Cholesteatoma-associated fibroblasts modulate epithelial growth and differentiation through KGF/FGF7 secretion

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• 作者：Salvatore Raffa (1)
  Laura Leone (1)
  Cristina Scrofani (1)
  Simonetta Monini (23)
  Maria Rosaria Torrisi (13) mara.torrisi@uniroma1.it
  Maurizio Barbara (23)
• 关键词：Keratinocyte growth factor – ; Fibroblast growth factor – ; Cholesteatoma – ; Cultured human fibroblasts – ; Metalloproteases
• 刊名：Histochemistry and Cell Biology
• 出版年：2012
• 出版时间：August 2012
• 年：2012
• 卷：138
• 期：2
• 页码：251-269
• 全文大小：2.4 MB
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• 作者单位：1. Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Clinical and Molecular Medicine, Sapienza University of Roma, Piazza Sassari 3, 00161 Rome, Italy2. Department of Neuroscience, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy3. Azienda Ospedaliera S. Andrea, Rome, Italy
• ISSN：1432-119X

文摘

The keratinocyte growth factor (KGF/FGF7), produced by stromal cells, is a key paracrine mediator of epithelial proliferation, differentiation and migration. Expression of the growth factor is increased in wound healing and in hyperproliferative epithelial diseases, as a consequence of the activation of dermal fibroblasts by the inflammatory microenvironment. The middle ear cholesteatoma, an aural epidermal pathology characterized by keratinocyte hyperproliferation and chronic inflammation, may represent a model condition to study the epithelial-mesenchymal interactions. To develop an in vitro model for this disease, we isolated and characterized human primary cultures of fibroblasts associated with the cholesteatoma lesion, analyzing their secretory behaviour and degree of differentiation or activation. Compared to the perilesional or control normal fibroblasts, all cultures derived from cholesteatoma tissues were less proliferating and more differentiated and their highly variable activated phenotype correlated with the secretion of KGF as well as of metalloproteases 2 and 9. Culture supernatants collected from the cholesteatoma-associated fibroblasts were able to increase the proliferation and differentiation of human keratinocytes assessed by the expression of Ki67 and keratin-1 markers. The single crucial contribution of the KGF released by fibroblasts on the keratinocyte biological response was shown by the specific, although partial, block induced by inhibiting the KGF receptor or by immunoneutralizing the growth factor. Altogether, these results suggest that the activation of the stromal fibroblasts present in the pathological tissue, and the consequent increased secretion of KGF, play a crucial role in the deregulation of the epidermal proliferation and differentiation.