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 Citations (Scopus)

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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Transforming Growth Factors
Bone Marrow Cells
Genetic Therapy
Bone Marrow
Neoplasm Metastasis
Neoplasms
Inbred C57BL Mouse
Tumor Escape
T-Lymphocytes
Immunologic Monitoring
Immunosuppressive Agents
Green Fluorescent Proteins
Bone Marrow Transplantation
Melanoma
Prostatic Neoplasms
Leukocytes
Cytokines
Lung
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shah, Ali H. ; Tabayoyong, William B. ; Kundu, Shilajit D ; Kim, Seong Jin ; Van Parijs, Luk ; Liu, Victoria C. ; Kwon, Eugene ; Greenberg, Norman M. ; Lee, Chung. / Suppression of tumor metastasis by blockade of transforming growth factor β signaling in bone marrow cells through a retroviral-mediated gene therapy in mice. In: Cancer Research. 2002 ; Vol. 62, No. 24. pp. 7135-7138.
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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.",
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Suppression of tumor metastasis by blockade of transforming growth factor β signaling in bone marrow cells through a retroviral-mediated gene therapy in mice. / Shah, Ali H.; Tabayoyong, William B.; Kundu, Shilajit D; Kim, Seong Jin; Van Parijs, Luk; Liu, Victoria C.; Kwon, Eugene; Greenberg, Norman M.; Lee, Chung.

In: Cancer Research, Vol. 62, No. 24, 15.12.2002, p. 7135-7138.

Research output: Contribution to journalArticle

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AU - Shah, Ali H.

AU - Tabayoyong, William B.

AU - Kundu, Shilajit D

AU - Kim, Seong Jin

AU - Van Parijs, Luk

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AU - Kwon, Eugene

AU - Greenberg, Norman M.

AU - Lee, Chung

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N2 - 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.

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