Cellular signaling in human cholesteatoma

Huisman, Margaretha Aleida (2007)

Doctoral Thesis

Cholesteatoma is a benign, gradually expanding destructive epithelial lesion of the temporal bone, often accompanied with inflammation. The complications can be severe, e.g., destruction of the ossicular chain and otic capsule with consecutive hearing loss. Several hypotheses for the pathogenesis of human cholesteatoma have been proposed but are still controversial. In this thesis, protein signaling pathways were investigated which are involved in different aspects of cholesteatoma pathogenesis, such as hyperproliferation, aberrant differentiation, and extra-cellular matrix deposition. In cholesteatoma epithelium increased expressions of those proteins were found which are involved in proliferation (Ki-67), cell cycle arrest (p53, p21), early terminal differentiation (involucrin) and survival (pAKT). The proteins of which the expressions were decreased were those concerning late terminal differentiation (filaggrin) and apoptosis (active caspase 3). Moreover, increased activation of MAPK- and its association with TGF_ cellular signaling cascades were demonstrated. In cholesteatoma stroma, increased extracellular matrix deposition, visualized by accumulation of EDA-Fibronectin, was present. These results were placed in the context of the interconnected signaling processes of wound healing. Concluding: cholesteatoma behaves as a chronic wound in which a persistent inflammation appears to be a contributing factor to its chronicity. Research into pharmacological interventions aimed at control of inflammation is recommended.

• Apoptosis
• Cell cycle arrest
• Cell signaling
• Cholesteatoma
• Differentiation
• Proliferation
• Survival
• Wound healing.

• All authors: Huisman, Margaretha Aleida
• Supervisor: Grote, J.J.
• Co-supervisor: Heer, E. de
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2007-01-24
• ISBN (print): 9090214798