This thesis describes the generation of cell-of-origin based models, using mesenchymal stem cells, to further elucidate the underlying mechanism of molecular alterations of the bone-forming tumours... Show moreThis thesis describes the generation of cell-of-origin based models, using mesenchymal stem cells, to further elucidate the underlying mechanism of molecular alterations of the bone-forming tumours osteoid osteoma, osteoblastoma and osteosarcoma. Furthermore, we describe the identification of novel treatment options for osteosarcoma using 2D and 3D in vitro models. Show less
A mesenchymal stem cell (MSC) based osteosarcoma model was established. The model provided evidence for a MSC origin of osteosarcoma. Normal MSCs transformed spontaneously to osteosarcoma-like... Show moreA mesenchymal stem cell (MSC) based osteosarcoma model was established. The model provided evidence for a MSC origin of osteosarcoma. Normal MSCs transformed spontaneously to osteosarcoma-like cells which was always accompanied by genomic instability and loss of the Cdkn2a locus. Accordingly loss of human CDKN2A/p16 protein expression in patients__ samples identified a subgroup of patients which did not respond to the chemotherapy and all showed poor survival (< 50 months). Moreover the CDKN2A/p16 gene expression loss in the human samples was caused by the same mechanism as in the mice cells, i.e. homozygous genomic deletion, validating the mouse model. Subsequently other useful models were identified by extensive characterization of osteosarcoma cell lines. From analyses of important signal transduction pathways (Wnt, BMP, TGF_ and Ihh) candidate targets for therapy, like a GSK3_-inhibitor, were identified. Furthermore a novel zebrafish model was established to study the progression of normal MSCs towards osteosarcoma-like cells in a high throughput manner. In this model both the behavior of the cells as well as the response of the host involved in processes like angiogenesis and migration were studied. The exploration of osteosarcoma at different levels was essential to broaden our knowledge about its origin, etiology and behavior. A better understanding of this complex malignancy offers more accurate targets to hit. Moreover it provides better opportunities to model the tumor which in turn allows for discovering and assaying novel treatment strategies Show less
