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Heterogeneity of Angiogenesis and Blood Vessel Maturation in Human Tumors: Implications for Antiangiogenic Tumor Therapies¹

Cell Biology Laboratory, Department of Gynecology and Obstetrics [A. E., S. K., V. G., H. G. A.] and Department of Pathology [B. H.], University of Göttingen Medical School, 37075 Göttingen, Germany, and Department of Neuropathology, Erlangen-Nürnberg University Medical School, 91054 Erlangen, Germany [K. H. P.]

Microvessel density (MVD) counting techniques have been widely used to assess the vasculature in tumors. MVD counts assess the presence of blood vessels but do not give an indication of the degree of angiogenesis and the functional status of the tumor neovasculature. To analyze angiogenesis and the functional status of the tumor vascular bed, we have quantitated endothelial cell proliferation and the recruitment of pericytes in human tumors [glioblastomas (n = 30), renal cell carcinomas (n = 22), colon carcinomas (n = 18), mammary carcinomas (n = 24), lung carcinomas (n = 15), and prostate carcinomas (n = 19)]. These findings were compared to the physiological angiogenesis in the cyclic bovine ovarian corpus luteum. Tissue sections were examined applying double-labeling immunohistochemical techniques to detect proliferating endothelial cells and to colocalize endothelial cells and pericytes. The following parameters were quantitated: (a) MVD count; (b) proliferating capillary index (PCI); (c) proliferating tumor versus endothelial cell index; and (d) microvessel pericyte coverage index (MPI). Based on endothelial cell proliferation, angiogenesis was found to be present in all tumors with characteristic and significant differences between the tumor types (glioblastomas, PCI = 9.6 ± 6.1%; renal cell carcinomas, PCI = 9.4 ± 5.2%; colon carcinomas, PCI = 7.8 ± 5.2%; mammary carcinomas, PCI = 5.0 ± 4.8%; lung carcinomas, PCI = 2.6 ± 2.5%; prostate carcinomas, PCI = 2.0 ± 1.4%). There was a considerable degree of heterogeneity in the intensity of angiogenesis within each tumor group, as indicated by large standard deviations. Even in the most angiogenic tumors, angiogenesis was found to be 4 to 20 times less intense as compared with the physiological angiogenesis in the growing ovarian corpus rubrum (PCI = 40.6 ± 6.2%). Varying degrees of pericyte recruitment to the tumor microvasculature were determined in the different tumor types (glio-blastomas, MPI = 12.7 ± 7.9%; renal cell carcinomas, MPI = 17.9 ± 7.8%; colon carcinomas, MPI = 65.4 ± 10.5%; mammary carcinomas, MPI = 67.3 ± 14.2%; lung carcinomas, MPI = 40.8 ± 14.5%; prostate carcinomas, MPI = 29.6 ± 9.5%). The data demonstrate distinct quantitative variations in the intensity of angiogenesis in malignant human tumors. Furthermore, the varying degrees of pericyte recruitment indicate differences in the functional status of the tumor vasculature in different tumors that may reflect varying degrees of maturation of the tumor vascular bed.

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				W. W. Spurbeck, C. Y. C. Ng, T. S. Strom, E. F. Vanin, and A. M. Davidoff Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model Blood, October 16, 2002; 100(9): 3361 - 3368. [Abstract] [Full Text] [PDF]

				G. A. Christoforidis, J. C. Grecula, H. B. Newton, A. Kangarlu, A. M. Abduljalil, P. Schmalbrock, and D. W Chakeres Visualization of Microvascularity in Glioblastoma Multiforme With 8-T High-Spatial-Resolution MR Imaging AJNR Am. J. Neuroradiol., October 1, 2002; 23(9): 1553 - 1556. [Abstract] [Full Text] [PDF]

				M. Hangai, N. Kitaya, J. Xu, C. K. Chan, J. J. Kim, Z. Werb, S. J. Ryan, and P. C. Brooks Matrix Metalloproteinase-9-Dependent Exposure of a Cryptic Migratory Control Site in Collagen is Required before Retinal Angiogenesis Am. J. Pathol., October 1, 2002; 161(4): 1429 - 1437. [Abstract] [Full Text] [PDF]

				F. A. Scappaticci Mechanisms and Future Directions for Angiogenesis-Based Cancer Therapies J. Clin. Oncol., September 15, 2002; 20(18): 3906 - 3927. [Abstract] [Full Text] [PDF]

				L. Hlatky, P. Hahnfeldt, and J. Folkman Clinical Application of Antiangiogenic Therapy: Microvessel Density, What It Does and Doesn't Tell Us J Natl Cancer Inst, June 19, 2002; 94(12): 883 - 893. [Full Text] [PDF]

				S. Man, G. Bocci, G. Francia, S. K. Green, S. Jothy, D. Hanahan, P. Bohlen, D. J. Hicklin, G. Bergers, and R. S. Kerbel Antitumor Effects in Mice of Low-dose (Metronomic) Cyclophosphamide Administered Continuously through the Drinking Water Cancer Res., May 1, 2002; 62(10): 2731 - 2735. [Abstract] [Full Text] [PDF]

				A. Adini, T. Kornaga, F. Firoozbakht, and L. E. Benjamin Placental Growth Factor Is a Survival Factor for Tumor Endothelial Cells and Macrophages Cancer Res., May 1, 2002; 62(10): 2749 - 2752. [Abstract] [Full Text] [PDF]

				A. Giatromanolaki, E. Sivridis, G. Minopoulos, A. Polychronidis, C. Manolas, C. Simopoulos, and M. I. Koukourakis Differential Assessment of Vascular Survival Ability and Tumor Angiogenic Activity in Colorectal Cancer Clin. Cancer Res., May 1, 2002; 8(5): 1185 - 1191. [Abstract] [Full Text] [PDF]

				S. Morikawa, P. Baluk, T. Kaidoh, A. Haskell, R. K. Jain, and D. M. McDonald Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors Am. J. Pathol., March 1, 2002; 160(3): 985 - 1000. [Abstract] [Full Text] [PDF]

				J. C. Lee, D. C. Kim, M. S. Gee, H. M. Saunders, C. M. Sehgal, M. D. Feldman, S. R. Ross, and W. M. F. Lee Interleukin-12 Inhibits Angiogenesis and Growth of Transplanted but not in Situ Mouse Mammary Tumor Virus-induced Mammary Carcinomas Cancer Res., February 1, 2002; 62(3): 747 - 755. [Abstract] [Full Text] [PDF]

				R. S. Kerbel, G. Klement, K. I. Pritchard, and B. Kamen Continuous low-dose anti-angiogenic/metronomic chemotherapy: from the research laboratory into the oncology clinic Ann. Onc., January 19, 2002; 13(1): 12 - 15. [Full Text] [PDF]

				A. K. Sood, M. S. Fletcher, and M. J. C. Hendrix The Embryonic-Like Properties of Aggressive Human Tumor Cells Reproductive Sciences, January 1, 2002; 9(1): 2 - 9. [Abstract] [PDF]

				S. Franco, I. Segura, H. H. Riese, and M. A. Blasco Decreased B16F10 Melanoma Growth and Impaired Vascularization in Telomerase-deficient Mice with Critically Short Telomeres Cancer Res., January 1, 2002; 62(2): 552 - 559. [Abstract] [Full Text] [PDF]

				G. Klement, P. Huang, B. Mayer, S. K. Green, S. Man, P. Bohlen, D. Hicklin, and R. S. Kerbel Differences in Therapeutic Indexes of Combination Metronomic Chemotherapy and an Anti-VEGFR-2 Antibody in Multidrug-resistant Human Breast Cancer Xenografts Clin. Cancer Res., January 1, 2002; 8(1): 221 - 232. [Abstract] [Full Text] [PDF]

				A. Abramsson, O. Berlin, H. Papayan, D. Paulin, M. Shani, and C. Betsholtz Analysis of Mural Cell Recruitment to Tumor Vessels Circulation, January 1, 2002; 105(1): 112 - 117. [Abstract] [Full Text] [PDF]

				Y. Song, L. Wu, J. C. Shryock, and L. Belardinelli Selective Attenuation of Isoproterenol-Stimulated Arrhythmic Activity by a Partial Agonist of Adenosine A1 Receptor Circulation, January 1, 2002; 105(1): 118 - 123. [Abstract] [Full Text] [PDF]

				C. Mundhenke, J. P. Thomas, G. Wilding, F. T. Lee, F. Kelzc, R. Chappell, R. Neider, L. A. Sebree, and A. Friedl Tissue Examination to Monitor Antiangiogenic Therapy: A Phase I Clinical Trial with Endostatin Clin. Cancer Res., November 1, 2001; 7(11): 3366 - 3374. [Abstract] [Full Text] [PDF]

				H. G. Augustin Tubes, Branches, and Pillars: The Many Ways of Forming a New Vasculature Circ. Res., October 12, 2001; 89(8): 645 - 647. [Full Text] [PDF]

				A R Padhani and M Neeman Challenges for imaging angiogenesis Br. J. Radiol., October 1, 2001; 74(886): 886 - 890. [Full Text] [PDF]

				Y. Dor, R. Porat, and E. Keshet Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1367 - C1374. [Abstract] [Full Text] [PDF]

				A. K. Sood, E. A. Seftor, M. S. Fletcher, L. M. G. Gardner, P. M. Heidger, R. E. Buller, R. E. B. Seftor, and M. J. C. Hendrix Molecular Determinants of Ovarian Cancer Plasticity Am. J. Pathol., April 1, 2001; 158(4): 1279 - 1288. [Abstract] [Full Text] [PDF]

				D. J. Brat and E. G. Van Meir Glomeruloid Microvascular Proliferation Orchestrated by VPF/VEGF : A New World of Angiogenesis Research Am. J. Pathol., March 1, 2001; 158(3): 789 - 796. [Full Text] [PDF]

				K. D. Miller, C. J. Sweeney, and G. W. Sledge Jr Redefining the Target: Chemotherapeutics as Antiangiogenics J. Clin. Oncol., February 15, 2001; 19(4): 1195 - 1206. [Abstract] [Full Text] [PDF]

				R. M. Shaheen, W. W. Tseng, D. W. Davis, W. Liu, N. Reinmuth, R. Vellagas, A. A. Wieczorek, Y. Ogura, D. J. McConkey, K. E. Drazan, et al. Tyrosine Kinase Inhibition of Multiple Angiogenic Growth Factor Receptors Improves Survival in Mice Bearing Colon Cancer Liver Metastases by Inhibition of Endothelial Cell Survival Mechanisms Cancer Res., February 1, 2001; 61(4): 1464 - 1468. [Abstract] [Full Text]

				D. H. Gorski and K. Walsh The Role of Homeobox Genes in Vascular Remodeling and Angiogenesis Circ. Res., November 10, 2000; 87(10): 865 - 872. [Abstract] [Full Text] [PDF]