Fuchs
Fakultäten » Medizinische Fakultät » Universitätsklinik Balgrist und Schweizerisches Paraplegikerzentrum » Orthopädie » Prof. Dr. Bruno Fuchs » Fuchs
Completed research project
| Title / Titel | GENETIC MARKERS OF OSTEOSARCOMA METASTASIS AS A BASIS FOR THE DEVELOPMENT OF NEW TREATMENT STRATEGIES | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | 1. Summary Osteosarcoma is the most frequent primary malignant bone tumor in children and adolescents with a high propensity for metastasis and therefore poor prognosis (Klein, et al., 2006). Despite the significant clinical improvements made over the past decades through the combined chemotherapeutic and surgical treatment, patients with metastatic or recurrent disease continue to have a very poor prognosis, with a 5-year survival rate of 10-20% (Gorlick, et al., 2003). Metastatic tumors are often refractory or only partially sensitive to current therapeutic strategies and are the primary cause of cancer-related mortality (Fuchs, et al., 2002). It is clear that current treatment strategies including the combination of chemotherapy and surgery are unable to combat metastatic disease in patients with osteosarcoma, and new avenues, e.g. prevention of metastasis, need to be explored to address this problem (Chou, et al., 2006). The molecular mechanisms which lead to metastasis are yet poorly understood (Pantel, et al., 2004). With the studies proposed here, we wish to identify and characterize molecular markers as indicators of the cellular processes which result in osteosarcoma metastasis. We speculate that there is an intrinsic cellular program which confers osteosarcoma cells to metastasis (Fidler, 2002). We hypothesize that understanding these mechanisms will allow to identify drug targets and to rationally design corresponding drugs. Therefore, identification of key regulatory molecules involved in osteosarcoma metastasis is crucial, not only for a basic understanding of the molecular and cellular processes involved, but also to devise targeted and rational therapeutic strategies and ultimately to improve the survival of the patients. The main goal of our laboratory is the identification and characterization of key molecules and signalling pathways involved in osteosarcoma metastasis, to set the stage for the development of modern treatment strategies. We have established a comprehensive collection of osteosarcoma cell lines that represent in vitro models of tumor cells with low and high metastatic potential. Gene expression profiles of these cell lines are generated by oligonucleotide microarray analysis and used for the identification of biologically relevant genetic targets and signalling networks involved in metastasis. These studies will be complemented by mRNA and protein expression analyses and gain- and loss- of function studies combined with functional in-vitro assays, to validate metastasis markers in-vitro. With the tissue microarrays generated from tumor material of osteosarcoma patients, we intend to correlate the clinical outcome with the expression of marker proteins in order to establish their prognostic and biological relevance. Moreover, marker molecules considered to be relevant in osteosarcoma mestastasis will be validated in vivo in mouse models. Our microarray analyses revealed several interesting candidate genes that encode proteins which are important in angiogenesis, cell adhesion and cell migration, including Cyr61, CTGF, and Semaphorins. The human matricellular cysteine-rich protein 61 (CYR61/CCN1) and the connective tissue growth factor (CTGF/CCN2) are secreted extracellular matrix-associated signalling molecules that belong to the CCN protein family (Perbal, 2004, Planque, et al., 2003). This family currently includes six distinct members which play fundamental biological roles in growth, differentiation, angiogenesis, migration, and extracellular matrix regulation. Aberrant expression of CCN genes is associated with several pathological conditions including fibrotic diseases and tumorigenesis (Bleau, et al., 2005, Brigstock, 1999, Lau, et al., 1999). However, the function of Cyr61 in the context of osteosarcoma metastasis was not investigated so far. Using tissue and cell line arrays, we demonstrated that Cyr61 expression in tumors from patients and in osteosarcoma cell lines correlates with the incidence of metastasis. We propose to investigate the function and the mechanisms of Cyr61-induced signal transduction that are involved in osteosarcoma metastasis. Our strategy of characterizing one specific marker in detail, after having identified a vast array of potentially important genetic targets by our screening approach, will allow us to finally characterize a whole network of markers involved in osteosarcoma metastasis, which will likely represent genes responsible for this process in patients and which may set the stage for future drug development. The identification of numerous markers with the here outlined strategies will ultimately help to understand pathophysiological mechanisms responsible for a cell to detach from the primary tumor and to spread to the lung. In the long run, we hope to be able to identify osteosarcoma patients with an increased risk of developing metastasis and to recognize patients who can expect a substantial benefit by interfering with the metastatic cascade. Corresponding therapeutic interventions that prevent metastasis are expected to improve the survival of these patients. |
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| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Universität Zürich (position pursuing an academic career), Foundation Krebsliga Zürich |
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| Duration of Project / Projektdauer | Jan 2004 to Dec 2010 |