| First Author | Shibahara K | Year | 2013 |
| Journal | Cancer Res | Volume | 73 |
| Issue | 1 | Pages | 459-68 |
| PubMed ID | 23117884 | Mgi Jnum | J:194125 |
| Mgi Id | MGI:5470369 | Doi | 10.1158/0008-5472.CAN-12-3141 |
| Citation | Shibahara K, et al. (2013) Production of gastrointestinal tumors in mice by modulating latent TGF-beta1 activation. Cancer Res 73(1):459-68 |
| abstractText | TGF-beta and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-beta is released from cells in a latent complex consisting of TGF-beta, the TGF-beta propeptide [latency associated protein (LAP)], and a latent TGF-beta binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-beta1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1(C33S/C33S) mice develop multiorgan inflammation and tumors consistent with reduced TGF-beta1 activity. To test whether further reduction in active TGF-beta levels would yield additional tumors and a phenotype more similar to Tgfb1(-/-) mice, we generated mice that express TGF-beta1(C33S) and are deficient in either integrin beta8 or TSP-1, known activators of latent TGF-beta1. 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-beta1 as Tgfb1(C33S/C33S) mice, and the amount of active TGF-beta1 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-beta1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/C33S) mice as determined from analyses of surrogate markers of active TGF-beta, 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-beta levels in a manner that determines tumor number and inflammation within the gastrointestinal tract. |
