Abstract
BackgroundCholesteatoma are cyst-like structures lined with a matrix of differentiated squamous epithelium overlying connective tissue. Although epithelium normally exhibits self-limited growth, cholesteatoma matrix erodes mucosa and bone suggesting changes in matrix protein constituents that permit destructive behaviour. Differential proteomic studies can measure and compare the cholesteatoma proteome to normal tissues, revealing protein alterations that may propagate the destructive process.MethodsHuman cholesteatoma matrix, cholesteatoma-involved ossicles, and normal middle ear mucosa, post-auricular skin, and non-involved ossicles were harvested. These tissues were subjected to multiplex peptide labeling followed by liquid chromatography and tandem mass spectrometry analysis. Relative protein abundances were compared and evaluated for ontologic function and putative involvement in cholesteatoma.ResultsOur methodology detected 10 764 peptides constituting 1662 unique proteins at 95 % confidence or greater. Twenty-nine candidate proteins were identified in soft tissue analysis, with 29 additional proteins showing altered abundances in bone samples. Ontologic functions and known relevance to cholesteatoma are discussed, with several candidates highlighted for their roles in epithelial integrity, evasion of apoptosis, and immunologic function.ConclusionThis study produced an extensive cholesteatoma proteome and identified 58 proteins with altered abundances contributing to disease pathopathysiology. As well, potential biomarkers of residual disease were highlighted. Further investigation into these proteins may provide useful options for novel therapeutics or monitoring disease status.
Highlights
Cholesteatoma are cyst-like structures lined with a matrix of differentiated squamous epithelium overlying connective tissue
Patient tissue samples were obtained during primary tympanomastoidectomy from patients with acquired cholesteatoma, whereby cholesteatoma matrix was excised and cleaned of keratin debris; middle ear mucosa was collected from uninvolved regions of the mastoid cavity; post-auricular skin was taken as a 1 mm wide strip of skin along the margin of the skin incision with subcutaneous tissue removed by sharp dissection under an operating microscope
Healthy mucosa not involved with cholesteatoma could not be identified in four patients and was not collected; three post-auricular skin samples were suboptimal samples and not included. isotopetagged relative abundance quantification (iTRAQ) analysis of the included samples detected 10 720 spectra representing 8372 unique peptides
Summary
Cholesteatoma are cyst-like structures lined with a matrix of differentiated squamous epithelium overlying connective tissue. Epithelium normally exhibits self-limited growth, cholesteatoma matrix erodes mucosa and bone suggesting changes in matrix protein constituents that permit destructive behaviour. Differential proteomic studies can measure and compare the cholesteatoma proteome to normal tissues, revealing protein alterations that may propagate the destructive process. Cholesteatoma is a benign epidermal inclusion cyst that develops within the temporal bone and exhibits locally destructive behavior. Cholesteatomas can progressively expand and destroy middle ear and temporal bone structures. This process can lead to secondary infections, which can result in complications such as tympanic membrane perforation, chronic otorrhea, hearing loss, vestibular dysfunction, facial nerve. Numerous targeted molecular and genome wide studies on cholesteatoma specimens support some of these hypotheses but fail to appreciate the complex interplay between multiple changes at the cellular level
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