Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. In order to investigate the pathogenesis of human osteosarcoma, there is a great need to develop a clinically relevant animal model. Here we report the development of an osteosarcoma animal model using three related human osteosarcoma lines, the parental TE-85 and two derivative lines MNNG/HOS and 143B. In vitro characterization demonstrated that the 143B line had the greatest cell migration and the least cell adhesion activities among the three lines. The 143B line also exhibited the greatest ability for anchorage independent growth. When GFP-tagged osteosarcoma cells were injected into the proximal tibia of athymic mice, we found that 143B cells were highly tumorigenic and metastatic, and MNNG/HOS cells were tumorigenic but significantly less metastatic. TE85 cells were neither tumorigenic nor metastatic. The number of pulmonary metastases was found 50-fold higher in 143B injected animals than that in MNNG/HOS injected mice. No pulmonary metastases were detected in TE85 injected animals for up to 8 weeks. Primary tumors formed by MNNG/HOS and 143B cells could be visualized by whole body fluorescence imaging, while the pulmonary metastases were visualized on the necropsied samples. The GFP tagged 143B cells (and to a lesser extent, MNNG/HOS cells) were readily recovered from lung metastases. This clinically relevant model of human osteosarcoma provides varying degrees of tumor growth at the primary site and metastatic potential. Thus, this orthotopic model should be a valuable tool to investigate factors that promote or inhibit osteosarcoma growth and/or metastasis.
The molecular events that precede the development of osteosarcoma, the most common primary malignancy of bone, are unclear, and concurrent molecular and genetic alterations associated with its pathogenesis have yet to be identified. Recent studies suggest that activation of -catenin signaling may play an important role in human tumorigenesis. To investigate the potential role of -catenin deregulation in human osteosarcoma, we analyzed a panel of 47 osteosarcoma samples for -catenin accumulation using immunohistochemistry. Potential activating mutations were investigated by sequencing exon 3 of the -catenin gene in genomic DNA isolated from tumor samples. Our findings revealed cytoplasmic and/or nuclear accumulation of -catenin in 33 of 47 samples (70.2%); however, mutation analysis failed to detect any genetic alterations within exon 3, suggesting that other regulatory mechanisms may play an important role in activating -catenin signaling in osteosarcoma. In our survival analysis, -catenin deregulation conferred a hazard ratio of 1.05, indicating that -catenin accumulation does not appear to be of prognostic value for osteosarcoma patients. When analyzed against other clinicopathologic parameters, -catenin accumulation correlated only with younger age at presentation (26.4 vs. 39.8 years). Nevertheless, our results demonstrate that the deregulation of -catenin signaling is a common occurrence in osteosarcoma that is implicated in the pathogenesis of osteosarcoma. © 2002 Wiley-Liss, Inc. Key words: Wnt signal; -catenin; osteosarcoma; tumorigenesis; bone tumorOsteosarcoma is the most common primary malignant tumor of bone, encompassing a class of osteoid-producing neoplasms that range in clinical behavior and responsiveness to therapeutic regimens. 1 Best known of these lesions, the classic high-grade osteosarcoma, primarily afflicts individuals in the second decade of life and is distinguished by its locally aggressive character and early metastatic potential. Despite advances in chemotherapy, 5-year survival has remained around 60%. 2 The molecular events that precede the development of osteosarcoma are poorly understood. Given its relatively early age at presentation and predilection for early metastasis, osteosarcoma is likely the result of underlying early somatic and/or germline mutations. Alterations in tumor-suppressor genes such as retinoblastoma (Rb1) and p53 have been identified in osteosarcoma and hypothesized to predispose individuals to this malignancy at an especially early age. [3][4][5][6] Although several putative chromosomal regions have been suggested to harbor potential tumor-suppressor genes, the molecular nature and identity of these genes have not been elucidated.-Catenin is a cellular protein with multiple functions. As an important component of the adherens junction complex, it helps to anchor E-cadherin to the intracellular actin cytoskeleton through interactions with ␣-catenin. 7,8 As an important Wnt signal transducer, -catenin plays an important role in many developmental...
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