© The Author 2006. Published by Oxford University Press.
ARTICLE |
Endorepellin In Vivo: Targeting the Tumor Vasculature and Retarding Cancer Growth and Metabolism
Affiliations of authors: Department of Pathology, Anatomy and Cell Biology and the Cellular Biology and Signaling Program, Kimmel Cancer Center (GB, RC, MB, JJZ, MW, RAI, RVI) and Radiopharmaceutical Research Center, Department of Radiation (CC, MLT), Thomas Jefferson University, Philadelphia, PA; Imaging and Molecular Therapeutics Section, Radiation Oncology Branch, National Cancer Institute, Bethesda, MD (CAB, KC)
Correspondence to: Renato V. Iozzo, MD, Department of Pathology, Anatomy and Cell Biology, Rm. 249 JAH, Thomas Jefferson University, Philadelphia, PA 19107 (e-mail: iozzo{at}mail.jci.tju.edu).
Background: The antiangiogenic approach to controlling cancer requires a better understanding of angiogenesis and the discovery of new compounds that modulate this key biological process. Here we investigated the role of endorepellin, an angiostatic protein fragment that is derived from the C-terminus of perlecan, a heparan sulfate proteoglycan, in controlling tumor angiogenesis in vivo. Methods: We administered human recombinant endorepellin systemically to mice bearing orthotopic squamous carcinoma xenografts or syngeneic Lewis lung carcinoma tumors. We monitored tumor growth, angiogenesis, metabolism, hypoxia, and mitotic index by using quantitative immunohistochemistry and positron emission tomography scan imaging. In addition, we determined the localization of injected endorepellin using near-infrared labeling and immunohistochemistry of frozen tumor sections. Finally, we isolated tumor-derived endothelial cells and tested whether endorepellin could interact with these cells and disrupt in vitro capillary morphogenesis. All statistical tests were two-sided. Results: Endorepellin specifically targeted the tumor vasculature as determined by immunohistochemical analysis and accumulated in the tumor perivascular zones where it persisted for several days as discrete deposits. This led to inhibition of tumor angiogenesis (as measured by decreased CD31-positive cells, mean control = 1902 CD31-positive pixels, mean endorepellin treated = 343.9, difference between means = 1558, 95% confidence interval [CI] = 1296 to 1820, P<.001), enhanced tumor hypoxia, and a statistically significant decrease in tumor metabolism and mitotic index (as measured by decreased Ki67-positive cells, mean control Ki67 pixels = 5970, mean endorepellin-treated Ki67 pixels = 3644, difference between means = 2326, 95% CI = 1904 to 2749, P<.001) compared to untreated controls. Endorepellin was actively internalized by tumor-derived endothelial cells causing a redistribution of 
2
1 integrin such that both proteins colocalized to punctate deposits in the perivascular region. Endorepellin treatment inhibited in vitro capillary morphogenesis of both normal and tumor-derived endothelia. Conclusions: Our results provide support for the hypothesis that endorepellin is an effective antitumor vasculature agent that could be used as a therapeutic modality to combat cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. D. San Antonio, J. J. Zoeller, K. Habursky, K. Turner, W. Pimtong, M. Burrows, S. Choi, S. Basra, J. S. Bennett, W. F. DeGrado, et al. A Key Role for the Integrin {alpha}2{beta}1 in Experimental and Developmental Angiogenesis Am. J. Pathol., September 1, 2009; 175(3): 1338 - 1347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Goldoni, D. G. Seidler, J. Heath, M. Fassan, R. Baffa, M. L. Thakur, R. T. Owens, D. J. McQuillan, and R. V. Iozzo An Antimetastatic Role for Decorin in Breast Cancer Am. J. Pathol., September 1, 2008; 173(3): 844 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Zoeller, A. McQuillan, J. Whitelock, S.-Y. Ho, and R. V. Iozzo A central function for perlecan in skeletal muscle and cardiovascular development J. Cell Biol., April 21, 2008; 181(2): 381 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Picchio, R. Beck, R. Haubner, S. Seidl, H.-J. Machulla, T. D. Johnson, H.-J. Wester, G. Reischl, M. Schwaiger, and M. Piert Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography J. Nucl. Med., April 1, 2008; 49(4): 597 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhang, N. E. Ramirez, T. E. Yankeelov, Z. Li, L. E. Ford, Y. Qi, A. Pozzi, and M. M. Zutter {alpha}2{beta}1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner Blood, February 15, 2008; 111(4): 1980 - 1988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P. Woodall, A. Nystrom, R. A. Iozzo, J. A. Eble, S. Niland, T. Krieg, B. Eckes, A. Pozzi, and R. V. Iozzo Integrin {alpha}2 1 Is the Required Receptor for Endorepellin Angiostatic Activity J. Biol. Chem., January 25, 2008; 283(4): 2335 - 2343. [Abstract] [Full Text] [PDF]
|
|