Production of gastrointestinal tumors in mice by modulating latent TGF-?1 activation.

ABSTRACT: TGF-? and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-? is released from cells in a latent complex consisting of TGF-?, the TGF-? propeptide [latency associated protein (LAP)], and a latent TGF-? binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-?1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1(C33S/C33S) mice develop multiorgan inflammation and tumors consistent with reduced TGF-?1 activity. To test whether further reduction in active TGF-? levels would yield additional tumors and a phenotype more similar to Tgfb1(-/-) mice, we generated mice that express TGF-?1(C33S) and are deficient in either integrin ?8 or TSP-1, known activators of latent TGF-?1. 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-?1 as Tgfb1(C33S/C33S) mice, and the amount of active TGF-?1 would be correspondingly decreased compared with Tgfb1(C33S/C33S) mice. These compound-mutant mice displayed more severe inflammation and higher tumor numbers than the parental Tgfb1(C33S/C33S) animals. The level of active TGF-?1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/C33S) mice as determined from analyses of surrogate markers of active TGF-?, 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-? levels in a manner that determines tumor number and inflammation within the gastrointestinal tract.

SUBMITTER: Shibahara K 

PROVIDER: S-EPMC3537847 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature