Heterogeneity of the Tumor Vasculature

 

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ABSTRACT

The blood vessels supplying tumors are strikingly heterogeneous and differ from their normal counterparts with respect to organization, structure, and function. Six distinctly different tumor vessel types have been identified, and much has been learned about the steps and mechanisms by which they form. Four of the six vessel types (mother vessels, capillaries, glomeruloid microvascular proliferations, and vascular malformations) develop from preexisting normal venules and capillaries by angiogenesis. The two remaining vessel types (feeder arteries and draining veins) develop from arterio-venogenesis, a parallel, poorly understood process that involves the remodeling of preexisting arteries and veins. All six of these tumor vessel types can be induced to form sequentially in normal mouse tissues by an adenoviral vector expressing vascular endothelial growth factor. Current antiangiogenic cancer therapies directed at VEGF-A or its receptors have been of only limited benefit to cancer patients, perhaps because they target only the endothelial cells of the tumor blood vessel subset that requires exogenous VEGF-A for maintenance. A goal of future work is to identify therapeutic targets on tumor blood vessel endothelial cells that have lost this requirement.

REFERENCES

• 1 Holash J, Maisonpierre P C, Compton D et al.. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.  Science. 1999;  284(5422) 1994-1998
  CrossrefPubMedGoogle Scholar
• 2 Leenders W P, Küsters B, de Waal R M. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis.  Endothelium. 2002;  9(2) 83-87
  CrossrefPubMedGoogle Scholar
• 3 Du R, Lu K V, Petritsch C et al.. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion.  Cancer Cell. 2008;  13(3) 206-220
  CrossrefPubMedGoogle Scholar
• 4 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285(21) 1182-1186
  CrossrefPubMedGoogle Scholar
• 5 Warren B. The vascular morphology of tumors. In: Peterson H-I Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors. Boca Raton, FL; CRC Press 1979: 1-47
  PubMedGoogle Scholar
• 6 Stubbs M, McSheehy P M, Griffiths J R, Bashford C L. Causes and consequences of tumour acidity and implications for treatment.  Mol Med Today. 2000;  6(1) 15-19
  CrossrefPubMedGoogle Scholar
• 7 Semenza G L. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology.  Trends Mol Med. 2001;  7(8) 345-350
  CrossrefPubMedGoogle Scholar
• 8 Nagy J A, Feng D, Vasile E et al.. Permeability properties of tumor surrogate blood vessels induced by VEGF-A.  Lab Invest. 2006;  86(8) 767-780
  PubMedGoogle Scholar
• 9 Dvorak H. Tumor blood vessels. In: Aird W The Endothelium: A Comprehensive Reference. Cambridge, United Kingdom; Cambridge University Press 2007
  PubMedGoogle Scholar
• 10 Dvorak H F. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma.  Am J Pathol. 2003;  162(6) 1747-1757
  CrossrefPubMedGoogle Scholar
• 11 Dvorak H F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.  N Engl J Med. 1986;  315(26) 1650-1659
  CrossrefPubMedGoogle Scholar
• 12 Chang H Y, Sneddon J B, Alizadeh A A et al.. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.  PLoS Biol. 2004;  2(2) E7
  CrossrefPubMedGoogle Scholar
• 13 Brown L F, Berse B, Jackman R W et al.. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer.  Hum Pathol. 1995;  26(1) 86-91
  CrossrefPubMedGoogle Scholar
• 14 Guidi A J, Abu-Jawdeh G, Berse B et al.. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia.  J Natl Cancer Inst. 1995;  87(16) 1237-1245
  CrossrefPubMedGoogle Scholar
• 15 Ellis L M, Rosen L, Gordon M S. Overview of anti-VEGF therapy and angiogenesis. Part 1: Angiogenesis inhibition in solid tumor malignancies.  Clin Adv Hematol Oncol. 2006;  4(suppl) 1-12
  PubMedGoogle Scholar
• 16 Hurwitz H, Fehrenbacher L, Novotny W et al.. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.  N Engl J Med. 2004;  350(23) 2335-2342
  CrossrefPubMedGoogle Scholar
• 17 Jain R K, Duda D G, Clark J W, Loeffler J S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer.  Nat Clin Pract Oncol. 2006;  3(1) 24-40
  CrossrefPubMedGoogle Scholar
• 18 Pettersson A, Nagy J A, Brown L F 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(1) 99-115
  CrossrefPubMedGoogle Scholar
• 19 Nagy J A, Dvorak H F, Dvorak A M. VEGF-A and the induction of pathological angiogenesis.  Annu Rev Pathol. 2007;  2 251-275
  CrossrefPubMedGoogle Scholar
• 20 Sundberg C, Nagy J A, Brown L F et al.. Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery.  Am J Pathol. 2001;  158(3) 1145-1160
  CrossrefPubMedGoogle Scholar
• 21 Nagy J A, Vasile E, Feng D et al.. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis.  J Exp Med. 2002;  196(11) 1497-1506
  CrossrefPubMedGoogle Scholar
• 22 Nagy J A, Vasile E, Feng D et al.. VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations.  Cold Spring Harb Symp Quant Biol. 2002;  67 227-237
  CrossrefPubMedGoogle Scholar
• 23 Dadras S S, Detmar M. Angiogenesis and lymphangiogenesis of skin cancers.  Hematol Oncol Clin North Am. 2004;  18(5) 1059-1070, viii
  CrossrefPubMedGoogle Scholar
• 24 He Y, Karpanen T, Alitalo K. Role of lymphangiogenic factors in tumor metastasis.  Biochim Biophys Acta. 2004;  1654(1) 3-12
  PubMedGoogle Scholar
• 25 Jain R K. Angiogenesis and lymphangiogenesis in tumors: insights from intravital microscopy.  Cold Spring Harb Symp Quant Biol. 2002;  67 239-248
  CrossrefPubMedGoogle Scholar
• 26 Wirzenius M, Tammela T, Uutela M et al.. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting.  J Exp Med. 2007;  204(6) 1431-1440
  CrossrefPubMedGoogle Scholar
• 27 Nagy J A, Chang S H, Dvorak A M, Dvorak H F. Why are tumour blood vessels abnormal and why is it important to know?.  Br J Cancer. 2009;  100(6) 865-869
  CrossrefPubMedGoogle Scholar
• 28 Paku S, Paweletz N. First steps of tumor-related angiogenesis.  Lab Invest. 1991;  65(3) 334-346
  PubMedGoogle Scholar
• 29 Brown L F, Yeo K T, Berse B et al.. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing.  J Exp Med. 1992;  176(5) 1375-1379
  CrossrefPubMedGoogle Scholar
• 30 Ren G, Michael L H, Entman M L, Frangogiannis N G. Morphological characteristics of the microvasculature in healing myocardial infarcts.  J Histochem Cytochem. 2002;  50(1) 71-79
  CrossrefPubMedGoogle Scholar
• 31 Secomb T W, Konerding M A, West C A, Su M, Young A J, Mentzer S J. Microangiectasias: structural regulators of lymphocyte transmigration.  Proc Natl Acad Sci U S A. 2003;  100(12) 7231-7234
  CrossrefPubMedGoogle Scholar
• 32 Denekamp J, Hobson B. Endothelial-cell proliferation in experimental tumours.  Br J Cancer. 1982;  46(5) 711-720
  CrossrefPubMedGoogle Scholar
• 33 Swayne G T, Smaje L H, Bergel D H. Distensibility of single capillaries and venules in the rat and frog mesentery.  Int J Microcirc Clin Exp. 1989;  8(1) 25-42
  PubMedGoogle Scholar
• 34 Chang S H, Kanasaki K, Gocheva V et al.. VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation.  Cancer Res. 2009;  69(10) 4537-4544
  CrossrefPubMedGoogle Scholar
• 35 Cox J L. Cystatins and cancer.  Front Biosci. 2009;  14 463-474
  PubMedGoogle Scholar
• 36 Dvorak A M, Kohn S, Morgan E S, Fox P, Nagy J A, Dvorak H F. The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation.  J Leukoc Biol. 1996;  59(1) 100-115
  PubMedGoogle Scholar
• 37 Feng D, Nagy J A, Hipp J, Dvorak H F, Dvorak A M. Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin.  J Exp Med. 1996;  183(5) 1981-1986
  CrossrefPubMedGoogle Scholar
• 38 Feng D, Nagy J A, Hipp J, Pyne K, Dvorak H F, Dvorak A M. Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guinea-pig, mouse and rat: many are transcellular pores.  J Physiol. 1997;  504(Pt 3) 747-761
  CrossrefPubMedGoogle Scholar
• 39 Feng D, Nagy J A, Dvorak A M, Dvorak H F. Different pathways of macromolecule extravasation from hyperpermeable tumor vessels.  Microvasc Res. 2000;  59(1) 24-37
  CrossrefPubMedGoogle Scholar
• 40 Nagy J A, Morgan E S, Herzberg K T, Manseau E J, Dvorak A M, Dvorak H F. Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling, and stroma formation in the peritoneal lining.  Cancer Res. 1995;  55(2) 376-385
  PubMedGoogle Scholar
• 41 Egginton S, Zhou A L, Brown M D, Hudlická O. Unorthodox angiogenesis in skeletal muscle.  Cardiovasc Res. 2001;  49(3) 634-646
  CrossrefPubMedGoogle Scholar
• 42 Goffin J R, Straume O, Chappuis P O 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(6) 1031-1034
  CrossrefPubMedGoogle Scholar
• 43 Straume O, Chappuis P O, Salvesen H B et al.. Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers.  Cancer Res. 2002;  62(23) 6808-6811
  PubMedGoogle Scholar
• 44 McKee P. Pathology of the Skin with Clinical Correlations. London, United Kingdom; Mosby International 1996
  PubMedGoogle Scholar
• 45 Nagy J A, Dvorak A M, Dvorak H F. VEGF-A(164/165) and PlGF: roles in angiogenesis and arteriogenesis.  Trends Cardiovasc Med. 2003;  13(5) 169-175
  CrossrefPubMedGoogle Scholar
• 46 Fu Y, Nagy J, Dvorak A, Dvorak H. Tumor blood vessels: structure and function. In: Teicher B, Ellis L Cancer Drug Discovery and Development. Antiangiogenic Agents in Cancer Therapy. Totowa, NJ; Humana Press 2007: 205-224
  PubMedGoogle Scholar
• 47 Baker J L. Retinal capillary hemangioma.  J Am Optom Assoc. 1991;  62(10) 776-779
  PubMedGoogle Scholar
• 48 Farah M E, Uno F, Höfling-Lima A L, Morales P H, Costa R A, Cardillo J A. Transretinal feeder vessel ligature in von Hippel-Lindau disease.  Eur J Ophthalmol. 2001;  11(4) 386-388
  PubMedGoogle Scholar
• 49 Goel A, Muzumdar D, Desai K, Chagla A. Retroorbital hemangiopericytoma and cavernous sinus schwannoma—case report.  Neurol Med Chir (Tokyo). 2003;  43(1) 47-50
  CrossrefPubMedGoogle Scholar
• 50 Folberg R, Hendrix M J, Maniotis A J. Vasculogenic mimicry and tumor angiogenesis.  Am J Pathol. 2000;  156(2) 361-381
  CrossrefPubMedGoogle Scholar
• 51 Hess A R, Seftor E A, Gruman L M, Kinch M S, Seftor R E, Hendrix M J. VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: implications for vasculogenic mimicry.  Cancer Biol Ther. 2006;  5(2) 228-233
  CrossrefPubMedGoogle Scholar
• 52 Lin A Y, Ai Z, Lee S C et al.. Comparing vasculogenic mimicry with endothelial cell-lined vessels: techniques for 3D reconstruction and quantitative analysis of tissue components from archival paraffin blocks.  Appl Immunohistochem Mol Morphol. 2007;  15(1) 113-119
  PubMedGoogle Scholar
• 53 McDonald D M, Munn L, Jain R K. Vasculogenic mimicry: how convincing, how novel, and how significant?.  Am J Pathol. 2000;  156(2) 383-388
  CrossrefPubMedGoogle Scholar
• 54 Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications.  Semin Oncol. 2002;  29(6, suppl 16) 10-14
  PubMedGoogle Scholar
• 55 Kim K J, Li B, Winer J et al.. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.  Nature. 1993;  362(6423) 841-844
  CrossrefPubMedGoogle Scholar
• 56 Jain R K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.  Science. 2005;  307(5706) 58-62
  CrossrefPubMedGoogle Scholar
• 57 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(9) 1287-1295
  CrossrefPubMedGoogle Scholar
• 58 Xue Q, Nagy J A, Manseau E J, Phung T L, Dvorak H F, Benjamin L E. Rapamycin inhibition of the Akt/mTOR pathway blocks select stages of VEGF-A164-driven angiogenesis, in part by blocking S6Kinase.  Arterioscler Thromb Vasc Biol. 2009;  29(8) 1172-1178
  CrossrefPubMedGoogle Scholar
• 59 Seaman S, Stevens J, Yang M Y, Logsdon D, Graff-Cherry C, St Croix B. Genes that distinguish physiological and pathological angiogenesis.  Cancer Cell. 2007;  11(6) 539-554
  CrossrefPubMedGoogle Scholar
• 60 Shih S C, Zukauskas A, Li D et al.. The L6 protein TM4SF1 is critical for endothelial cell function and tumor angiogenesis.  Cancer Res. 2009;  69(8) 3272-3277
  CrossrefPubMedGoogle Scholar

Harold F DvorakM.D. 

Department of Pathology, Beth Israel Deaconess Medical Center

330 Brookline Avenue, RN227c, Boston, MA 02215

Email: hdvorak@bidmc.harvard.edu