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Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects
Open accessAbstract
TGF-βs play diverse and complex roles in many biological processes. In tumorigenesis, they can function either as tumor suppressors or as pro-oncogenic factors, depending on the stage of the disease. We have developed transgenic mice expressing a TGF-β antagonist of the soluble type II TGF-β receptor:Fc fusion protein class, under the regulation of the mammary-selective MMTV-LTR promoter/enhancer. Biologically significant levels of antagonist were detectable in the serum and most tissues of this mouse line. The mice were resistant to the development of metastases at multiple organ sites when compared with wild-type controls, both in a tail vein metastasis assay using isogenic melanoma cells and in crosses with the MMTV-neu transgenic mouse model of metastatic breast cancer. Importantly, metastasis from endogenous mammary tumors was suppressed without any enhancement of primary tumorigenesis. Furthermore, aged transgenic mice did not exhibit the severe pathology characteristic of TGF-β null mice, despite lifetime exposure to the antagonist. The data suggest that in vivo the antagonist may selectively neutralize the undesirable TGF-β associated with metastasis, while sparing the regulatory roles of TGF-βs in normal tissues. Thus this soluble TGF-β antagonist has potential for long-term clinical use in the prevention of metastasis.
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“The Fc-TβRII trap was also the basis for the development of a bi-specific trap that combines TGF-β binding by the TβRII ectodomains with a human PD-L1-blocking IgG1308,309,312.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [308]
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“Bifunctional fusion proteins that bind and block both TGF-β and CTLA-4 or PD-L1 have been generated, thus biochemically linking immune checkpoint inhibition with blocking TGF-β signaling308,309,365.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [308]
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Metadata
- Authors
- Yang, Y.-A., Dukhanina, O., Tang, B., Mamura, M., Letterio, J. J., MacGregor, J., Patel, S. C., Khozin, S., Liu, Z.-Y., Green, J., Anver, M. R., Merlino, G., & Wakefield, L. M.
- Affiliations
- National Institutes of Health (US)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Wakefield, Lalage M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2002-06-15
- Volume
- 109
- Issue
- 12
- Pages
- 1607-1615
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC151015
- OpenAlex
- W2118916648
- Cited by
- 404
- References
- 50
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 9 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 17 · 2013: 19 · 2012: 30
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health (n01co12400-79-0-22, NO1-CO12400)
- National Cancer Institute (N01CO12400, N01-CO-012400, NO1‐CO‐12400)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- TGF-beta antagonists, Fc fusion protein, metastasis prevention, melanoma metastasis, MMTV-neu transgenic mice, breast cancer, transgenic mice
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Female, Genetic Vectors, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Liver Neoplasms, Mammary Tumor Virus, Mouse, Melanoma, Experimental, Mice, Transgenic, Neoplasm Metastasis, Recombinant Fusion Proteins, Solubility, Tumor Cells, Cultured, Mammary Neoplasms, Animal, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Mice
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