Production of gastrointestinal tumors in mice by modulating latent TGF-β1 activation.
Production of gastrointestinal tumors in mice by modulating latent TGF-β1 activation.
复制标题
通过调节潜在的 TGF-β1 激活在小鼠体内产生胃肠道肿瘤。
DOI：
10.1158/0008-5472.can-12-3141
复制
发表时间：
2013-01-01
期刊：
影响因子：
11.2
通讯作者：
Rifkin DB
中科院分区：
文献类型：
--
作者：
Shibahara K;Ota M;Horiguchi M;Yoshinaga K;Melamed J;Rifkin DB
Transforming growth factor-β (TGF-β) and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal (GI) tract. TGF-β is released from cells in a latent complex consisting of TGF-β, the TGF-β propeptide (LAP) and a latent TGF-β binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-β1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1C33S/C33S mice develop multiorgan inflammation and tumors consistent with reduced TGF-β1 activity. To test whether further reduction in active TGF-β levels would yield additional tumors and a phenotype more similar to Tgfb1-/- mice, we generated mice that express TGF-β1C33S and are deficient in either integrin β8 or TSP-1, known activators of latent TGF-β1. In addition we generated mice that have one mutant allele and one null allele at the Tgfb1 locus, reasoning that these mice should synthesize half the total amount of TGF-β1 as Tgfb1C33S/C33S mice and the amount of active TGF-β1 would be correspondingly decreased compared to Tgfb1C33S/C33S mice. These compound mutant mice displayed more severe inflammation and higher tumor numbers than the parental Tgfb1C33S/C33S animals. The level of active TGF-β1 in compound mutant mice appeared to be decreased compared to Tgfb1C33S/C33S mice as determined from analyses of surrogate markers of active TGF-β, such as P-Smad2, C-Myc, KI-67, and markers of cell cycle traverse. We conclude that these mutant mice provide a useful system for modulating TGF-β levels in a manner that determines tumor number and inflammation within the GI tract.
