Abstract
TGF-betas are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-beta interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-beta type II receptor fusion protein (Fc:TbetaRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TbetaRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TbetaRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TbetaRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TbetaRII. Therefore, blockade of TGF-beta signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Apoptosis*
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Autocrine Communication
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Breast / drug effects
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Breast / pathology
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Cell Movement
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Cell Survival
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Female
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Genetic Vectors
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Immunoglobulin Fc Fragments / administration & dosage
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / physiology*
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Immunoglobulin G / administration & dosage
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Immunoglobulin G / genetics
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Immunoglobulin G / physiology*
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Lung Neoplasms / secondary*
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Mammary Neoplasms, Animal / pathology*
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Mammary Tumor Virus, Mouse
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Neoplasm Metastasis
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Neovascularization, Pathologic
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / administration & dosage
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Receptors, Transforming Growth Factor beta / immunology
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Receptors, Transforming Growth Factor beta / physiology*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction*
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Solubility
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta1
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Tumor Cells, Cultured
Substances
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Antigens, Polyomavirus Transforming
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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Tgfb1 protein, mouse
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II