Camussi G . Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J 2008; 22: 3696–3705.
Potenta S, Zeisberg E, Kalluri R . The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 2008; 99: 1375–1379.
Fidler IJ . The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3: 453–458.
Hirakawa S . From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci 2009; 100: 983–989.
Van den Eynden GG, Van der Auwera I, Van Laere SJ, Colpaert CG, Turley H, Harris AL et al. Angiogenesis and hypoxia in lymph node metastases is predicted by the angiogenesis and hypoxia in the primary tumour in patients with breast cancer. Br J Cancer 2005; 93: 1128–1136.
Guidi AJ, Berry DA, Broadwater G, Perloff M, Norton L, Barcos MP et al. Association of angiogenesis in lymph node metastases with outcome of breast cancer. J Natl Cancer Inst 2000; 92: 486–492.
Arapandoni-Dadioti P, Giatromanolaki A, Trihia H, Harris AL, Koukourakis MI . Angiogenesis in ductal breast carcinoma. Comparison of microvessel density between primary tumour and lymph node metastasis. Cancer Lett 1999; 137: 145–150.
Van der Auwera I, Van den Eynden GG, Colpaert CG, Van Laere SJ, van Dam P, Van Marck EA et al. Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin Cancer Res 2005; 11: 7637–7642.
Qian CN, Berghuis B, Tsarfaty G, Bruch M, Kort EJ, Ditlev J et al. Preparing the ‘soil’: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res 2006; 66: 10365–10376.
Qian CN, Resau JH, Teh BT . Prospects for vasculature reorganization in sentinel lymph nodes. Cell Cycle 2007; 6: 514–517.
Carriere V, Colisson R, Jiguet-Jiglaire C, Bellard E, Bouche G, Al Saati T et al. Cancer cells regulate lymphocyte recruitment and leukocyte-endothelium interactions in the tumor-draining lymph node. Cancer Res 2005; 65: 11639–11648.
Chung MK, Do IG, Jung E, Son YI, Jeong HS, Baek CH . Lymphatic vessels and high endothelial venules are increased in the sentinel lymph nodes of patients with oral squamous cell carcinoma before the arrival of tumor cells. Ann Surg Oncol 2012; 19: 1595–1601.
Lee SY, Qian CN, Ooi AS, Chen P, Tan VK, Chia CS et al 2011. Young Surgeon’s Award Winner: high endothelial venules: a novel prognostic marker in cancer metastasis and the missing link? Ann Acad Med Singapore 2012; 41: 21–28.
Farnsworth RH, Karnezis T, Shayan R, Matsumoto M, Nowell CJ, Achen MG et al. A role for bone morphogenic protein-4 in vascular endothelial growth factor-D mediated tumor growth, metastasis and vessel remodelling. Cancer Res 2011; 71: 6547–6557.
Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R . Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 2006; 6: 659–670.
Liao S, Ruddle NH . Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol 2006; 177: 3369–3379.
Girard JP, Moussion C, Forster R . HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 2012; 12: 762–773.
Hayasaka H, Taniguchi K, Fukai S, Miyasaka M . Neogenesis and development of the high endothelial venules that mediate lymphocyte trafficking. Cancer Sci 2010; 101: 2302–2308.
Zhao YC, Ni XJ, Wang MH, Zha XM, Zhao Y, Wang S . Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients. Med Oncol 2012; 29: 2594–2600.
Ishii H, Chikamatsu K, Sakakura K, Miyata M, Furuya N, Masuyama K . Primary tumor induces sentinel lymph node lymphangiogenesis in oral squamous cell carcinoma. Oral Oncol 2010; 46: 373–378.
Kurahara H, Takao S, Shinchi H, Maemura K, Mataki Y, Sakoda M et al. Significance of lymphangiogenesis in primary tumor and draining lymph nodes during lymphatic metastasis of pancreatic head cancer. J Surg Oncol 2010; 102: 809–815.
Hirakawa S, Detmar M, Kerjaschki D, Nagamatsu S, Matsuo K, Tanemura A et al. Nodal lymphangiogenesis and metastasis: Role of tumor-induced lymphatic vessel activation in extramammary Paget’s disease. Am J Pathol 2009; 175: 2235–2248.
Ruddell A, Kelly-Spratt KS, Furuya M, Parghi SS, Kemp CJ . p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis. Oncogene 2008; 27: 3145–3155.
Ruddell A, Mezquita P, Brandvold KA, Farr A, Iritani BM . B lymphocyte-specific c-Myc expression stimulates early and functional expansion of the vasculature and lymphatics during lymphomagenesis. Am J Pathol 2003; 163: 2233–2245.
Harrell MI, Iritani BM, Ruddell A . Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 2007; 170: 774–786.
Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M . VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 2007; 109: 1010–1017.
Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M . VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 2005; 201: 1089–1099.
Van den Eynden GG, Van der Auwera I, Van Laere SJ, Huygelen V, Colpaert CG, van Dam P et al. Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer. Br J Cancer 2006; 95: 1362–1366.
Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S et al. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J Clin Invest 2011; 121: 2000–2012.
van der Schaft DW, Pauwels P, Hulsmans S, Zimmermann M, van de Poll-Franse LV, Griffioen AW . Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett 2007; 254: 128–136.
Jakob C, Aust DE, Liebscher B, Baretton GB, Datta K, Muders MH . Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant treatment. PLoS One 2011; 6: e27402.
Yu JL, Rak JW . Host microenvironment in breast cancer development: inflammatory and immune cells in tumour angiogenesis and arteriogenesis. Breast Cancer Res 2003; 5: 83–88.
Soderberg KA, Payne GW, Sato A, Medzhitov R, Segal SS, Iwasaki A . Innate control of adaptive immunity via remodeling of lymph node feed arteriole. Proc Natl Acad Sci USA 2005; 102: 16315–16320.
Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 2006; 66: 8065–8075.
Paget S . The distribution of secondary growths in cancer of the breast. Lancet 1889; 1: 571–573.
Sleeman JP, Cremers N . New concepts in breast cancer metastasis: tumor initiating cells and the microenvironment. Clin Exp Metastasis 2007; 24: 707–715.
Psaila B, Lyden D . The metastatic niche: adapting the foreign soil. Nat Rev Cancer 2009; 9: 285–293.
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature (London) 2005; 438: 820–827.
Kaplan RN, Rafii S, Lyden D . Preparing the ‘soil’: the premetastatic niche. Cancer Res 2006; 66: 11089–11093.
Peinado H, Lavotshkin S, Lyden D . The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 2011; 21: 139–146.
Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012; 18: 883–891.
Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 2011; 71: 5346–5356.
Ferrara N . VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002; 2: 795–803.
Hurwitz H . Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin Colorectal Cancer 2004; 4 (Suppl 2): S62–S68.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med 2004; 350: 2335–2342.
Van Cutsem E, Lambrechts D, Prenen H, Jain RK, Carmeliet P . Lessons from the adjuvant bevacizumab trial on colon cancer: what next? J Clin Oncol 2011; 29: 1–4.
Jain RK . Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307: 58–62.
Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007; 11: 83–95.
Halford MM, Tebbutt NC, Desai J, Achen MG, Stacker SA . Towards the biomarker-guided rational use of anti-angiogenic agents in the treatment of metastatic colorectal cancer. Colorectal Cancer 2012; 1: 149–161.
Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 1996; 15: 290–298.
Achen MG, Stacker SA . Vascular endothelial growth factor-D:signalling mechanisms, biology and clinical relevance. Growth Factors 2012; 5: 283–296.
Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA 1998; 95: 548–553.
Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem 1999; 274: 32127–32136.
McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J et al. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J 2007; 21: 1088–1098.
Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE . Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res 2013; 73: 1649–1657.
von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S et al. Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res 2011; 17: 6192–6205.
MGA and SAS are supported by Research Fellowships and a Program Grant from the National Health and Medical Research Council of Australia. We apologize to authors whose work could not be quoted due to space limitations.
MGA and SAS are shareholders of Circadian Technologies, which has a commercial interest in antiangiogenesis and antilymphangiogenesis in cancer, and Ark Therapeutics, which has an interest in the application of growth factors in vascular disease. RHF and ML declare no conflict of interest.
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Farnsworth, R., Lackmann, M., Achen, M. et al. Vascular remodeling in cancer. Oncogene 33, 3496–3505 (2014). https://doi.org/10.1038/onc.2013.304
- endothelial cell
- lymph node
- tumor microenvironment
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