In sarcomas, the TP53 tumour suppressor pathway may be altered either by TP53 mutations or by amplification of MDM2, encoding a protein that inhibits TP53 and targets it for 26S-proteasome degradation. However, in the majority of the analysed clinical samples, neither of these types of aberrations are found, suggesting that additional mechanisms are involved. The present study shows that COPS3, located in 17p11 and encoding a component of the proteasome pathway, is more frequently amplified in osteosarcomas (OS) than is MDM2. We present detailed analysis of TP53 mutations and MDM2 and COPS3 expression levels in a set of 23 OS. Our results show that none of the tumours with COPS3 amplification had MDM2 amplification nor TP53 mutations, consistent with the hypothesis that one of the three aberrations is sufficient. The results suggest that inactivation of otherwise intact TP53 by aberrations in the proteasome pathway may contribute to the characteristic aneuploidy observed in OS.

No abstract

Global gene expression analysis was performed on a panel of 23 osteosarcoma samples of primary and metastatic origin using the Applied Biosystems Gene Expression Array System. When comparing the primary tumours with the metastases, we found a significantly increased expression of genes involved in immunological processes, for example coding for cytokines and chemokines, in the metastatic samples. In addition, a comparison of the gene expression in primary samples from patients with or without metastases demonstrated that patients who later developed metastases had high expression of the chemokine (C-X-C motif) receptor 4 (CXCR4), similar to the metastatic samples, suggesting that these signal molecules play an important role in promoting metastasis. Increased knowledge of mechanisms and interactions between specified molecular signalling pathways in osteosarcomas could lead to a more rational strategy for development of targeted therapy.

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PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly ampli®ed in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired a nity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found ampli®cation of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant ®brous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE ampli®cation was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE ampli®cation developed metastases. A similar situation was observed in all breast carcinomas with ampli®cation of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, ampli®-cation and overexpression of PRUNE has the same e ect in the tumours. We suggest that ampli®cation and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that a ect the development or progression of these tumours. Oncogene (2001) 20, 6881 ± 6890.