beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds.
Fibroproliferative processes are a group of disorders in which there is excessive proliferation of spindle (mesenchymal fibroblast-like) cells. They range from hypertrophic scars to neoplasms such as aggressive fibromatosis. Cells from these disorders share cytologic similarity with fibroblasts present during the proliferative phase of wound healing, suggesting that they represent a prolonged wounding response. A critical role for beta-catenin in mesenchymal cells in fibroproliferative processes is suggested by its high rate of somatic mutation in aggressive fibromatosis. Using a Tcf-reporter mouse we found that beta-catenin protein level and Tcf-transcriptional activity are elevated in fibroblasts during the proliferative phase of healing. We generated a transgenic mouse in which stabilized beta-catenin is expressed in mesenchymal cells under control of a tetracycline-regulated promoter. Fibroblasts from the transgenic mice exhibited increased proliferation, motility, and invasiveness when expressing stabilized beta-catenin and induced tumors after induction of the transgene when grafted into nude mice. Mice developed aggressive fibromatoses and hyperplastic gastrointestinal polyps after 3 months of transgene induction and healed with hyperplastic cutaneous wounds compared with control mice, which demonstrates an important function for beta-catenin in mesenchymal cells and shows a central role for beta-catenin in wound healing and fibroproliferative disorders.
Cheon
Sophia S
SS
Program in Developmental Biology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
Cheah
Alexander Y L
AY
Turley
Stefanie
S
Nadesan
Puviindran
P
Poon
Raymond
R
Clevers
Hans
H
Alman
Benjamin A
BA
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology; D018222:Desmoid Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007417:Intestinal Polyps; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D012867:Skin / Q000293:injuries; D015534:Trans-Activators; D015533:Transcriptional Activation; D014945:Wound Healing; D014947:Wounds and Injuries / Q000378:metabolism; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin