Suppression of tumor metastasis by blockade of transforming growth factor β signaling in bone marrow cells through a retroviral-mediated gene therapy in mice

Ali H. Shah, William B. Tabayoyong, Shilajit D. Kundu, Seong Jin Kim, Luk Van Parijs, Victoria C. Liu, Eugene Kwon, Norman M. Greenberg, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Transforming growth factor B (TGF-β) 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-β type II receptor (TβRIIDN) 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-β via retroviral expression of the TβRIIDN construct and were transplanted in C57BL/6 mice before tumor challenge. After i.v. administration of 5 × 105 B16-F10 murine melanoma cells into TβRIIDN-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 TβRIIDN-BM mice showed a virtual absence of metastatic lesions in the lung. We also investigated the utility of the TGF-β-targeted approach in a mouse metastatic model of prostate cancer, TRAMP-C2. Treatment of male C57BL/6 mice with TβRIIDN-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 TβRIIDN-BM-treated mice, suggesting that a gene therapy approach to inducing TGF-β insensitivity in transplanted BM cells may be a potent anticancer therapy.

Original languageEnglish (US)
Pages (from-to)7135-7138
Number of pages4
JournalCancer Research
Volume62
Issue number24
StatePublished - Dec 15 2002

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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