545 A twist on keloid pathogenesis

Keloids are fibroproliferative scars that invade the surrounding tissue beyond the original wound site. The cellular and molecular mechanism for the pathogenesis of keloid scars are still unknown. We investigated the role of the transcription factor Twist, a key regulator in epithelial-to-mesenchymal transition, its upstream regulators, and downstream targets, which are associated with self-renewal, proliferation and invasion, in keloid tissue. Multicolour immunofluorescence microscopy was performed on frozen tissue sections of keloid scars, normal scars and normal skin staining for Twist, and related molecules such as Bmi1, active β-catenin and inhibitor of differentiation 1 (Id1). Staining of these markers was quantified using Metamorph software. Endothelial and mesenchymal cells were identified and inflammatory infiltrates were investigated using markers for T cells, B cells, and macrophages. Our results reveal remarkable upregulation of Twist expression in keloids compared to normal scar and normal skin. Furthermore, we show a significant increase in expression of Bmi1, active β-catenin and Id1 in keloids compared to normal scar and normal skin tissues. The most striking upregulation of these markers is seen in the centre of the keloid mass. In addition, we clearly visualise the presence of immune infiltrates in keloids with a distinct abundance of T cell clusters. This is the first clear evidence of Twist and its target gene Bmi1 being over-expressed in keloids. As Twist is a key regulator of proliferation, self-renewal and invasion, which are defining characteristics of keloid scars, we hypothesize that Twist could be responsible for the formation and growth of keloid scars. Our results suggest that Twist expression might be initiated in response to the ongoing inflammation in the keloid microenvironment via activation of β-catenin. These results are of significant interest because therapeutic inhibition of the pathways involved in Twist expression may lead to the first successful therapeutic treatment for keloid scars.