title: Production of gastrointestinal tumors in mice by modulating latent TGF-β1 activation.
abstract: TGF-β and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-β is released from cells in a latent complex consisting of TGF-β, the TGF-β propeptide [latency associated protein (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 Tgfb1(C33S/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-β1(C33S) 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 Tgfb1(C33S/C33S) mice, and the amount of active TGF-β1 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-β1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/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 gastrointestinal tract.
authors.affiliation: Department of Cell Biology, New York University Langone School of Medicine, New York, NY 10016, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shibahara
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ota
authors.forename: Masahito
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Keiji
authors.initials: K
authors.lastname: Yoshinaga
authors.forename: Jonathan
authors.initials: J
authors.lastname: Melamed
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000818:Animals; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1