This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Shah, A. H. Articles by Lee, C. Search for Related Content PubMed PubMed Citation Articles by Shah, A. H. Articles by Lee, C.

Suppression of Tumor Metastasis by Blockade of Transforming Growth Factor ß Signaling in Bone Marrow Cells through a Retroviral-mediated Gene Therapy in Mice¹

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 [A. H. S., W. B. T., S. D. K., V. C. L., C. L.]; Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892 [S-J. K.]; Department of Biology, Massachusetts Institute of Technology, Cambridge Massachusetts 02139 [L. V. P.]; Department of Urology, Mayo Clinic, Rochester, Minnesota 55905 [E. K.]; and Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030 [N. M. G.]

Transforming growth factor B (TGF-ß) is a potent immunosuppressive cytokine that is frequently associated with mechanisms of tumor escape from immunosurveillance. We report that transplantation of murine bone marrow (BM) expressing a dominant-negative TGF-ß type II receptor (TßRIIDN) leads to the generation of mature leukocytes capable of a potent antitumor response in vivo. Hematopoietic precursors in murine BM from donor mice were rendered insensitive to TGF-ß via retroviral expression of the TßRIIDN construct and were transplanted in C57BL/6 mice before tumor challenge. After i.v. administration of 5 x 10⁵ B16-F10 murine melanoma cells into TßRIIDN-BM transplanted recipients, survival of challenged mice at 45 days was 70% (7 of 10) versus 0% (0 of 10) for vector-control treated mice, and surviving TßRIIDN-BM mice showed a virtual absence of metastatic lesions in the lung. We also investigated the utility of the TGF-ß-targeted approach in a mouse metastatic model of prostate cancer, TRAMP-C2. Treatment of male C57BL/6 mice with TßRIIDN-BM resulted in the survival of 80% (4 of 5) of recipients versus 0% (0 of 5) in green fluorescent protein-BM recipients or wild-type controls. Cytolytic T-cell assays indicate that a specific T-cell response against B16-F10 cells was generated in the TßRIIDN-BM-treated mice, suggesting that a gene therapy approach to inducing TGF-ß insensitivity in transplanted BM cells may be a potent anticancer therapy.

This article has been cited by other articles:

				K. A. Shafer-Weaver, M. J. Anderson, K. Stagliano, A. Malyguine, N. M. Greenberg, and A. A. Hurwitz Cutting Edge: Tumor-Specific CD8+ T Cells Infiltrating Prostatic Tumors Are Induced to Become Suppressor Cells J. Immunol., October 15, 2009; 183(8): 4848 - 4852. [Abstract] [Full Text] [PDF]

				P. Laje, D. Shang, W. Cao, M. Niiya, M. Endo, A. Radu, N. DeRogatis, F. Scheiflinger, P. W. Zoltick, A. W. Flake, et al. Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell-mediated gene therapy Blood, March 5, 2009; 113(10): 2172 - 2180. [Abstract] [Full Text] [PDF]

				M. Zhang, B. E. Berndt, J.-J. Chen, and J. Y. Kao Expression of a Soluble TGF-{beta} Receptor by Tumor Cells Enhances Dendritic Cell/Tumor Fusion Vaccine Efficacy J. Immunol., September 1, 2008; 181(5): 3690 - 3697. [Abstract] [Full Text] [PDF]

				B. A Teicher, J. M Yingling, and J. M McPherson TGF{beta} Blockade as Anticancer Therapy Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 71 - 81. [Abstract] [Full Text] [PDF]

				Y. Shintani, M. Maeda, N. Chaika, K. R. Johnson, and M. J. Wheelock Collagen I Promotes Epithelial-to-Mesenchymal Transition in Lung Cancer Cells via Transforming Growth Factor Signaling Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 95 - 104. [Abstract] [Full Text] [PDF]

				B. A. Teicher Transforming Growth Factor-{beta} and the Immune Response to Malignant Disease Clin. Cancer Res., November 1, 2007; 13(21): 6247 - 6251. [Abstract] [Full Text] [PDF]

				G. T. Lee, J. H. Hong, C. Kwak, J. Woo, V. Liu, C. Lee, and I. Y. Kim Effect of Dominant Negative Transforming Growth Factor-{beta} Receptor Type II on Cytotoxic Activity of RAW 264.7, a Murine Macrophage Cell Line Cancer Res., July 15, 2007; 67(14): 6717 - 6724. [Abstract] [Full Text] [PDF]

				E. Suzuki, S. Kim, H.-K. Cheung, M. J. Corbley, X. Zhang, L. Sun, F. Shan, J. Singh, W.-C. Lee, S. M. Albelda, et al. A Novel Small-Molecule Inhibitor of Transforming Growth Factor {beta} Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection Cancer Res., March 1, 2007; 67(5): 2351 - 2359. [Abstract] [Full Text] [PDF]

				B. Zhu, K. Fukada, H. Zhu, and N. Kyprianou Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor {beta} Signaling in Human Prostate Cancer Cells. Cancer Res., September 1, 2006; 66(17): 8640 - 8647. [Abstract] [Full Text] [PDF]

				Q. Zhang, X. J. Yang, S. D. Kundu, M. Pins, B. Javonovic, R. Meyer, S.-J. Kim, N. M. Greenberg, T. Kuzel, R. Meagher, et al. Blockade of transforming growth factor-{beta} signaling in tumor-reactive CD8+ T cells activates the antitumor immune response cycle. Mol. Cancer Ther., July 1, 2006; 5(7): 1733 - 1743. [Abstract] [Full Text] [PDF]

				S. Varghese, S. D. Rabkin, P. G. Nielsen, W. Wang, and R. L. Martuza Systemic oncolytic herpes virus therapy of poorly immunogenic prostate cancer metastatic to lung. Clin. Cancer Res., May 1, 2006; 12(9): 2919 - 2927. [Abstract] [Full Text] [PDF]

				H. W. van Deventer, W. O'Connor Jr., W. J. Brickey, R. M. Aris, J. P.Y. Ting, and J. S. Serody C-C Chemokine Receptor 5 on Stromal Cells Promotes Pulmonary Metastasis Cancer Res., April 15, 2005; 65(8): 3374 - 3379. [Abstract] [Full Text] [PDF]

				Q. Zhang, X. Yang, M. Pins, B. Javonovic, T. Kuzel, S.-J. Kim, L. V. Parijs, N. M. Greenberg, V. Liu, Y. Guo, et al. Adoptive Transfer of Tumor-Reactive Transforming Growth Factor-{beta}-Insensitive CD8+ T Cells: Eradication of Autologous Mouse Prostate Cancer Cancer Res., March 1, 2005; 65(5): 1761 - 1769. [Abstract] [Full Text] [PDF]

				S.S. Prime, M. Davies, M. Pring, and I.C. Paterson THE ROLE OF TGF-{beta} IN EPITHELIAL MALIGNANCY AND ITS RELEVANCE TO THE PATHOGENESIS OF ORAL CANCER (PART II) Critical Reviews in Oral Biology & Medicine, November 1, 2004; 15(6): 337 - 347. [Abstract] [Full Text] [PDF]

				J. L. Kopp, P. J. Wilder, M. Desler, J.-H. Kim, J. Hou, T. Nowling, and A. Rizzino Unique and Selective Effects of Five Ets Family Members, Elf3, Ets1, Ets2, PEA3, and PU.1, on the Promoter of the Type II Transforming Growth Factor-{beta} Receptor Gene J. Biol. Chem., May 7, 2004; 279(19): 19407 - 19420. [Abstract] [Full Text] [PDF]

				D. T. Bolick, M. E. Hatley, S. Srinivasan, C. C. Hedrick, and J. L. Nadler Lisofylline, a Novel Antiinflammatory Compound, Protects Mesangial Cells from Hyperglycemia- and Angiotensin II-Mediated Extracellular Matrix Deposition Endocrinology, December 1, 2003; 144(12): 5227 - 5231. [Abstract] [Full Text] [PDF]