Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma

Abstract

Although the etiology of squamous cell carcinomas of the oral mucosa is well understood, the cellular origin and the exact molecular mechanisms leading to their formation are not. Previously, we observed the coordinated loss of E-cadherin (CDH1) and transforming growth factor beta receptor II (TGFBR2) in esophageal squamous tumors. To investigate if the coordinated loss of Cdh1 and Tgfbr2 is sufficient to induce tumorigenesis in vivo, we developed two mouse models targeting ablation of both genes constitutively or inducibly in the oral-esophageal epithelium. We show that the loss of both Cdh1 and Tgfbr2 in both models is sufficient to induce squamous cell carcinomas with animals succumbing to the invasive disease by 18 months of age. Advanced tumors have the ability to invade regional lymph nodes and to establish distant pulmonary metastasis. The mouse tumors showed molecular characteristics of human tumors such as overexpression of Cyclin D1. We addressed the question whether TGFβ signaling may target known stem cell markers and thereby influence tumorigenesis. From our mouse and human models, we conclude that TGFβ signaling regulates key aspects of stemness and quiescence in vitro and in vivo. This provides a new explanation for the importance of TGFβ in mucosal homeostasis.

Cellular and developmental basis of orofacial clefts

“…Immunofluorescent studies reveal adherens junctions in the MES (Kitase & Shuler, 2013; Tudela et al, 2002). However, knocking out Cdh1 in epithelial cells with K14‐Cre does not cause CP (Andl et al, 2014). This may be because the K14‐Cre used in the study expresses only in the basal layer and not in the periderm, in which proper adhesion dynamics are important (Vasioukhin, Degenstein, Wise, & Fuchs, 1999).…”

Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling

“…E-cadherin is an epithelial cell marker and controls cell-cell junctions 28 . E-cadherin can be viewed as an inhibitor of EMT 29 . The protein expression of E-cadherin was significantly downregulated in HK-2 cells by inducing TGF-β1 or Ang II ( Figure 2B-E).…”

Immunocompromised and immunocompetent mouse models for head and neck squamous cell carcinoma

“…This promotes the building of the targeted and inducible models on which gene mutation in the targeted cells of animals can be generated. Andl et al 136 developed two mouse models targeting ablation of Cdh1 and Tgfbr2 genes constitutively or inducibly in the oral–esophageal epithelium, which had long latency and could phenocopy the human disease quite accurately. Opitz et al 137 generated L2-cyclin D1 (L2D1(+)) mice and crossbred these with p53-deficient mice; L2D1(+)/p53(+/−) mice provided a well-defined, novel, and faithful model of oral–esophageal cancer.…”