| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
* Departments of Medicine and Oncology, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada H3A 1A1;
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Department of Clinical Biochemistry, Haddassah Medical School, Jerusalem, Israel IL-91120;
§ Institute for Cancer Research and Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Ft. Worth, Texas 76107, USA;
** Department of Biology; Ångstrom Pharmaceuticals Inc., San Diego, California 92121, USA; and
Northwestern University School of Medicine, Chicago, Illinois 60611, USA
2Correspondence: McGill University Health Center, Room H4.67, 687 Pine Ave. West, Montreal, Quebec, Canada H3A 1A1. E-mail: srabbani{at}med.mcgill.ca; Å6 correspondence should be addressed to: T.R.J., mazar{at}angstrominc.com
Urokinase plasminogen activator (uPA) plays an important role in the progression of several malignancies including breast cancer. We have identified a noncompetitive antagonist of the uPA–uPAR interaction derived from a nonreceptor binding region of uPA (amino acids 136–143). This 8-mer capped peptide (Å6) inhibited breast cancer cell invasion and endothelial cell migration in a dose-dependent manner in vitro without altering cell doubling time. Intraperitoneal administration of Å6 resulted in a significant inhibition of tumor growth and suppressed the development of lymph node metastases in several models of breast cancer cell growth and metastasis. Large areas of tumor necrosis and extensive positive staining by TUNEL were observed on histological and immunohistochemical analysis of experimental tumor sections from Å6-treated animals. Å6 treatment also resulted in a decrease in factor VIII-positive tumor microvessel hot-spots. These results identify a new epitope in uPA that is involved in the uPA–uPAR interaction and indicate that an antagonist based on this epitope is able to inhibit tumor progression by modulating the tumor microenvironment in the absence of direct cytotoxic effects in vivo.—Guo, Y., Higazi, A. A., Arakelian, A., Sachais, B. S., Cines, D., Goldfarb, R. H., Jones, T. R., Kwaan, H., Mazar, A. P., Rabbani, S. A. A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo.
Key Words: apoptosis • breast cancer • endothelial cell • tumor necrosis
This article has been cited by other articles:
|
|
 |
|
  M. Nakamura, B. Han, T. Nishishita, Y. Bai, and K. Kakudo Calcitonin targets extracellular signal-regulated kinase signaling pathway in human cancers J. Mol. Endocrinol., December 1, 2007; 39(6): 375 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Colombo, G. Menicucci, P. G. McGuire, and A. Das Hepatocyte Growth Factor/Scatter Factor Promotes Retinal Angiogenesis through Increased Urokinase Expression Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1793 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Jallal, M.-L. Valentino, G. Chen, F. Boschelli, S. Ali, and S. A. Rabbani A Src/Abl Kinase Inhibitor, SKI-606, Blocks Breast Cancer Invasion, Growth, and Metastasis In vitro and In vivo Cancer Res., February 15, 2007; 67(4): 1580 - 1588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Khalili, A. Arakelian, G. Chen, M. L. Plunkett, I. Beck, G. C. Parry, F. Donate, D. E. Shaw, A. P. Mazar, and S. A. Rabbani A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol. Cancer Ther., September 1, 2006; 5(9): 2271 - 2280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. W.M. van Hinsbergh, M. A. Engelse, and P. H.A. Quax Pericellular Proteases in Angiogenesis and Vasculogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 716 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Bauer, W. Liu, F. Fan, E. R. Camp, A. Yang, R. J. Somcio, C. D. Bucana, J. Callahan, G. C. Parry, D. B. Evans, et al. Targeting of Urokinase Plasminogen Activator Receptor in Human Pancreatic Carcinoma Cells Inhibits c-Met- and Insulin-like Growth Factor-I Receptor-Mediated Migration and Invasion and Orthotopic Tumor Growth in Mice Cancer Res., September 1, 2005; 65(17): 7775 - 7781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Rabbani, P. Khalili, A. Arakelian, H. Pizzi, G. Chen, and D. Goltzman Regulation of Parathyroid Hormone-Related Peptide by Estradiol: Effect on Tumor Growth and Metastasis in Vitro and in Vivo Endocrinology, July 1, 2005; 146(7): 2885 - 2894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Lakka, C. S. Gondi, D. H. Dinh, W. C. Olivero, M. Gujrati, V. H. Rao, C. Sioka, and J. S. Rao Specific Interference of Urokinase-type Plasminogen Activator Receptor and Matrix Metalloproteinase-9 Gene Expression Induced by Double-stranded RNA Results in Decreased Invasion, Tumor Growth, and Angiogenesis in Gliomas J. Biol. Chem., June 10, 2005; 280(23): 21882 - 21892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Das, N. Boyd, T. R. Jones, N. Talarico, and P. G. McGuire Inhibition of Choroidal Neovascularization by a Peptide Inhibitor of the Urokinase Plasminogen Activator and Receptor System in a Mouse Model Arch Ophthalmol, December 1, 2004; 122(12): 1844 - 1849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pakneshan, M. Szyf, R. Farias-Eisner, and S. A. Rabbani Reversal of the Hypomethylation Status of Urokinase (uPA) Promoter Blocks Breast Cancer Growth and Metastasis J. Biol. Chem., July 23, 2004; 279(30): 31735 - 31744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Gondi, S. S. Lakka, N. Yanamandra, W. C. Olivero, D. H. Dinh, M. Gujrati, C. H. Tung, R. Weissleder, and J. S. Rao Adenovirus-Mediated Expression of Antisense Urokinase Plasminogen Activator Receptor and Antisense Cathepsin B Inhibits Tumor Growth, Invasion, and Angiogenesis in Gliomas Cancer Res., June 15, 2004; 64(12): 4069 - 4077. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pakneshan, B. Tetu, and S. A. Rabbani Demethylation of Urokinase Promoter as a Prognostic Marker in Patients with Breast Carcinoma Clin. Cancer Res., May 1, 2004; 10(9): 3035 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Boyd, H. Wang, H. Avila, N. U. Parikh, H. Kessler, V. Magdolen, and G. E. Gallick Combination of an Src Kinase Inhibitor with a Novel Pharmacological Antagonist of the Urokinase Receptor Diminishes in Vitro Colon Cancer Invasiveness Clin. Cancer Res., February 15, 2004; 10(4): 1545 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Koh, K. Bessho, L. Cheng, D.-U. Bartsch, T. R. Jones, G. Bergeron-Lynn, and W. R. Freeman Inhibition of Choroidal Neovascularization in Rats by the Urokinase-Derived Peptide A6 Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 635 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. O. Nielsen, H. N. Andrews, M. Cheang, J. E. Kucab, F. D. Hsu, J. Ragaz, C. B. Gilks, N. Makretsov, C. D. Bajdik, C. Brookes, et al. Expression of the Insulin-Like Growth Factor I Receptor and Urokinase Plasminogen Activator in Breast Cancer Is Associated with Poor Survival: Potential for Intervention with 17-Allylamino Geldanamycin Cancer Res., January 1, 2004; 64(1): 286 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. McGuire, T. R. Jones, N. Talarico, E. Warren, and A. Das The Urokinase/Urokinase Receptor System in Retinal Neovascularization: Inhibition by A6 Suggests a New Therapeutic Target Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2736 - 2742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. PAKNESHAN, R. H. XING, and S. A. RABBANI Methylation status of uPA promoter as a molecular mechanism regulating prostate cancer invasion and growth in vitro and in vivo FASEB J, June 1, 2003; 17(9): 1081 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Lakka, C. S. Gondi, N. Yanamandra, D. H. Dinh, W. C. Olivero, M. Gujrati, and J. S. Rao Synergistic Down-Regulation of Urokinase Plasminogen Activator Receptor and Matrix Metalloproteinase-9 in SNB19 Glioblastoma Cells Efficiently Inhibits Glioma Cell Invasion, Angiogenesis, and Tumor Growth Cancer Res., May 15, 2003; 63(10): 2454 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Kim, Y.-K. Hong, Y. A. Joe, Y. Lee, J.-Y. Shin, H.-E. Park, I.-H. Lee, S.-Y. Lee, D.-K. Kang, S.-I. Chang, et al. Anti-angiogenic Activity of the Recombinant Kringle Domain of Urokinase and Its Specific Entry into Endothelial Cells J. Biol. Chem., March 21, 2003; 278(13): 11449 - 11456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Guo, P. Pakneshan, J. Gladu, A. Slack, M. Szyf, and S. A. Rabbani Regulation of DNA Methylation in Human Breast Cancer. EFFECT ON THE UROKINASE-TYPE PLASMINOGEN ACTIVATOR GENE PRODUCTION AND TUMOR INVASION J. Biol. Chem., October 25, 2002; 277(44): 41571 - 41579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Guo, A. P. Mazar, J.-J. Lebrun, and S. A. Rabbani An Antiangiogenic Urokinase-derived Peptide Combined with Tamoxifen Decreases Tumor Growth and Metastasis in a Syngeneic Model of Breast Cancer Cancer Res., August 15, 2002; 62(16): 4678 - 4684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Rabbani and J. Gladu Urokinase Receptor Antibody Can Reduce Tumor Volume and Detect the Presence of Occult Tumor Metastases in Vivo Cancer Res., April 1, 2002; 62(8): 2390 - 2397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Pepper Role of the Matrix Metalloproteinase and Plasminogen Activator-Plasmin Systems in Angiogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1104 - 1117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Conway, D. Collen, and P. Carmeliet Molecular mechanisms of blood vessel growth Cardiovasc Res, February 16, 2001; 49(3): 507 - 521. [Full Text] [PDF]
|
|
|
|
 |
|
 S. IDELL, A. P. MAZAR, P. BITTERMAN, S. MOHLA, and A. L. HARABIN Fibrin Turnover in Lung Inflammation and Neoplasia Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 578 - 584. [Full Text]
|
|
|
|
|
|
S. E. Dunn, J. V. Torres, J. S. Oh, D. M. Cykert, and J. C. Barrett Up-Regulation of Urokinase-Type Plasminogen Activator by Insulin-like Growth Factor-I Depends upon Phosphatidylinositol-3 Kinase and Mitogen-activated Protein Kinase Kinase Cancer Res., February 1, 2001; 61(4): 1367 - 1374. [Abstract] [Full Text]
|
|
|
|
|
|
A. HAJ-YEHIA, T. NASSAR, B. S. SACHAIS, A. KUO, K. BDEIR, A. B. AL-MEHDI, A. MAZAR, D. B. CINES, and A. A.-R. HIGAZI Urokinase-derived peptides regulate vascular smooth muscle contraction in vitro and in vivo FASEB J, July 1, 2000; 14(10): 1411 - 1422. [Abstract] [Full Text]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
