Abstract
Advances in imaging are transforming our understanding of angiogenesis and the evaluation of drugs that stimulate or inhibit angiogenesis in preclinical models and human disease. Vascular imaging makes it possible to quantify the number and spacing of blood vessels, measure blood flow and vascular permeability, and analyze cellular and molecular abnormalities in blood vessel walls. Microscopic methods ranging from fluorescence, confocal and multiphoton microscopy to electron microscopic imaging are particularly useful for elucidating structural and functional abnormalities of angiogenic blood vessels. Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), ultrasonography and optical imaging provide noninvasive, functionally relevant images of angiogenesis in animals and humans. An ongoing dilemma is, however, that microscopic methods provide their highest resolution on preserved tissue specimens, whereas clinical methods give images of living tissues deep within the body but at much lower resolution and specificity and generally cannot resolve vessels of the microcirculation. Future challenges include developing new imaging methods that can bridge this resolution gap and specifically identify angiogenic vessels. Another goal is to determine which microscopic techniques are the best benchmarks for interpreting clinical images. The importance of angiogenesis in cancer, chronic inflammatory diseases, age-related macular degeneration and reversal of ischemic heart and limb disease provides incentive for meeting these challenges.
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References
Brown, E.B. et al. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat. Med. 7, 864–868 (2001).
Weissleder, R. Scaling down imaging: molecular mapping of cancer in mice. Nat. Rev. Cancer 2, 11–18 (2002).
Pearlman, J.D., Laham, R.J., Post, M., Leiner, T. & Simons, M. Medical imaging techniques in the evaluation of strategies for therapeutic angiogenesis. Curr. Pharm. Des. 8, 1467–1496 (2002).
Neeman, M. Functional and molecular MR imaging of angiogenesis: seeing the target, seeing it work. J. Cell. Biochem. Suppl. 39, 11–17 (2002).
Costouros, N.G., Diehn, F.E. & Libutti, S.K. Molecular imaging of tumor angiogenesis. J. Cell. Biochem. Suppl. 39, 72–78 (2002).
Weissleder, R. & Ntziachristos, V. Shedding light onto live molecular targets. Nat. Med. 9, 123–128 (2003).
Less, J.R., Skalak, T.C., Sevick, E.M. & Jain, R.K. Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res. 51, 265–273 (1991).
Konerding, M.A., Miodonski, A.J. & Lametschwandtner, A. Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc. 9, 1233–1244 (1995).
Schlaeger, T.M. et al. Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice. Proc. Natl. Acad. Sci. USA 94, 3058–3063 (1997).
Motoike, T. et al. Universal GFP reporter for the study of vascular development. Genesis 28, 75–81 (2000).
Gale, N.W. et al. Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev. Biol. 230, 151–160 (2001).
Miettinen, M., Lindenmayer, A.E. & Chaubal, A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens—evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod. Pathol. 7, 82–90 (1994).
Schmidt, D. & von Hochstetter, A.R. The use of CD31 and collagen IV as vascular markers. A study of 56 vascular lesions. Pathol. Res. Pract. 191, 410–414 (1995).
Weidner, N. Intratumor microvessel density as a prognostic factor in cancer. Am. J. Pathol. 147, 9–19 (1995).
Hlatky, L., Hahnfeldt, P. & Folkman, J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J. Natl. Cancer Inst. 94, 883–893 (2002).
Rubin, M.A. et al. Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology 53, 542–547 (1999).
MacLennan, G.T. & Bostwick, D.G. Microvessel density in renal cell carcinoma: lack of prognostic significance. Urology 46, 27–30 (1995).
Folkman, J., Browder, T. & Palmblad, J. Angiogenesis research: guidelines for translation to clinical application. Thromb. Haemost. 86, 23–33 (2001).
Thurston, G. et al. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J. Clin. Invest. 101, 1401–1413 (1998).
Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).
Trotter, M.J., Olive, P.L. & Chaplin, D.J. Effect of vascular marker Hoechst 33342 on tumour perfusion and cardiovascular function in the mouse. Br. J. Cancer 62, 903–908 (1990).
Maniotis, A.J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999).
Shirakawa, K. et al. Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res. 61, 445–451 (2001).
Lobo, C.L., Bernardes, R.C., Santos, F.J. & Cunha-Vaz, J.G. Mapping retinal fluorescein leakage with confocal scanning laser fluorometry of the human vitreous. Arch. Ophthalmol. 117, 631–637 (1999).
Mueller, A.J., Bartsch, D.U., Schaller, U., Freeman, W.R. & Kampik, A. Imaging the microcirculation of untreated and treated human choroidal melanomas. Int. Ophthalmol. 23, 385–393 (2001).
Vale, P.R., Isner, J.M. & Rosenfield, K. Therapeutic angiogenesis in critical limb and myocardial ischemia. J. Interv. Cardiol. 14, 511–528 (2001).
Kobayashi, H. et al. 3D-micro-MR angiography of mice using macromolecular MR contrast agents with polyamidoamine dendrimer core with reference to their pharmacokinetic properties. Magn. Reson. Med. 45, 454–460 (2001).
Fleischer, A.C. et al. Quantified color Doppler sonography of tumor vascularity in an animal model. J. Ultrasound. Med. 18, 547–551 (1999).
Forsberg, F. et al. Tissue-specific US contrast agent for evaluation of hepatic and splenic parenchyma. Radiology 210, 125–132 (1999).
Iordanescu, I., Becker, C., Zetter, B., Dunning, P. & Taylor, G.A. Tumor vascularity: evaluation in a murine model with contrast-enhanced color Doppler US effect of angiogenesis inhibitors. Radiology 222, 460–467 (2002).
Forsberg, F., Merton, D.A., Liu, J.B., Needleman, L. & Goldberg, B.B. Clinical applications of ultrasound contrast agents. Ultrasonics 36, 695–701 (1998).
Calliada, F., Campani, R., Bottinelli, O., Bozzini, A. & Sommaruga, M.G. Ultrasound contrast agents: basic principles. Eur. J. Radiol. 27 (suppl. 2), S157–S160 (1998).
Yang, M. et al. Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proc. Natl. Acad. Sci. USA 99, 3824–3829 (2002).
Jain, R.K., Munn, L.L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266–276 (2002).
Helmlinger, G., Yuan, F., Dellian, M. & Jain, R.K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med. 3, 177–182 (1997).
Fukumura, D. & Jain, R.K. Role of nitric oxide in angiogenesis and microcirculation in tumors. Cancer Metastasis Rev. 17, 77–89 (1998).
Cha, S. et al. Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging. Radiology 223, 11–29 (2002).
Hawighorst, H. et al. Angiogenesis of uterine cervical carcinoma: characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement. Cancer Res. 57, 4777–4786 (1997).
Buckley, D.L. Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magn. Reson. Med. 47, 601–606 (2002).
Bremer, C. et al. Steady-state blood volume measurements in experimental tumors with different angiogenic burdens a study in mice. Radiology 226, 214–220 (2003).
Lewin, M. et al. In vivo assessment of vascular endothelial growth factor-induced angiogenesis. Int. J. Cancer 83, 798–802 (1999).
Turetschek, K. et al. Tumor microvascular characterization using ultrasmall superparamagnetic iron oxide particles (USPIO) in an experimental breast cancer model. J. Magn. Reson. Imaging 13, 882–888 (2001).
Okuhata, Y. et al. Tumor blood volume assays using contrast-enhanced magnetic resonance imaging: regional heterogeneity and postmortem artifacts. J. Magn. Reson. Imaging 9, 685–690 (1999).
Bacharach, S.L. & Sundaram, S.K. 18F-FDG in cardiology and oncology: the bitter with the sweet. J. Nucl. Med. 43, 1542–1544 (2002).
Budinger, T.F. PET instrumentation: what are the limits? Semin. Nucl. Med. 28, 247–267 (1998).
McDonald, D.M. & Baluk, P. Significance of blood vessel leakiness in cancer. Cancer Res. 62, 5381–5385 (2002).
Jain, R.K. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev. 9, 253–266 (1990).
Yuan, F. et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55, 3752–3756 (1995).
Hobbs, S.K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95, 4607–4612 (1998).
Warren, B.A. The vascular morphology of tumors. in Tumor Blood Circulation: Angiogenesis, Vascular Morphology and Blood Flow of Experimental and Human Tumors (ed. Peterson, H.-I.) 1–48 (CRC Press, Boca Raton, 1979).
Dvorak, A.M. et al. The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation. J. Leukoc. Biol. 59, 100–115 (1996).
Dvorak, H.F. et al. Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann. NY Acad. Sci. 667, 101–111 (1992).
Biggerstaff, J., Amirkhosravi, A. & Francis, J.L. Three-dimensional visualization and quantitation of fibrin in solid tumors by confocal laser scanning microscopy. Cytometry 29, 122–127 (1997).
Lichtenbeld, H.C., Yuan, F., Michel, C.C. & Jain, R.K. Perfusion of single tumor microvessels: application to vascular permeability measurement. Microcirculation 3, 349–357 (1996).
Padhani, A.R. et al. Effects of androgen deprivation on prostatic morphology and vascular permeability evaluated with MR imaging. Radiology 218, 365–374 (2001).
Bhujwalla, Z.M., Artemov, D., Natarajan, K., Ackerstaff, E. & Solaiyappan, M. Vascular differences detected by MRI for metastatic versus nonmetastatic breast and prostate cancer xenografts. Neoplasia 3, 143–153 (2001).
Pham, C.D. et al. Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest. 16, 225–230 (1998).
Padhani, A.R. & Neeman, M. Challenges for imaging angiogenesis. Br. J. Radiol. 74, 886–890 (2001).
Miles, K.A. et al. Application of CT in the investigation of angiogenesis in oncology. Acad. Radiol. 7, 840–850 (2000).
McDonald, D.M. & Foss, A.J. Endothelial cells of tumor vessels: abnormal but not absent. Cancer Metastasis Rev 19, 109–20 (2000).
Chang, Y.S. et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl. Acad. Sci. USA 97, 14608–14613 (2000).
Brooks, P.C. et al. Antiintegrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J. Clin. Invest. 96, 1815–1822 (1995).
Kim, S., Bell, K., Mousa, S.A. & Varner, J.A. Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am. J. Pathol. 156, 1345–1362 (2000).
Burrows, F.J. et al. Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin. Cancer Res. 1, 1623–1634 (1995).
Bredow, S., Lewin, M., Hofmann, B., Marecos, E. & Weissleder, R. Imaging of tumour neovasculature by targeting the TGF-β binding receptor endoglin. Eur. J. Cancer 36, 675–681 (2000).
Brekken, R.A., Huang, X., King, S.W. & Thorpe, P.E. Vascular endothelial growth factor as a marker of tumor endothelium. Cancer Res. 58, 1952–1959 (1998).
de la Torre, M. et al. Expression of the 85-kd membrane protein in primary human breast cancer: relationship to hormone receptor levels, DNA ploidy, and tumor grade. Hum. Pathol. 26, 180–185 (1995).
Bogdanov, A., Jr. et al. Treatment of experimental brain tumors with thrombospondin-1 derived peptides: an in vivo imaging study. Neoplasia 1, 438–445 (1999).
Lee, W.S. et al. Thy-1, a novel marker for angiogenesis upregulated by inflammatory cytokines. Circ. Res. 82, 845–851 (1998).
Chang, S.S. et al. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res. 59, 3192–3198 (1999).
St Croix, B. et al. Genes expressed in human tumor endothelium. Science 289, 1197–1202 (2000).
Pasqualini, R., Arap, W. & McDonald, D.M. Probing the structural and molecular diversity of tumor vasculature. Trends Mol. Med. 8, 563–571 (2002).
Koivunen, E., Wang, B. & Ruoslahti, E. Phage libraries displaying cyclic peptides with different ring sizes: ligand specificities of the RGD-directed integrins. Biotechnology (New York) 13, 265–270 (1995).
Pasqualini, R., Koivunen, E. & Ruoslahti, E. αv integrins as receptors for tumor targeting by circulating ligands. Nat. Biotechnol. 15, 542–546 (1997).
Haubner, R. et al. Noninvasive imaging of αvβ3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res. 61, 1781–1785 (2001).
Sipkins, D.A. et al. Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging. Nat. Med. 4, 623–626 (1998).
Leong-Poi, H., Christiansen, J., Klibanov, A.L., Kaul, S. & Lindner, J.R. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to αv-integrins. Circulation 107, 455–460 (2003).
Santimaria, M. et al. Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. Clin. Cancer Res. 9, 571–579 (2003).
Ran, S. & Thorpe, P.E. Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy. Int. J. Radiat. Oncol. Biol. Phys. 54, 1479–1484 (2002).
Campbell, R.B. et al. Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res. 62, 6831–6836 (2002).
Kunstfeld, R. et al. Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and melanoma growth in a “humanized” SCID mouse model. J. Invest. Dermatol. 120, 476–482 (2003).
Benjamin, L.E., Golijanin, D., Itin, A., Pode, D. & Keshet, E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103, 159–165 (1999).
Eberhard, A. et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 60, 1388–1393 (2000).
Gee, M.S. et al. Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am. J. Pathol. 162, 183–193 (2003).
Nehls, V. & Drenckhahn, D. Heterogeneity of microvascular pericytes for smooth muscle type α-actin. J. Cell. Biol. 113, 147–154 (1991).
Abramsson, A. et al. Analysis of mural cell recruitment to tumor vessels. Circulation 105, 112–117 (2002).
Nehls, V., Denzer, K. & Drenckhahn, D. Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res. 270, 469–474 (1992).
Alliot, F., Rutin, J., Leenen, P.J. & Pessac, B. Pericytes and periendothelial cells of brain parenchyma vessels co-express aminopeptidase N, aminopeptidase A, and nestin. J. Neurosci. Res. 58, 367–378 (1999).
Joyce, N.C., Haire, M.F. & Palade, G.E. Contractile proteins in pericytes. II. Immunocytochemical evidence for the presence of two isomyosins in graded concentrations. J. Cell Biol. 100, 1387–1395 (1985).
Joyce, N.C., Haire, M.F. & Palade, G.E. Contractile proteins in pericytes. I. Immunoperoxidase localization of tropomyosin. J. Cell. Biol. 100, 1379–1386 (1985).
Ozerdem, U., Grako, K.A., Dahlin-Huppe, K., Monosov, E. & Stallcup, W.B. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev. Dyn. 222, 218–227 (2001).
Schlingemann, R.O., Oosterwijk, E., Wesseling, P., Rietveld, F.J. & Ruiter, D.J. Aminopeptidase A is a constituent of activated pericytes in angiogenesis. J. Pathol. 179, 436–442 (1996).
Nielsen, B.S. et al. Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. Lab. Invest. 77, 345–355 (1997).
Buschard, K. et al. Presence of sulphatide (3′-sulphogalactosylceramide) in pericytes in the choroid layer of the eye: sharing of this glycolipid autoantigen with islets of Langerhans. Diabetologia 39, 658–666 (1996).
Takagi, H., King, G.L. & Aiello, L.P. Identification and characterization of vascular endothelial growth factor receptor (Flt) in bovine retinal pericytes. Diabetes 45, 1016–1023 (1996).
Cho, H., Kozasa, T., Bondjers, C., Betsholtz, C. & Kehrl, J.H. Pericyte-specific expression of Rgs5: implications for PDGF and EDG receptor signaling during vascular maturation. FASEB J. 440–442 (2003).
Schlingemann, R.O. et al. Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue. Am. J. Pathol. 138, 1335–1347 (1991).
Pasqualini, R. et al. Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res. 60, 722–727 (2000).
Morikawa, S. et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 160, 985–1000 (2002).
Uemura, A. et al. Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J. Clin. Invest. 110, 1619–1628 (2002).
Timpl, R. & Brown, J.C. Supramolecular assembly of basement membranes. Bioessays 18, 123–132 (1996).
Vracko, R. Basal lamina scaffold-anatomy and significance for maintenance of orderly tissue structure. Am. J. Pathol. 77, 314–346 (1974).
Latker, C.H. & Kuwabara, T. Regression of the tunica vasculosa lentis in the postnatal rat. Invest. Ophthalmol. Vis. Sci. 21, 689–699 (1981).
Taylor, N.J. et al. BOLD MRI of human tumor oxygenation during carbogen breathing. J. Magn. Reson. Imaging 14, 156–163 (2001).
Krishna, M.C., Subramanian, S., Kuppusamy, P. & Mitchell, J.B. Magnetic resonance imaging for in vivo assessment of tissue oxygen concentration. Semin. Radiat. Oncol. 11, 58–69 (2001).
Williams, B.B. et al. Imaging spin probe distribution in the tumor of a living mouse with 250 MHz EPR: correlation with BOLD MRI. Magn. Reson. Med. 47, 634–638 (2002).
Zhao, D., Constantinescu, A., Jiang, L., Hahn, E.W. & Mason, R.P. Prognostic radiology: quantitative assessment of tumor oxygen dynamics by MRI. Am. J. Clin. Oncol. 24, 462–466 (2001).
Mitchell, C.A., Risau, W. & Drexler, H.C. Regression of vessels in the tunica vasculosa lentis is initiated by coordinated endothelial apoptosis: a role for vascular endothelial growth factor as a survival factor for endothelium. Dev. Dyn. 213, 322–333 (1998).
Bartel, H. & Lametschwandtner, A. Regression of blood vessels in the ventral velum of Xenopus laevis Daudin during metamorphosis: light microscopic and transmission electron microscopic study. J. Anat. 197, 157–166 (2000).
Modlich, U., Kaup, F.J. & Augustin, H.G. Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion. Lab. Invest. 74, 771–780 (1996).
Kisker, O. et al. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 61, 7669–7674 (2001).
Laird, A.D. et al. SU6668 inhibits Flk-1/KDR and PDGFRβ in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice. FASEB J. 16, 681–690 (2002).
Sweeney, P. et al. Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin. Cancer Res. 8, 2714–2724 (2002).
Zhang, W., Ran, S., Sambade, M., Huang, X. & Thorpe, P.E. A monoclonal antibody that blocks VEGF binding to VEGFR2 (KDR/Flk-1) inhibits vascular expression of Flk-1 and tumor growth in an orthotopic human breast cancer model. Angiogenesis 5, 35–44 (2002).
Jain, R.K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl. Acad. Sci. USA 95, 10820–10825 (1998).
Jain, R.K. Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin. Oncol. 29, 3–9 (2002).
Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R.K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).
Jain, R.K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).
Fox, S.B. et al. Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res. 53, 4161–4163 (1993).
Vartanian, R.K. & Weidner, N. Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma. Am. J. Pathol. 144, 1188–1194 (1994).
Vartanian, R.K. & Weidner, N. Endothelial cell proliferation in prostatic carcinoma and prostatic hyperplasia: correlation with Gleason's score, microvessel density, and epithelial cell proliferation. Lab. Invest. 73, 844–850 (1995).
Dickson, S.E., Bicknell, R. & Fraser, H.M. Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor. J. Endocrinol. 168, 409–416 (2001).
Herbst, R.S. et al. Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. J. Clin. Oncol. 20, 3804–3814 (2002).
Thomas, J.P. et al. Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J. Clin. Oncol. 21, 223–231 (2003).
Drevs, J. et al. PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res. 62, 4015–4022 (2002).
Li, K.C., Guccione, S. & Bednarski, M.D. Combined vascular targeted imaging and therapy: a paradigm for personalized treatment. J. Cell Biochem. Suppl. 39, 65–71 (2002).
Yang, D.J. et al. Assessment of antiangiogenic effect using 99mTc-EC-endostatin. Cancer Biother. Radiopharm. 17, 233–245 (2002).
Hood, J.D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404–2407 (2002).
Anderson, S.A. et al. Magnetic resonance contrast enhancement of neovasculature with αvβ3-targeted nanoparticles. Magn. Reson. Med. 44, 433–439 (2000).
Griffioen, A.W., Damen, C.A., Martinotti, S., Blijham, G.H. & Groenewegen, G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 56, 1111–1117 (1996).
Kuzu, I., Bicknell, R., Fletcher, C.D. & Gatter, K.C. Expression of adhesion molecules on the endothelium of normal tissue vessels and vascular tumors. Lab. Invest. 69, 322–328 (1993).
Solovey, A.N. et al. Identification and functional assessment of endothelial P1H12. J. Lab. Clin. Med. 138, 322–331 (2001).
Renkonen, R., Paavonen, T., Nortamo, P. & Gahmberg, C.G. Expression of endothelial adhesion molecules in vivo. Increased endothelial ICAM-2 expression in lymphoid malignancies. Am. J. Pathol. 140, 763–767 (1992).
Burgio, V.L. et al. Characterization of EN4 monoclonal antibody: a reagent with CD31 specificity. Clin. Exp. Immunol. 96, 170–176 (1994).
Yonezawa, S. et al. Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin. Am. J. Clin. Pathol. 88, 405–411 (1987).
Padera, T.P. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002).
Roussel, F. & Dalion, J. Lectins as markers of endothelial cells: comparative study between human and animal cells. Lab. Anim. 22, 135–140 (1988).
Martin-Padura, I. et al. Expression of VE (vascular endothelial)-cadherin and other endothelial- specific markers in haemangiomas. J. Pathol. 175, 51–57 (1995).
Witmer, A.N., Dai, J., Weich, H.A., Vrensen, G.F. & Schlingemann, R.O. Expression of vascular endothelial growth factor receptors 1, 2, and 3 in quiescent endothelia. J. Histochem. Cytochem. 50, 767–777 (2002).
Holash, J. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl. Acad. Sci. USA 99, 11393–11398 (2002).
Acknowledgements
We thank P. Baluk, H. Hashizume, A. Haskell, T. Inai, I. Kasman, M. Mancuso and S. Morikawa (all in the McDonald lab), M. Krishna (National Cancer Institute), and M. Konerding (University of Mainz, Germany) for supplying many of the images; R. Pasqualini and W. Arap (M.D. Anderson Cancer Center, Houston), and V. Yao and M. Ozawa (University of California, San Francisco) for the RGD-4C phage; R. Brekken (University of Washington) for the antibody to VEGFR-2; A. Uemura (Kyoto University, Japan), for the antibody to PDGFR-β; and G. Thurston (Regeneron Pharmaceuticals) for the VEGF-Trap. Supported in part by National Institutes of Health grants HL-24136 and HL-59157 from the National, Heart, Lung and Blood Institute and P50-CA90270 from the National Cancer Institute, University of California BioSTAR Project 00-10106 in conjunction with Eos Biotechnology, Inc., and funding from AngelWorks Foundation and the Vascular Mapping Project (D.M.M.).
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McDonald, D., Choyke, P. Imaging of angiogenesis: from microscope to clinic. Nat Med 9, 713–725 (2003). https://doi.org/10.1038/nm0603-713
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DOI: https://doi.org/10.1038/nm0603-713
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