transforming-growth-factor-alpha and Cholesteatoma

There are at least three possible molecular models of cholesteatoma pathogenesis. Cholesteatoma may arise as a result of 1) the induction of a preneoplastic or neoplastic transformation event; 2) a defective wound-healing process; and/or 3) a pathologic collision of the host inflammatory response, normal middle ear epithelium, and a bacterial infection.. There have been a number of speculations concerning the factors that foster the development of cholesteatoma. Before resolving the molecular basis for the pathogenesis of cholesteatomas, it is important to present and test plausible models that could explain how a cholesteatoma becomes invasive, migratory, hyperproliferative, aggressive, and recidivistic.. The authors evaluated by various techniques (e.g., immunohistochemistry, flow cytometry, and image analysis) a large number of cholesteatomas of all types (e.g., primary and secondary acquired, recurrent, and congenital) and a range of normal tissues (tympanic membrane, canal wall skin, and postauricular skin) for the expression of various proteins (e.g., p53, ectopeptidases, tryptase) and for the presence of DNA aneuploidy.. The authors' published and unpublished studies to date support several suppositions concerning the pathology of cholesteatomas. First, cholesteatoma epithelium behaves more like a wound-healing process than a neoplasm. The available evidence to date does not indicate that cholesteatomas have inherent genetic instability, a critical feature of all malignant lesions. Second, the induction of hyperproliferative cells in all layers of the cholesteatoma epidermis implicates a potential idiopathic response to both internal events as well as external stimuli in the form of cytokines released by infiltrating inflammatory cells. Third, the presence of bacteria may provide a critical link between the cholesteatoma and the host, which prevents the cholesteatoma epithelium from terminating specific differentiation programs and returning to a quiescent state in which it becomes minimally proliferative, nonmigratory, and noninvasive. Fourth, none of our data suggest that there are any obvious molecular or cellular differences among the various types of cholesteatomas (e.g., primary and secondary acquired, recidivistic, and congenital). Continued research should delineate the precise molecular and cellular dysfunction involved in the pathogenesis of cholesteatomas and how this knowledge can be useful in the clinical management of cholesteatomas.

Topics: Aminopeptidases; Cell Movement; Cholesteatoma; Cytokines; DNA; ErbB Receptors; Genes, p53; Humans; Keratinocytes; Mast Cells; Ploidies; Transforming Growth Factor alpha; Tympanic Membrane; Wound Healing

After an epoch in which was pretended to explain the etiopathogenetic phenomena observed in Cholesteatoma through enzymatic studies, nowadays other investigations focus the topic in the possible presence of immunobiologic alterations at cellular level, so the research work is directed to the occurrence, distribution and activity of several growth factors and leukins. In this paper the AA. made a perusal of the new acquisitions and devote themselves to two important aspects of the cholesteatoma: the biologic behaviour of the squamous cell epithelia with an uncontrolled growth and to the immunobiologic mechanisms responsible for the bone resorption.

Topics: Bone Resorption; Cholesteatoma; Ear, Middle; Epithelial Cells; HLA-DR Antigens; Humans; Keratinocytes; Keratins; Osteolysis; Transforming Growth Factor alpha

Previous studies have shown an altered epithelial cell proliferation in middle ear cholesteatoma, reporting an aberrant expression of epidermal growth factor receptor (EGF-R) glycoprotein by immunohistochemistry. In this study, we quantified the presence of EGF-R using enzyme-linked immunosorbent assays (ELISAs) on tissue extracts, as well as the EGF-R gene expression by in situ hybridization on frozen sections. Human skin obtained from the external ear canal was used as control. The amounts of EGF-R glycoprotein in cholesteatoma were very similar to those in human skin. Human skin showed EGF-R messenger RNA (mRNA) only in the basal layer. A higher percentage of cells hybridized for the anti-sense probes EGF-R was found in cholesteatoma epithelium. Furthermore, we could find suprabasal cells with EGF-R mRNA. Our results confirm that the abnormal growth of cholesteatoma epithelium is reflected in an aberrant expression of EGF receptor.

Topics: Binding Sites; Cholesteatoma; DNA Probes; DNA, Complementary; Ear, Middle; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Gene Expression; Glycoproteins; Humans; In Situ Hybridization; Keratinocytes; Protein Biosynthesis; RNA, Messenger; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGF-alpha) is a growth-regulatory peptide found in a wide range of embryonic and adult tissues. TGF-alpha is produced by keratinocytes and has been reported to be overexpressed in several epidermal diseases, including middle ear cholesteatoma. This report describes ear pathology in the waved-1 mutant mouse, which is severely deficient in TGF-alpha. Morphologic changes of the external and middle ear were studied histologically in waved-1 mutants 2 weeks to 6.5 months of age. Abnormalities found in the mutants included epidermal hyperplasia of the external ear canal (EAC) and tympanic membrane (TM) and enlargement of specialized sebaceous glands adjacent to the cartilaginous EAC. Sebum and desquamated keratin progressively accumulated within the EAC, displacing the TM into the middle ear. These changes appear similar to those occurring in Mongolian gerbils, which are known to develop cholesteatoma. The alterations found in waved-1 mutants are discussed in relation to the possible involvement of TGF-alpha in cholesteatoma pathogenesis.

Topics: Animals; Cholesteatoma; Ear, External; Mice; Transforming Growth Factor alpha; Tympanic Membrane

To study the possible autocrine growth stimulation of cholesteatoma epithelium, the expression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) in middle ear cholesteatoma was investigated by immunohistochemical staining techniques. Twenty cholesteatoma samples obtained at operation and six normal skin specimens collected from the external ear canal were used in the study. Immunostaining for TGF-alpha showed a diffuse cytoplasmic staining pattern. It was weakly expressed in the basal layer of the normal epidermal epithelium but was more strongly expressed in all cholesteatoma specimens. EGFR showed a dot-like/diffuse cytoplasmic and cell membrane staining pattern. EGFR-positive cells were seen in the basal layer of normal epidermis. In the cholesteatoma specimens, expression of EGFR was not only confined to the basal layer but persisted into the upper layers of the epithelium. Our findings indicate that an autocrine growth stimulation by TGF-alpha and EGFR may contribute to the unrestrained growth of cholesteatoma epithelium in the middle ear cavity.

Topics: Adult; Aged; Child, Preschool; Cholesteatoma; Ear, Middle; ErbB Receptors; Female; Humans; Immunohistochemistry; Male; Transforming Growth Factor alpha

Cholesteatoma epithelium is characterized by a keratinocyte dysregulation with an aggressive growth that leads to the destruction of normal middle ear mucosa. The abnormal behavior of cholesteatoma epithelium seems to be induced by the presence of a heavy immune cell infiltrate releasing different cytokines and growth factors in high amounts. Middle ear mucosa rests are often observed within the cholesteatoma stroma or adjacent to the advancing front of cholesteatoma epithelium. This study investigated the presence of interleukin-1 (IL-1), transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), and epidermal growth factor-receptor (EGF-R) in the mucosa rests as well as the expression of an activation marker, 4F2. The findings were correlated with the features of a surrounding stroma with an enhanced immune cell infiltrate. Cholesteatoma epithelium showed a high staining intensity of IL-1, TGF-alpha, and EGF-R. In contrast to this, middle ear mucosa did not show any positive reactions for the mentioned factors. Epidermal growth factor immunoreactivity was found in neither cholesteatoma epithelium nor in middle ear mucosa residues. The authors found a high concentration of lymphocytes and macrophages in the surrounding stroma. Most of these cells expressed TGF-alpha, IL-1, and 4F2, suggesting an activated form. Results indicate that keratinocytes present in the middle ear mucosa do not appear to react to the stimuli released by the inflamed stroma, reflecting important differences in the cell biological features of the keratinocytes that form parts of both types of epithelium.

Topics: Cholesteatoma; Ear, Middle; Epithelium; ErbB Receptors; Humans; Interleukin-1; Lymphocytes; Macrophages; Stromal Cells; Transforming Growth Factor alpha

Middle ear cholesteatoma is characterised by the presence of a stratified squamous epithelium with keratin depositions in the middle ear cavity. The vascularisation of the stroma of cholesteatoma was examined using a monoclonal antibody against human factor VIII related antigen as an endothelial cell marker. Normal aural skin sections were stained for comparison. The vascularisation was frequently more numerous in the stroma of cholesteatoma than in normal skin. It was generally noted that the morphology of the blood vessels differed between both clinical types of cholesteatoma. Furthermore, the number of transforming growth factor-alpha positive cells was found to be increased in the stroma of cholesteatoma. In the surroundings of the blood vessels an abundant infiltration of macrophages was observed. Macrophages are known to produce significant amounts of transforming growth factor-alpha. Therefore, hypervascularization could be induced by enhanced expression of growth factors from activated immune cells in the stroma of cholesteatoma and could substantially contribute to the unrestricted abnormal growth of cholesteatoma.

Topics: Antibodies, Monoclonal; Cholesteatoma; Ear, Middle; Endothelium, Vascular; Factor VIII; Humans; Immunoenzyme Techniques; Macrophages; Neovascularization, Pathologic; Skin; Stromal Cells; Transforming Growth Factor alpha

Transforming growth factor alpha (TGF alpha) and interleukin 1 alpha (IL-1 alpha) are known to be produced by normal human keratinocytes stimulating their proliferation. The distribution and expression of TGF alpha and IL-1 alpha were examined in specimens of middle ear cholesteatoma by means of immunohistochemical methods using a monoclonal antibody against TGF alpha and a polyclonal one against IL-1 alpha. Normal retroauricular skin was stained for comparison. Staining for TGF alpha was consistently stronger in cholesteatoma epithelium than in normal epidermis, and encompassed all epithelial cell layers. Immune cells occurring in the stroma of cholesteatoma also reacted positively for TGF alpha. The intensity of staining for IL-1 alpha was markedly stronger in cholesteatoma tissue than in normal epidermis. All cellular layers of the squamous epithelium of cholesteatoma stained strongly and uniformly for IL-1 alpha, whereas the keratin layer was negative for IL-1 alpha. In the connective tissue beneath the cholesteatoma epithelium intensely positive cells were scattered between negative stromal cells. These data are consistent with autocrine stimulation of the squamous epithelium of cholesteatoma by TGF alpha and IL-1 alpha as well as with a paracrine stimulation by immune cells. Both factors contribute to the unrestrained growth of cholesteatoma in the middle ear cavity.

Topics: Cell Division; Cholesteatoma; Ear Diseases; Ear, Middle; Epithelium; Humans; Immunoenzyme Techniques; Interleukin-1; Transforming Growth Factor alpha