Abstract
Tumors depend on a vascular supply for their growth. Tumor blood vessels, which are derived from normal tissue vasculature, display a markedly abnormal phenotype. Tumor endothelial properties are highly varied in space and time. An important goal is to delineate the range of phenotypes in tumor endothelium and to identify tumor endothelial-specific molecular signatures. This information should lead to a more complete understanding of the mechanisms of tumor growth, the discovery of new therapeutic targets, and the development of biomarkers for diagnosis and surveillance. The goals of this review are to outline recent advances in dissecting tumor endothelial-cell-specific gene expression, to address mechanisms of phenotypic heterogeneity in tumor vascular beds, and to discuss the therapeutic implications of these findings.
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Abid MR, Yi X, Yano K, Shih SC, Aird WC (2006) Vascular endocan is preferentially expressed in tumor endothelium. Microvasc Res 72:136–145
Aird WC (2006) Mechanisms of endothelial cell heterogeneity in health and disease. Circ Res 98:159–162
Aird WC (2007a) Endothelial biomedicine. Cambridge University Press, Cambridge New York
Aird WC (2007b) Phenotypic heterogeneity of the endothelium. I. Structure, function, and mechanisms. Circ Res 100:158–173
Aird WC (2007c) Phenotypic heterogeneity of the endothelium. II. Representative vascular beds. Circ Res 100:174–190
Arap W, Pasqualini R, Ruoslahti E (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279:377–380
Bagley RG, Walter-Yohrling J, Cao X, Weber W, Simons B, Cook BP et al (2003) Endothelial precursor cells as a model of tumor endothelium: characterization and comparison with mature endothelial cells. Cancer Res 63:5866–5873
Balestrieri ML, Napoli C (2007) Novel challenges in exploring peptide ligands and corresponding tissue-specific endothelial receptors. Eur J Cancer 43:1242–1250
Baluk P, Hashizume H, McDonald DM (2005) Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 15:102–111
Barnes CM, Huang S, Kaipainen A, Sanoudou D, Chen EJ, Eichler GS et al (2005) Evidence by molecular profiling for a placental origin of infantile hemangioma. Proc Natl Acad Sci USA 102:19097–19102
Boye E, Yu Y, Paranya G, Mulliken JB, Olsen BR, Bischoff J (2001) Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107:745–752
Buckanovich RJ, Sasaroli D, O’Brien-Jenkins A, Botbyl J, Hammond R, Katsaros D et al (2007) Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol 25:852–861
Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW et al (1995) Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1:1623–1634
Bussolati B, Deambrosis I, Russo S, Deregibus MC, Camussi G (2003) Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J 17:1159–1161
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257
Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW, St Croix B (2001) Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res 61:6649–6655
Carson-Walter EB, Hampton J, Shue E, Geynisman DM, Pillai PK, Sathanoori R et al (2005) Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis. Clin Cancer Res 11:7643–7650
Chang SS, O’Keefe DS, Bacich DJ, Reuter VE, Heston WD, Gaudin PB (1999) Prostate-specific membrane antigen is produced in tumor-associated neovasculature. Clin Cancer Res 5:2674–2681
Curnis F, Gasparri A, Sacchi A, Longhi R, Corti A (2004) Coupling tumor necrosis factor-alpha with alphaV integrin ligands improves its antineoplastic activity. Cancer Res 64:565–571
Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582–1584
Davies G, Cunnick GH, Mansel RE, Mason MD, Jiang WG (2004) Levels of expression of endothelial markers specific to tumour-associated endothelial cells and their correlation with prognosis in patients with breast cancer. Clin Exp Metastasis 21:31–37
Denekamp J, Hobson B (1982) Endothelial-cell proliferation in experimental tumours. Br J Cancer 46:711–720
di Tomaso E, Capen D, Haskell A, Hart J, Logie JJ, Jain RK et al (2005) Mosaic tumor vessels: cellular basis and ultrastructure of focal regions lacking endothelial cell markers. Cancer Res 65:5740–5749
Durr E, Yu J, Krasinska KM, Carver LA, Yates JR, Testa JE et al (2004) Direct proteomic mapping of the lung microvascular endothelial cell surface in vivo and in cell culture. Nat Biotechnol 22:985–992
Dwenger A, Rosenthal F, Machein M, Waller C, Spyridonidis A (2004) Transplanted bone marrow cells preferentially home to the vessels of in situ generated murine tumors rather than of normal organs. Stem Cells 22:86–92
Espina V, Wulfkuhle JD, Calvert VS, VanMeter A, Zhou W, Coukos G et al (2006) Laser-capture microdissection. Nat Protoc 1:586–603
Essler M, Ruoslahti E (2002) Molecular specialization of breast vasculature: a breast-homing phage-displayed peptide binds to aminopeptidase P in breast vasculature. Proc Natl Acad Sci USA 99:2252–2257
Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286
Fukumura D, Jain RK (2007) Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 74:72–84
Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK (1997) Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am J Pathol 151:679–688
Gasparini G, Brooks PC, Biganzoli E, Vermeulen PB, Bonoldi E, Dirix LY et al (1998) Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. Clin Cancer Res 4:2625–2634
Gerritsen ME, Tomlinson JE, Zlot C, Ziman M, Hwang S (2003) Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. Br J Pharmacol 140:595–610
Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G (1996) Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res 56:1111–1117
Hellebrekers DM, Castermans K, Vire E, Dings RP, Hoebers NT, Mayo KH et al (2006a) Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications. Cancer Res 66:10770–10777
Hellebrekers DM, Jair KW, Vire E, Eguchi S, Hoebers NT, Fraga MF et al (2006b) Angiostatic activity of DNA methyltransferase inhibitors. Mol Cancer Ther 5:467–475
Hellebrekers DM, Melotte V, Vire E, Langenkamp E, Molema G, Fuks F et al (2007) Identification of epigenetically silenced genes in tumor endothelial cells. Cancer Res 67:4138–4148
Hellwig SM, Damen CA, Adrichem NP van, Blijham GH, Groenewegen G, Griffioen AW (1997) Endothelial CD34 is suppressed in human malignancies: role of angiogenic factors. Cancer Lett 120:203–211
Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, Klagsbrun M (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64:8249–8255
Hinnen P, Eskens FA (2007) Vascular disrupting agents in clinical development. Br J Cancer 96:1159–1165
Hoffman JA, Giraudo E, Singh M, Zhang L, Inoue M, Porkka K et al (2003) Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 4:383–391
Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998
Hughes CC (2008) Endothelial-stromal interactions in angiogenesis. Curr Opin Hematol 15:204–209
Hwa C, Sebastian A, Aird WC (2005) Endothelial biomedicine: its status as an interdisciplinary field, its progress as a basic science, and its translational bench-to-bedside gap. Endothelium 12:139–151
Jih YJ, Lien WH, Tsai WC, Yang GW, Li C, Wu LW (2001) Distinct regulation of genes by bFGF and VEGF-A in endothelial cells. Angiogenesis 4:313–321
Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049
Kim S, Bell K, Mousa SA, Varner JA (2000) Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 156:1345–1362
Laakkonen P, Porkka K, Hoffman JA, Ruoslahti E (2002) A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 8:751–755
Lee HK, Bae HR, Park HK, Seo IA, Lee EY, Suh DJ, Park HT (2005) Cloning, characterization and neuronal expression profiles of tumor endothelial marker 7 in the rat brain. Brain Res Mol Brain Res 136:189–198
Li JL, Harris AL (2007) The potential of new tumor endothelium-specific markers for the development of antivascular therapy. Cancer Cell 11:478–481
Li H, Fan X, Houghton J (2007) Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 101:805–815
Liu H, Moy P, Kim S, Xia Y, Rajasekaran A, Navarro Vet al (1997) Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res 57:3629–3634
Lu C, Bonome T, Li Y, Kamat AA, Han LY, Schmandt R et al (2007) Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res 67:1757–1768
Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201
Madden SL, Cook BP, Nacht M, Weber WD, Callahan MR, Jiang Y et al (2004) Vascular gene expression in nonneoplastic and malignant brain. Am J Pathol 165:601–608
McDonald DM, Baluk P (2002) Significance of blood vessel leakiness in cancer. Cancer Res 62:5381–5385
Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000
Neri D, Bicknell R (2005) Tumour vascular targeting. Nat Rev Cancer 5:436–446
Oh P, Li Y, Yu J, Durr E, Krasinska KM, Carver LA et al (2004) Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature 429:629–635
Opavsky R, Haviernik P, Jurkovicova D, Garin MT, Copeland NG, Gilbert DJ et al (2001) Molecular characterization of the mouse Tem1/endosialin gene regulated by cell density in vitro and expressed in normal cells in vivo. J Biol Chem 6:6
Parker BS, Argani P, Cook BP, Liangfeng H, Chartrand SD, Zhang M et al (2004) Alterations in vascular gene expression in invasive breast carcinoma. Cancer Res 64:7857–7866
Pasqualini R, Koivunen E, Kain R, Lahdenranta J, Sakamoto M, Stryhn A et al (2000) Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60:722–727
Pen A, Moreno MJ, Martin J, Stanimirovic DB (2007) Molecular markers of extracellular matrix remodeling in glioblastoma vessels: microarray study of laser-captured glioblastoma vessels. Glia 55:559–572
Popkov M, Jendreyko N, McGavern DB, Rader C, Barbas CF (2005) Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody. Cancer Res 65:972–981
Purhonen S, Palm J, Rossi D, Kaskenpaa N, Rajantie I, Ylä-Herttuala S et al (2008) Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 105:6620–6625
Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44
Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Jaffe EA, Old LJ (1992) Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci USA 89:10832–10836
Rmali KA, Puntis MC, Jiang WG (2005) Prognostic values of tumor endothelial markers in patients with colorectal cancer. World J Gastroenterol 11:1283–1286
Roberts WG, Delaat J, Nagane M, Huang S, Cavenee WK, Palade GE (1998) Host microvasculature influence on tumor vascular morphology and endothelial gene expression. Am J Pathol 153:1239–1248
Ruoslahti E, Rajotte D (2000) An address system in the vasculature of normal tissues and tumors. Annu Rev Immunol 18:813–827
Schliemann C, Neri D (2007) Antibody-based targeting of the tumor vasculature. Biochim Biophys Acta 1776:175–192
Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St Croix B (2007) Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11:539–554
Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81–85
Simonson AB, Schnitzer JE (2007) Vascular proteomic mapping in vivo. J Thromb Haemost 5 (Suppl 1):183–187
St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E et al (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202
Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP, Belperio JA (2006) Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer 42:768–778
Teicher BA (2007) Newer vascular targets: endosialin (review). Int J Oncol 30:305–312
Teodoro JG, Parker AE, Zhu X, Green MR (2006) p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 313:968–971
Tozer GM, Kanthou C, Baguley BC (2005) Disrupting tumour blood vessels. Nat Rev Cancer 5:423–435
Unger RE, Oltrogge JB, Briesen H von, Engelhardt B, Woelki U, Schlote W et al (2002) Isolation and molecular characterization of brain microvascular endothelial cells from human brain tumors. In Vitro Cell Dev Biol Anim 38:273–281
Valadon P, Garnett JD, Testa JE, Bauerle M, Oh P, Schnitzer JE (2006) Screening phage display libraries for organ-specific vascular immunotargeting in vivo. Proc Natl Acad Sci USA 103:407–412
van Beijnum JR, Griffioen AW (2005) In silico analysis of angiogenesis associated gene expression identifies angiogenic stage related profiles. Biochim Biophys Acta 1755:121–134
van Beijnum JR, Dings RP, Linden E van der, Zwaans BM, Ramaekers FC, Mayo KH, Griffioen AW (2006) Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood 108:2339–2348
Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Mäkinen T et al (2004) Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36:687–693
Yung YC, Cheshier S, Santarelli JG, Huang Z, Wagers A, Weissman I, Tse V (2004) Incorporation of naive bone marrow derived cells into the vascular architecture of brain tumor. Microcirculation 11:699–708
Zhang L, Hoffman JA, Ruoslahti E (2005) Molecular profiling of heart endothelial cells. Circulation 112:1601–1611
Zhang L, Giraudo E, Hoffman JA, Hanahan D, Ruoslahti E (2006) Lymphatic zip codes in premalignant lesions and tumors. Cancer Res 66:5696–5706
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The author thanks Steven Moskowitz for his artwork and Marianne Grant for her help with formatting. This work was supported by NIH grant HL076540.
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Aird, W.C. Molecular heterogeneity of tumor endothelium. Cell Tissue Res 335, 271–281 (2009). https://doi.org/10.1007/s00441-008-0672-y
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DOI: https://doi.org/10.1007/s00441-008-0672-y