Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects
Yu-an Yang, Oksana Dukhanina, Binwu Tang, Mizuko Mamura, John J. Letterio, Jennifer MacGregor, Sejal C. Patel, Shahram Khozin, Zi-yao Liu, Jeffrey Green, Miriam R. Anver, Glenn Merlino, Lalage M. Wakefield
Yu-an Yang, Oksana Dukhanina, Binwu Tang, Mizuko Mamura, John J. Letterio, Jennifer MacGregor, Sejal C. Patel, Shahram Khozin, Zi-yao Liu, Jeffrey Green, Miriam R. Anver, Glenn Merlino, Lalage M. Wakefield
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Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects

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.

Authors

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

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Effect of SR2F on metastatic efficiency in a tail-vein injection assay. ...
Effect of SR2F on metastatic efficiency in a tail-vein injection assay. (a) Macroscopically detectable liver metastases at different times after inoculation. Wild-type or transgenic (SR2F) mice were injected in the tail vein with 106 isogenic 37-32 melanoma cells. After 21, 28, and 35 days, mice were necropsied and the number of macroscopically visible metastases on the liver surface was quantified. The 21-day timepoint had five mice per genotype group, while the remaining timepoints had ten mice per genotype group. (b) Effects on metastatic efficiency in different internal organs. The number of histologically evident metastases was quantified in all tissues that showed evidence of gross metastases in mice necropsied at 35 days after inoculation. Two representative cross sections of each lobe were assessed for the liver and a single representative cross section was analyzed for other organs. Ten mice were used per genotype group. (c) Dose dependency of SR2F effect on metastatic efficiency. In a replicate experiment of the one described in a, the number of histologically detectable metastases in representative cross sections of the liver were quantitated and plotted against the circulating SR2F levels, as measured by sandwich ELISA on serum prepared at necropsy. The data for the wild-type cohort (0 ng/ml SR2F) are presented as mean ± SD (n = 4). R represents the correlation coefficient for the linear curve fit.