Cited by 405TGF-β signaling in diseasesMechanisms of cancer metastasisCancer Cells and Metastasis

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Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects

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Yang, Yu-an, Dukhanina, Oksana, Tang, Binwu, Mamura, Mizuko, Letterio, John J., MacGregor, Jennifer, Patel, Sejal C., Khozin, Shahram, Liu, Zi-yao, Green, Jeffrey, Anver, Miriam R., Merlino, Glenn, Wakefield, Lalage M.·2002·Journal of Clinical Investigation

DOI 10.1172/jci200215333PMC PMC151015

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Abstract

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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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: Mamura, Mizuko
Letterio, John J.
Green, Jeffrey
Anver, Miriam R.
Merlino, Glenn
Wakefield, Lalage M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2002-06-15
Volume: 109
Issue: 12
Pages: 1607-1615
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci200215333
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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Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects

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