title: Expression of the E-cadherin repressors Snail, Slug and Zeb1 in urothelial carcinoma of the urinary bladder: relation to stromal fibroblast activation and invasive behaviour of carcinoma cells.
abstract: Epithelial-mesenchymal transition (EMT) is regulated by interaction of carcinoma and stromal cells and crucial for progression of urinary bladder carcinoma (UBC). Therefore, the influence of activated fibroblasts on the expression of E-cadherin repressors as well as EMT and invasion in UBC was investigated. A correlative analysis of the immunohistochemical expression of fibroblast (ASMA, S100A4, FAP, SDF1, PDGFRβ) and EMT (Snail, Slug, Zeb1, E-cadherin) markers was performed on 49 UBC cases of different stages. The impact of distinguishable growth factor stimulated fibroblasts on invasion, EMT, and E-cadherin repressor expression was investigated in an invasion model. In situ, invasiveness was significantly correlated to the loss of membranous E-cadherin (E-cad_m) and increased Snail, Slug, Zeb1 in tumour cells, as well as to increased ASMA, S100A4, and PDGFRβ in stromal cells. A significant correlation to nodal metastasis could be evidenced for the loss of E-Cad_m, and for an increase in S100A4 and PDGFRβ. Comparison of stromal and EMT markers revealed significant correlations of ASMA to Snail and Slug; of S100A4 to the loss of E-cad_m and Zeb1; and of PDGFRβ to the loss of E-Cad_m, Slug and Zeb1. In vitro, TGFβ1 induced myofibroblasts were the strongest attractants, while aFGF or TGFβ1/aFGF stimulated fibroblasts were the most potent EMT inductors. As shown here for the first time, distinct sub-populations of fibroblasts are to various extents associated with EMT and tumour progression in UBC. These relevant findings might be the basis for the identification of new diagnostic markers and therapeutic targets selectively affecting tumour supporting CAF effects.
authors: Institute of Pathology, Jena University Hospital, 07740 Jena, Germany.
authors: Julia
authors: J
authors: Schulte
authors: Michaela
authors: M
authors: Weidig
authors: Philipp
authors: P
authors: Balzer
authors: Petra
authors: P
authors: Richter
authors: Marcus
authors: M
authors: Franz
authors: Kerstin
authors: K
authors: Junker
authors: Mieczyslaw
authors: M
authors: Gajda
authors: Karlheinz
authors: K
authors: Friedrich
authors: Heiko
authors: H
authors: Wunderlich
authors: Arne
authors: A
authors: Östman
authors: Iver
authors: I
authors: Petersen
authors: Alexander
authors: A
authors: Berndt
mesh_terms: D015820:Cadherins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000032:analysis* / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D000071250:Snail Family Transcription Factors; D017154:Stromal Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis* / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1