This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, S. J. Articles by Gallick, G. E. Search for Related Content PubMed PubMed Citation Articles by Kim, S. J. Articles by Gallick, G. E. Related Collections Commentary

Reduced c-Met Expression by an Adenovirus Expressing a c-Met Ribozyme Inhibits Tumorigenic Growth and Lymph Node Metastases of PC3-LN4 Prostate Tumor Cells in an Orthotopic Nude Mouse Model

Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas [S. J. K., M. J., K. K., H. U.], and The Program in Cancer Biology, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas [M. H. H., G. E. G.]

ABSTRACT

Purpose: The expression of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, frequently increases during prostate tumor progression. However, whether reduced c-Met expression inhibits tumor growth and metastasis has not been ascertained.

Experimental Design: c-Met expression was reduced by infection of an adenovirus expressing a c-Met ribozyme into the highly metastatic human prostate cancer cell line PC3-LN4. In vitro, effects on c-Met, Akt, and extracellular signal-regulated kinase 1/2 expression and phosphorylation, Src expression and activity, and vascular endothelial growth factor expression were determined, as were effects on cell migration and invasion. Prostate tumor formation and metastasis to regional lymph nodes in nude mice were examined after both ex vivo and in vivo infection of cells.

Results: Infection of PC3-LN4 cells with the Ad-c-Met-expressing ribozyme decreased steady-state c-Met levels, decreased Src kinase activity, decreased vascular endothelial growth factor expression, and decreased migration and invasion versus the pU1 (control) virus. Significant inhibition of tumorigenicity (histologically confirmed tumors in only 1 of 10 mice) and consequent lymph node metastasis were observed upon ex vivo infection of Ad-c-Met. Similarly, gene therapy experiments led to complete inhibition of tumor growth in 7 of 8 mice.

Conclusions: Reduction in c-Met expression substantially inhibits both tumor growth and lymph node metastasis of PC3-LN4 cells in orthotopic nude mouse models. Therefore, targeting the c-Met signaling pathways may be important in controlling tumor growth and metastasis in human prostate cancers.

Commentary

Suppression of Met Expression: A Possible Cancer Treatment: Commentary re: S. J. Kim et al., Reduced c-Met Expression by an Adenovirus Expressing a c-Met Ribozyme Inhibits Tumorigenic Growth and Lymph Node Metastases of PC3-LN4 Prostate Tumor Cells in an Orthotopic Nude Mouse Model. Clin. Cancer Res., 14: 5161-5170, 2003.

Nariyoshi Shinomiya and George F. Vande Woude
Clin. Cancer Res. 2003 9: 5085-5090. [Full Text] [PDF]

This article has been cited by other articles:

				S. I. Park, J. Zhang, K. A. Phillips, J. C. Araujo, A. M. Najjar, A. Y. Volgin, J. G. Gelovani, S.-J. Kim, Z. Wang, and G. E. Gallick Targeting Src Family Kinases Inhibits Growth and Lymph Node Metastases of Prostate Cancer in an Orthotopic Nude Mouse Model Cancer Res., May 1, 2008; 68(9): 3323 - 3333. [Abstract] [Full Text] [PDF]

				S. F. Bellon, P. Kaplan-Lefko, Y. Yang, Y. Zhang, J. Moriguchi, K. Rex, C. W. Johnson, P. E. Rose, A. M. Long, A. B. O'Connor, et al. c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations J. Biol. Chem., February 1, 2008; 283(5): 2675 - 2683. [Abstract] [Full Text] [PDF]

				I. Mukhopadhyay, E. A. Sausville, J. H. Doroshow, and K. K. Roy Molecular Mechanism of Adaphostin-mediated G1 Arrest in Prostate Cancer (PC-3) Cells: SIGNALING EVENTS MEDIATED BY HEPATOCYTE GROWTH FACTOR RECEPTOR, c-Met, AND p38 MAPK PATHWAYS J. Biol. Chem., December 8, 2006; 281(49): 37330 - 37344. [Abstract] [Full Text] [PDF]

				K. M. Hoffmann, J. A. Tapia, M. J. Berna, M. Thill, T. Braunschweig, S. A. Mantey, T. W. Moody, and R. T. Jensen Gastrointestinal Hormones Cause Rapid c-Met Receptor Down-regulation by a Novel Mechanism Involving Clathrin-mediated Endocytosis and a Lysosome-dependent Mechanism J. Biol. Chem., December 8, 2006; 281(49): 37705 - 37719. [Abstract] [Full Text] [PDF]

				A. Strat, L. Gao, T. Utsuki, B. Cheng, S. Nuthalapaty, J. M. Mathis, Y. Odaka, and T. Giordano Specific and nontoxic silencing in mammalian cells with expressed long dsRNAs Nucleic Acids Res., August 11, 2006; 34(13): 3803 - 3810. [Abstract] [Full Text] [PDF]

				Q. Shu, B. Antalffy, J. M. F. Su, A. Adesina, C.-N. Ou, T. Pietsch, S. M. Blaney, C. C. Lau, and X.-N. Li Valproic Acid Prolongs Survival Time of Severe Combined Immunodeficient Mice Bearing Intracerebellar Orthotopic Medulloblastoma Xenografts Clin. Cancer Res., August 1, 2006; 12(15): 4687 - 4694. [Abstract] [Full Text] [PDF]

				S. Ashida, M. Furihata, T. Katagiri, K. Tamura, Y. Anazawa, H. Yoshioka, T. Miki, T. Fujioka, T. Shuin, Y. Nakamura, et al. Expression of Novel Molecules, MICAL2-PV (MICAL2 Prostate Cancer Variants), Increases with High Gleason Score and Prostate Cancer Progression. Clin. Cancer Res., May 1, 2006; 12(9): 2767 - 2773. [Abstract] [Full Text] [PDF]

				S. M. Pulukuri, C. S. Gondi, S. S. Lakka, A. Jutla, N. Estes, M. Gujrati, and J. S. Rao RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo J. Biol. Chem., October 28, 2005; 280(43): 36529 - 36540. [Abstract] [Full Text] [PDF]

				N. Cabioglu, J. Summy, C. Miller, N. U. Parikh, A. A. Sahin, S. Tuzlali, K. Pumiglia, G. E. Gallick, and J. E. Price CXCL-12/Stromal Cell-Derived Factor-1{alpha} Transactivates HER2-neu in Breast Cancer Cells by a Novel Pathway Involving Src Kinase Activation Cancer Res., August 1, 2005; 65(15): 6493 - 6497. [Abstract] [Full Text] [PDF]

				D M Peehl Primary cell cultures as models of prostate cancer development Endocr. Relat. Cancer, March 1, 2005; 12(1): 19 - 47. [Abstract] [Full Text] [PDF]

				J. Akervall, X. Guo, C.-N. Qian, J. Schoumans, B. Leeser, E. Kort, A. Cole, J. Resau, C. Bradford, T. Carey, et al. Genetic and Expression Profiles of Squamous Cell Carcinoma of the Head and Neck Correlate with Cisplatin Sensitivity and Resistance in Cell Lines and Patients Clin. Cancer Res., December 15, 2004; 10(24): 8204 - 8213. [Abstract] [Full Text] [PDF]