| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
¶¶
From the Biomedical Graduate Program,* the Departments of Medicine and Pathology and Laboratory Medicine, and the Cancer Center, University of Pennsylvania School of Medicine, Philadelphia; and the Veterans Affairs Medical Center,¶ Philadelphia, Pennsylvania
The effect of anti-vascular agents on the growth of experimental tumors is well studied. Their impact on tumor vasculature, the primary therapeutic target of these agents, is not as well characterized, even though this primarily determines treatment outcome. Hypothesizing that the response of vessels to therapy is influenced by their stage of maturation, we studied vascular development and the vascular effects of therapy in several transplanted murine tumor models. Based on size, perfusion, endothelial cell (EC) proliferation, and the presence of pericytes, tumor vessels segregated into three categories. Least mature were highly proliferative, nonperfused EC sprouts emanating from functional vessels. Intermediate were small, perfused vessels which, like the angiogenic sprouts, were not covered by pericytes. Most mature were larger vessels, which were predominantly pericyte-covered with quiescent ECs and few associated sprouts. Thus, a developmental order, similar to that described during physiological neovascularization, was evident among vessels in growing tumors. This order markedly influenced tumor vessel response to anti-vascular therapy with recombinant interleukin-12. Therapy reduced tumor vessel density, which was attributable to a decrease in angiogenic sprouts and induction of EC apoptosis in pericyte-negative vessels. Although the great majority of vessels in growing tumors lacked pericyte coverage, selective loss of less mature vessels with therapy significantly increased the fraction of pericyte-positive vessels after therapy. These data indicate that the therapeutic susceptibility of tumor vasculature to recombinant murine IL-12 and, potentially, other anti-vascular agents is limited by its level of maturation. An implication is that tumor susceptibility is similarly limited, making pericyte coverage of tumor vasculature a potential indicator of tumor responsiveness.
Related articles in Am J Pathol:
This article has been cited by other articles:
 |
|
 |
|
  D. T. Dang, S. Y. Chun, K. Burkitt, M. Abe, S. Chen, P. Havre, N. J. Mabjeesh, E. I. Heath, N. J. Vogelzang, M. Cruz-Correa, et al. Hypoxia-Inducible Factor-1 Target Genes as Indicators of Tumor Vessel Response to Vascular Endothelial Growth Factor Inhibition Cancer Res., March 15, 2008; 68(6): 1872 - 1880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ju, C. Mailhos, J. Bradley, T. Dowie, M. Ganley, G. Cook, P. Calias, N. Lange, A. P. Adamis, D. T. Shima, et al. Simultaneous but Not Prior Inhibition of VEGF165 Enhances the Efficacy of Photodynamic Therapy in Multiple Models of Ocular Neovascularization Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 662 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Atluri, C. M. Panlilio, G. P. Liao, E. E. Suarez, R. C. McCormick, W. Hiesinger, J. E. Cohen, M. J. Smith, A. B. Patel, W. Feng, et al. Transmyocardial revascularization to enhance myocardial vasculogenesis and hemodynamic function. J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 283 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Braun, H. Xu, F. Hu, P. Kocherlakota, D. Siegel, P. Chander, Z. Ungvari, A. Csiszar, M. Nedergaard, and P. Ballabh Paucity of Pericytes in Germinal Matrix Vasculature of Premature Infants J. Neurosci., October 31, 2007; 27(44): 12012 - 12024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Kutcher, A. Y. Kolyada, H. K. Surks, and I. M. Herman Pericyte Rho GTPase Mediates Both Pericyte Contractile Phenotype and Capillary Endothelial Growth State Am. J. Pathol., August 1, 2007; 171(2): 693 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lu, A. A. Kamat, Y. G. Lin, W. M. Merritt, C. N. Landen, T. J. Kim, W. Spannuth, T. Arumugam, L. Y. Han, N. B. Jennings, et al. Dual Targeting of Endothelial Cells and Pericytes in Antivascular Therapy for Ovarian Carcinoma Clin. Cancer Res., July 15, 2007; 13(14): 4209 - 4217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-E. Jockovich, M. L. Bajenaru, Y. Pina, F. Suarez, W. Feuer, M. E. Fini, and T. G. Murray Retinoblastoma Tumor Vessel Maturation Impacts Efficacy of Vessel Targeting in the LHBETATAG Mouse Model Invest. Ophthalmol. Vis. Sci., June 1, 2007; 48(6): 2476 - 2482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ramsauer and P. A. D'Amore Contextual role for angiopoietins and TGFbeta1 in blood vessel stabilization J. Cell Sci., May 15, 2007; 120(10): 1810 - 1817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Avramis, E. H. Panosyan, F. Dorey, J. S. Holcenberg, and V. I. Avramis Correlation between High Vascular Endothelial Growth Factor-A Serum Levels and Treatment Outcome in Patients with Standard-Risk Acute Lymphoblastic Leukemia: A Report from Children's Oncology Group Study CCG-1962 Clin. Cancer Res., December 1, 2006; 12(23): 6978 - 6984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Murphy, S. Makonnen, W. Lassoued, M. D. Feldman, C. Carter, and W. M.F. Lee Inhibition of Tumor Endothelial ERK Activation, Angiogenesis, and Tumor Growth by Sorafenib (BAY43-9006) Am. J. Pathol., November 1, 2006; 169(5): 1875 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, E. Taguchi, T. Miura, A. Yamamoto, K. Takahashi, F. Bichat, N. Guilbaud, K. Hasegawa, K. Kubo, Y. Fujiwara, et al. KRN951, a Highly Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Has Antitumor Activities and Affects Functional Vascular Properties. Cancer Res., September 15, 2006; 66(18): 9134 - 9142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy. Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]
|
|
|
|
|
|
N. S. Patel, M. S. Dobbie, M. Rochester, G. Steers, R. Poulsom, K. Le Monnier, D. W. Cranston, J.-L. Li, and A. L. Harris Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer. Clin. Cancer Res., August 15, 2006; 12(16): 4836 - 4844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bondjers, L. He, M. Takemoto, J. Norlin, N. Asker, M. Hellstrom, P. Lindahl, and C. Betsholtz Microarray analysis of blood microvessels from PDGF-B and PDGF-R{beta} mutant mice identifies novel markers for brain pericytes FASEB J, August 1, 2006; 20(10): 1703 - 1705. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Munchhof, F. Li, H. A. White, L. E. Mead, T. R. Krier, A. Fenoglio, X. Li, J. Yuan, F.-C. Yang, and D. A. Ingram Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells Hum. Mol. Genet., June 1, 2006; 15(11): 1858 - 1869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Martinive, J. De Wever, C. Bouzin, C. Baudelet, P. Sonveaux, V. Gregoire, B. Gallez, and O. Feron Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery. Mol. Cancer Ther., June 1, 2006; 5(6): 1620 - 1627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Jo, C. Mailhos, M. Ju, E. Cheung, J. Bradley, K. Nishijima, G. S. Robinson, A. P. Adamis, and D. T. Shima Inhibition of Platelet-Derived Growth Factor B Signaling Enhances the Efficacy of Anti-Vascular Endothelial Growth Factor Therapy in Multiple Models of Ocular Neovascularization Am. J. Pathol., June 1, 2006; 168(6): 2036 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Atluri, G. P. Liao, C. M. Panlilio, V. M. Hsu, M. J. Leskowitz, K. J. Morine, J. E. Cohen, M. F. Berry, E. E. Suarez, D. A. Murphy, et al. Neovasculogenic therapy to augment perfusion and preserve viability in ischemic cardiomyopathy. Ann. Thorac. Surg., May 1, 2006; 81(5): 1728 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Kan, S. Phongkitkarun, S. Kobayashi, Y. Tang, L. M. Ellis, T. Y. Lee, and C. Charnsangavej Functional CT for Quantifying Tumor Perfusion in Antiangiogenic Therapy in a Rat Model Radiology, October 1, 2005; 237(1): 151 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. W. B. Jeffes, J. G. Zhang, N. Hoa, A. Petkar, C. Delgado, S. Chong, A. Obenaus, R. Sanchez, S. Khalaghizadeh, T. Khomenko, et al. Antiangiogenic Drugs Synergize with a Membrane Macrophage Colony-Stimulating Factor-Based Tumor Vaccine to Therapeutically Treat Rats with an Established Malignant Intracranial Glioma J. Immunol., March 1, 2005; 174(5): 2533 - 2543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. McCarty, J. Wey, O. Stoeltzing, W. Liu, F. Fan, C. Bucana, P. F. Mansfield, A. J. Ryan, and L. M. Ellis ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer Mol. Cancer Ther., September 1, 2004; 3(9): 1041 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Fenton, S. F. Paoni, and I. Ding Pathophysiological Effects of Vascular Endothelial Growth Factor Receptor-2-Blocking Antibody plus Fractionated Radiotherapy on Murine Mammary Tumors Cancer Res., August 15, 2004; 64(16): 5712 - 5719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Furuhashi, T. Sjoblom, A. Abramsson, J. Ellingsen, P. Micke, H. Li, E. Bergsten-Folestad, U. Eriksson, R. Heuchel, C. Betsholtz, et al. Platelet-Derived Growth Factor Production by B16 Melanoma Cells Leads to Increased Pericyte Abundance in Tumors and an Associated Increase in Tumor Growth Rate Cancer Res., April 15, 2004; 64(8): 2725 - 2733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Cattley and B. R. Radinsky Cancer Therapeutics: Understanding the Mechanism of Action Toxicol Pathol, January 1, 2004; 32(1_suppl): 116 - 121. [Abstract] [PDF]
|
|
|
|
|
|
M. S. Gee, S. Makonnen, K. al-Kofahi, B. Roysam, F. Payvandi, H.-W. Man, G. W. Muller, and W. M. F. Lee Selective Cytokine Inhibitory Drugs with Enhanced Antiangiogenic Activity Control Tumor Growth through Vascular Inhibition Cancer Res., December 1, 2003; 63(23): 8073 - 8078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Baluk, S. Morikawa, A. Haskell, M. Mancuso, and D. M. McDonald Abnormalities of Basement Membrane on Blood Vessels and Endothelial Sprouts in Tumors Am. J. Pathol., November 1, 2003; 163(5): 1801 - 1815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. McAlhany, S. J. Ressler, M. Larsen, J. A. Tuxhorn, F. Yang, T. D. Dang, and D. R. Rowley Promotion of Angiogenesis by ps20 in the Differential Reactive Stroma Prostate Cancer Xenograft Model Cancer Res., September 15, 2003; 63(18): 5859 - 5865. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
