Production of gastrointestinal tumors in mice by modulating latent TGF-β1 activation

Cancer Res. 2013 Jan 1;73(1):459-68. doi: 10.1158/0008-5472.CAN-12-3141. Epub 2012 Nov 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gastrointestinal Neoplasms / metabolism*
  • Gastrointestinal Neoplasms / pathology*
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains*
  • Real-Time Polymerase Chain Reaction
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Transforming Growth Factor beta1