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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

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.

Call for proposal

FP6-2004-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

KAROLINSKA INSTITUTET
Address
Nobels Vag 5
Stockholm
Sweden