No abstract

With the goal of establishing efficacious peptide-based immunotherapy for patients with bone and soft tissue sarcomas, we previously identified the cytotoxic T lymphocyte-defined osteosarcoma antigenic gene Papillomavirus binding factor. The present study was designed to determine the status of HLA class I expression in osteosarcoma and other bone and soft tissue sarcomas. Seventy-four formalinfixed paraffin-embedded specimens of various bone and soft tissue sarcomas, including 33 osteosarcomas, were stained with the anti-HLA class I monoclonal antibody EMR8-5, which we recently generated. The expression of HLA class I was lost or downregulated in 46 of these specimens (62%). With respect to osteosarcoma, loss or downregulation of HLA class I expression was seen in 13 (52%) of 25 primary tumors and seven (88%) of eight metastatic tumors. In six of 11 HLA class I-negative osteosarcoma specimens, the expression of β β β β-2 microglobulin was also lost. Subsequently the prognostic significance of HLA class I expression was analyzed in 21 patients with osteosarcoma who had completed multidrug neoadjuvant chemotherapy and undergone adequate surgery. Patients with osteosarcoma highly expressing HLA class I showed significantly better overall and event-free survival than those with HLA class I-negative osteosarcoma. In contrast, such prognostic significance of HLA class I expression was not found in 15 patients with malignant fibrous histiocytoma of soft tissue. These findings suggest that the class I-restricted cytotoxic T lymphocyte pathway plays a major role in immune surveillance of patients with osteosarcoma. (Cancer Sci 2006; 97: 1374-1380)

The authors performed PINK1 mutation analysis of 51 families with autosomal recessive Parkinson disease (ARPD). They found two novel PINK1 mutations: one was a homozygous deletion (13516-18118del) and the other a homozygous missense mutation (C388R). Clinically, the patients with the deletion had dementia. Thus, early-onset PD with dementia may be considered PINK1-linked parkinsonism. Furthermore, patients with PINK1 mutations form 8.9% of parkin- and DJ-1-negative ARPD families.

BACKGROUND: Several human cancers have been found to contain cancer stem-like cells (CSCs) having cancer-initiating ability. However, only a few reports have shown the existence of CSCs in bone and soft tissue sarcomas. In this study, we identified and characterised side population (SP) cells that showed drug-resistant features in human bone sarcoma cell lines. METHODS: In seven osteosarcoma cell lines (OS2000, KIKU, NY, Huo9, HOS, U2OS and Saos2) and in one bone malignant fibrous histiocytoma (MFH) cell line (MFH2003), the frequency of SP cells was analysed. Tumourigenicity of SP cells was assessed in vitro and in vivo. Gene profiles of SP cells and other populations (main population; MP) of cells were characterised using cDNA microarrays. RESULTS: SP cells were found in NY (0.31%) and MFH2003 (5.28%). SP cells of MFH2003 formed spherical colonies and re-populated into SP and MP cells. In an NOD/SCID mice xenograft model, 1 Â 10 3 sorted SP cell-induced tumourigenesis. cDNA microarray analysis showed that 23 genes were upregulated in SP cells. CONCLUSIONS: We showed that SP cells existed in bone sarcoma cell lines. SP cells of MFH2003 had cancer-initiating ability in vitro and in vivo. The gene profiles of SP cells could serve as candidate markers for CSCs in bone sarcomas.

BACKGROUND Elevated ErbB2 expression and gene amplification have been shown to be associated with poor prognosis in many cancers. Recently, it has been demonstrated that overexpression of ErbB2 protein in osteosarcoma is associated with the presence of pulmonary metastasis and decreased survival. By contrast, a previous study showed that the expression of ErbB2 declines in individual osteosarcomas as they become metastatic. In the current study, the authors determined the relation between ErbB2 status and outcome in a large number of selected patients with high‐grade osteosarcoma. METHODS ErbB2 status was determined immunohistochemically in biopsy specimens of osteosarcoma of the extremities from 81 patients who were treated with surgery and chemotherapy. None of the patients had metastatic disease at presentation (Stage II), and all were followed‐up for at least five years. The ErbB2 status was analyzed in relation to the lengths of event‐free and overall survival. RESULTS Of the 81 tumors examined, 51 (61%) demonstrated high levels of ErbB2 expression. The presence of increased levels of ErbB2 in osteosarcoma was significantly associated with the increased probability of event‐free (72.2% v. 45.6% at 5 years, P = 0.03) and overall survival (79.7% v. 58.2% at 5 years, P = 0.03). Cox multivariate analysis showed that the risk of adverse events and death was increased substantially (rate ratio: 2.24 and 2.54; 95% confidence interval, 1.07–4.72 and 1.09–5.67, respectively) among patients with decreased levels of ErbB2 protein in tumor cells, as compared with patients who had increased levels of ErbB2 in tumor cells. CONCLUSIONS In patients with high‐grade osteosarcoma without metastatic disease at presentation and treated with surgery and chemotherapy, the presence of increased levels of ErbB2 in tumor cells is associated with a significantly increased probability of event‐free and overall survival. Further data are needed before this marker can be used in making clinical decisions. Cancer 2002;94:1397–404. © 2002 American Cancer Society. DOI 10.1002/cncr.10360

No abstract

We report here that the Id2 (inhibitor of DNA binding 2) gene is a novel target of transcriptional activation by EWS -FLI1 and EWS -ERG, two fusion proteins that characterize Ewing family tumors (EFTs). To identify downstream targets of these EWS -ETS fusion proteins, we introduced EWS -ETS fusion constructs into a human fibrosarcoma cell line by retroviral transduction. cDNA microarray analysis revealed that Id2 expression was up-regulated by introducing the EWS -ETS fusion gene but not by the normal full-length ETS gene. An Id2 promoter-luciferase reporter assay showed that transactivation by EWS -ETS involves the minimal Id2 promoter and may function in cooperation with c-Myc within the full-length regulatory region. A chromatin immunoprecipitation assay revealed direct interaction between the Id2 promoter and EWS-FLI1 fusion protein in vivo. Significantly higher expression of Id2 and c-Myc was observed in all of the six EFT cell lines examined compared to six other sarcoma cell lines. Moreover, high levels of Id2 expression were also observed in five of the six primary tumors examined. Id2 is generally thought to affect the balance between cell differentiation and proliferation in development and is highly expressed in several cancer types. Considering these previous studies, our data suggest that the oncogenic effect of EWS -ETS may be mediated in part by up-regulating Id2 expression.

No abstract