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.

Epithelial-to-Mesenchymal Transition in Penile Squamous Cell Carcinoma

“…EMT is widely associated with lymphatic metastasis of several malignant tumors. 7,13,22,23 However, in this series we found no such association. A low sample size effect could explain this phenomenon.…”

Long Non-Coding RNA MALAT1 Decreases the Sensitivity of Resistant Glioblastoma Cell Lines to Temozolomide

“…However, the knowledge of the precise mechanisms in their relationship is very limited. It is well known that the loss of E-cadherin is the fundamental event in EMT and that this loss is induced by several E-cadherin repressors such as Snail, Slug and ZEB1 [28]. Here, we found that the protein expression levels of ZEB1, Snail, and SLUG were increased in the TMZ-resistant cells compared with the glioblastoma cells, indicating that EMT might contribute to the TMZ resistance of the glioblastoma cell line.…”

A common framework for EMT and collective cell migration

“…Furthermore, when cells lose apico-basal polarity, this goes hand in hand with a loss of adherens junctions and vice versa. Accordingly, EMT is often driven by repressing the expression of adherens junction components, such as E-cadherin; owing to the pivotal role of E-cadherin loss, transcription factors that affect EMT, such as Snail, Twist and Zebs, are often referred to as E-cadherin repressors (Galván et al, 2015;Nieto, 2011;Schulte et al, 2012). Intriguingly, it is also possible to affect EMT via the repression of apico-basal polarity proteins without affecting E-cadherin transcription; the loss of apico-basal polarity in turn leads to destabilisation of adhesion junctions (Campbell et al, 2011;Lim and Thiery, 2011).…”