CASTEMHEDGEHOG · The role of stem cells in cancer development in skin and mammary gland using tissue specific expression of Gli1 protein - main effector of the hedgehog signalling pathway
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-01-01 → 2007-12-31
- EU contribution
- €165,354
- Participants
- 1
- Scheme
- EIF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
Recent evidence suggests that only a subset of tumour cells is capable of giving rise to a new tumour. These tumour stem cells are functionally similar to stem cells in adult tissues and are identified in tumours of hematopoietic system, brain and mammary gland. Whether transformation of adult stem cells into tumour stem cells is the event leading to the disease is not clear. Alternatively, tumours could arise from the population of committed progenitors, which have de novo acquired self-renewal properties.The purpose of this project is to investigate the contribution of stem cell and progenitor populations into carcinogenesis in skin and mammary gland. The questions to be answered:1. Does oncogene activation alter the amount and proliferation properties of stem cells and/or progenitors?2. Are stem cells involved in carcinogenesis in skin and mammary gland?3. Are there stem cell-like cells in skin tumours?The activity of hedgehog (Hh) pathway has been shown to be required for growth of a variety of tumours including basal cell carcinoma. Here the tetracycline-controlled conditional expression of the main effector of the Hh signalling pathway - Glil in mouse skin and mammary gland is used as a model system. The dynamics of changes in the cellular composition after Gli 1 induction are monitored and the proliferative potential of different cell subpopulations is evaluated.A cross of inducible Gli1 mice and ubiquitously lacz expressing mice will be created to follow the progeny of stem cells. The potential tumourigenecity of sorted and engrafted populations of stem and progenitor cells is evaluated following Gli1 activation. Finally identification of tumour stem cells from tumours induced in Gli1 expressing mice will be attempted by cell culture methods. The outcome of this project will contribute to our understanding of cancer development in general and have implications to the therapeutic strategies of skin and mammary cancer.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
Data: CORDIS, © European Union