Final Activity Report Summary - CASTEMHEDGEHOG (The role of stem cells in cancer development in skin and mammary gland using tissue specific expression of Gli1 protein ...)
Current work was focused on the investigation of the epidermal stem cells and their role in the development of the most wide-spread malignancy in the western world - the 'basal cell carcinoma' (BCC). The objectives of the project were to define the role of the epidermal stem cell compartment in the development of the BCC and to define the cellular identity and characteristics of a cell population positive for a novel stem cell marker LGR5/CD49.
To study the BCC transgenic animal model was used where BCC was induced by hyperactivation of the Hedgehog (Hh) signal pathway in the epidermis. Deregulation of the Hh pathway is also the main cause for the appearance of this tumour in humans. The formation of BCC in transgenic mice was accompanied by increased proliferation and abnormal differentiation of the epidermis. Interestingly the number of cells positive for epidermal stem cell markers was drastically reduced and the keratinocyte stem cell activity was practically absent in the mice with deregulated Hh pathway. The absence of stem cell activity in the experimental BCCs correlates well with the benign clinical course of the BCC in humans as this tumour does not metastasise and cannot be transplanted to immunodeficient recipient animals.
Secondly we described a novel keratinocyte stem cell population, which is characterised by the expression of an orphan G-protein-coupled receptor LGR5/GPR49. It has been shown previously that the expression of this gene marks stem cells in the mouse intestine. This cell population is extremely potent in growth in the tissue culture conditions and in regeneration of the mouse hair follicles. Unlike the already described epidermal stem cell populations this cell population is proliferative and motile. High proliferativity combined with multipotency and self renewal properties make this cell population an attractive target for therapy of different skin diseases and traumas including alopecia.
To study the BCC transgenic animal model was used where BCC was induced by hyperactivation of the Hedgehog (Hh) signal pathway in the epidermis. Deregulation of the Hh pathway is also the main cause for the appearance of this tumour in humans. The formation of BCC in transgenic mice was accompanied by increased proliferation and abnormal differentiation of the epidermis. Interestingly the number of cells positive for epidermal stem cell markers was drastically reduced and the keratinocyte stem cell activity was practically absent in the mice with deregulated Hh pathway. The absence of stem cell activity in the experimental BCCs correlates well with the benign clinical course of the BCC in humans as this tumour does not metastasise and cannot be transplanted to immunodeficient recipient animals.
Secondly we described a novel keratinocyte stem cell population, which is characterised by the expression of an orphan G-protein-coupled receptor LGR5/GPR49. It has been shown previously that the expression of this gene marks stem cells in the mouse intestine. This cell population is extremely potent in growth in the tissue culture conditions and in regeneration of the mouse hair follicles. Unlike the already described epidermal stem cell populations this cell population is proliferative and motile. High proliferativity combined with multipotency and self renewal properties make this cell population an attractive target for therapy of different skin diseases and traumas including alopecia.