Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amplification and rearrangement of cellular proto-oncogenes are two of the several possible genetic alterations implicated in carcinogenesis and tumor progression. Although morphologically similar tumors may be heterogeneous at the level of the genome, some tumor types have shown relatively frequent and consistent abnormalities of specific oncogenes. In order to determine the frequency of oncogene amplification and rearrangement in several types of human sarcomas and to determine if histologically similar tumors have common genetic alterations, we analyzed 26 primary sarcomas by Southern hybridization. The oncogene probes utilized were N- and H-ras, sis, EGF-R (erb-B-1), neu (erb-B-2), fos, N- and c-myc, mos, and yes. The tumors studied included: five rhabdomyosarcomas (one alveolar, four embryonal), six malignant fibrous histiocytomas, six leiomyosarcomas, four liposarcomas, two Ewing's sarcomas, one osteosarcoma, and two fibrosarcomas. Oncogene abnormalities were identified in three tumors. One rhabdomyosarcoma showed 12-fold amplification and concurrent rearrangement of sis. This particular tumor also revealed rearrangement of H-ras and 15-fold amplification of c-myc. A second rhabdomyosarcoma revealed rearrangement of neu. A liposarcoma had a sis rearrangement. These findings suggest that many sarcomas show no common structural oncogene abnormalities. The presence of differing oncogene alterations within the rhabdomyosarcoma group indicates genetic heterogeneity among histologically similar sarcomas. The finding of a sis rearrangement in both a liposarcoma and a rhabdomyosarcoma, however, may suggest common oncogenesis among different tumor types.
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PMID:Genomic alterations in sarcomas: a histologic correlative study with use of oncogene panels. 149 46

We reported previously that the adenovirus E1a gene reversed the transformed phenotype of one human melanoma and one fibrosarcoma cell line (S. Frisch, Proc. Natl. Acad. Sci. USA, 88: 9077-9081, 1991). To determine the generality of the tumor suppression effects of E1a, a diversity of tumor cell lines, including A204 rhabdomyosarcoma, RD rhabdomyosarcoma, Saos-2 osteosarcoma, NCI-H23 non-small cell lung carcinoma, MDA-MB435S breast carcinoma, and ras-transformed MDCK kidney epithelial cells, were infected with a retrovirus bearing the 12S E1a coding sequence. We demonstrate here that the expression of E1a severely reduced the anchorage-independent and tumorigenic growth of these cell lines without affecting their growth under normal culture conditions. The parental tumor cells used in this study did not overexpress c-erbB-2/neu, and E1a did not affect its expression in these cells. Thus, tumor suppression by E1a can operate in a wide variety of human tumor cells by c-erbB-2/neu-independent mechanisms. E1a also sensitized these cell lines to the cytotoxic effects of the anticancer drugs etoposide and cisplatin. The results suggest that E1a could prove useful for the gene therapy of a wide variety of human cancers.
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PMID:Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism. 758 33

The retinoblastoma tumor suppressor gene product (pRb) is involved in controlling cell cycle progression from G1 into S. pRb functions, in part, by regulating the activities of several transcription factors, making pRb involved in the transcriptional control of cellular genes. Transient-transfection assays have implicated pRb in the transcription of several genes, including c-fos, the interleukin-6 gene, c-myc, cdc-2, c-neu, and the transforming growth factor beta2 gene. However, these assays place the promoter in an artificial context and exclude the effects of far 5' upstream regions and chromosomal architecture on gene transcription. In these experiments, we have studied the role of pRb in the control of cell cycle-related genes within a chromosomal context and within the context of the G1 phase of the cell cycle. We have used adenovirus vectors to overexpress pRb in human osteosarcoma cells and breast cells synchronized in early G1. By RNase protection assays, we have assayed the effects of this virus-produced pRb on gene expression in these cells. These results indicate that pRb is involved in the transcriptional downregulation of the E2F-1, E2F-2, dihydrofolate reductase, thymidine kinase, c-myc, proliferating-cell nuclear antigen, p107, and p21/Cip1 genes. However, it has no effect on the transcription of the E2F-3, E2F-4, E2F-5, DP-1, DP-2, or p16/Ink4 genes. The results are consistent with the notion that pRb controls the transcription of genes involved in S-phase promotion. They also suggest that pRb negatively regulates the transcription of two of the transcription factors whose activity it also represses, E2F-1 and E2F-2, and that it plays a role in downregulating the immediate-early gene response to serum stimulation.
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PMID:Regulation of cellular genes in a chromosomal context by the retinoblastoma tumor suppressor protein. 967 66

The purpose of this study was to investigate whether Her-2/neu expression at diagnosis of osteosarcoma could provide biologic and prognostic information that predicts the risk of pulmonary metastases and outcome. Human epidermal growth factor (Her-2/neu) expression in 25 initial pretreatment osteosarcoma biopsies and 12 posttreatment pulmonary metastatic osteosarcoma resection specimens was assessed by standard immunohistochemical techniques on formalin-fixed paraffin-embedded tissue. As a screening analysis to determine if gene amplification may be a mechanism for increased Her-2/neu expression, FISH analysis was conducted on seven Her-2/neu immunostain-positive samples and five Her-2/neu immunostain-negative samples. Cytoplasmic Her-2/neu reactivity was identified in 11/25 (44%) of primary tumors and in 7/12 (58%) resection specimens from pulmonary metastases. Cytoplasmic Her-2/neu expression was associated with shorter overall metastasis-free survival. Her-2/neu gene amplification was identified by FISH analysis in six of the seven immunostain-positive samples but was also identified in two of the five immunostain-negative samples. Her-2/neu expression in patients with osteosarcoma is associated with an increased risk of metastasis and may define a subset of patients with a more aggressive tumor phenotype. Her-2/neu gene amplification may provide a mechanism for Her-2/neu overexpression in certain cases of osteosarcoma. Whether Her-2/neu expression influences outcome needs to be examined further in a prospective fashion. The hope is that Her-2/neu expression will identify patients who may benefit from the addition of directed biologic therapy.
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PMID:Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. 1254 70

Histologic response to chemotherapy is currently the strongest prognostic factor in high-grade osteosarcoma, but it can only be assessed after several weeks of therapy. Thus, detection of chemosensitivity at the time of diagnosis would be of great clinical importance. The expression of the proto-oncogene Her-2/neu has been shown to be of predictive value in breast cancer and has also been considered as prognostic marker for osteosarcomas, but reports of mainly immunohistochemical studies are controversial. Therefore, the aim of this study was to investigate Her-2/neu gene expression in laser-microdissected osteosarcoma cells. Laser microdissection enables the precise isolation of morphological defined cells from archival tissue specimens and is in combination with the highly sensitive real-time RT-PCR technique a valuable tool for cell-specific analysis of gene expression. Through optimization of current protocols, we could show that this technique can be successfully applied on formalin-fixed, paraffin-embedded and decalcified osteosarcoma tissue with high sensitivity and reproducibility. In all 17 osteosarcoma biopsies analyzed, we could detect Her-2/neu gene expression. Expression correlated significantly with the response to preoperative chemotherapy, which was assessed histologically according to the six-grade scale of Salzer-Kuntschik. Risk assessment on the basis of increased Her-2/neu gene expression matched the histologic findings in 16 out of 17 cases (94%). These data demonstrate the reliability of laser microdissection in the analysis of gene expression and suggest a possible role of Her-2/neu as prognostic marker for therapy outcome in osteosarcomas.
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PMID:Evaluation of the predictive value of Her-2/neu gene expression on osteosarcoma therapy in laser-microdissected paraffin-embedded tissue. 1463 80

The overexpression of HER-2/neu and p53 has been associated with poor outcome in many neoplasms. Their role in patients with osteosarcoma is unclear. We studied the expression of HER-2/neu and p53 in 22 osteosarcoma samples (from 20 patients--2 had locally recurrent disease) biopsied at the University of Medicine and Dentistry of New Jersey (UMDNJ) from 1996-2000 using both immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Fourteen patients (14 samples) presented with Stage II and 6 patients (8 samples) presented with Stage III disease. Median follow-up is two years (range one year to five years). Four of 22 (18%) samples showed focal membranous or cytoplasmic positivity for HER-2/neu and six of 22 samples (27%) showed nuclear positivity for p53 by IHC analysis. In contrast, none of 22 tested samples showed gene amplification for HER-2/neu by FISH analysis. Seven of 13 HER-2/neu and p53 negative patients (54%) are currently disease free (between one year to five years). In this sample of patients, the HER-2/neu oncogene is not overexpressed or amplified in osteosarcoma; six of 22 samples (27%) showed overexpression of p53 by IHC analysis. By FISH, none of the samples demonstrated deletion of p53. Neither HER2/neu nor p53 expression was important for the biology of osteosarcoma in this population.
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PMID:HER-2/neu and p53 in osteosarcoma: an immunohistochemical and fluorescence in situ hybridization analysis. 1506 60

The status of the erbB-2 (human epidermal growth factor receptor 2/neu) proto-oncogene in canine osteosarcoma (OSA) has not been reported previously. In this study we used real-time reverse transcriptase polymerase chain reaction to evaluate erbB-2 expression in seven canine OSA cell lines and 10 canine OSA tissue samples. We determined erbB-2 to be significantly overexpressed in 86% (six of seven) of the cell lines and 40% (4 of 10) of the OSA tissues samples. Given the importance of erbB-2 in human breast cancer, the finding of erbB-2 overexpression in canine OSA may be important in further understanding the pathogenesis and possible therapies of OSA.
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PMID:Overexpression of the erbB-2 proto-oncogene in canine osteosarcoma cell lines and tumors. 1513 83

Low-grade osteosarcoma is a rare variant of osteosarcoma. Although malignant, it must be distinguished from conventional osteosarcomas because of its excellent prognosis. Numerous published papers have described the expression of HER2/neu oncogene in osteosarcoma as a poor prognostic factor; however their results are discordant. To address the expression of HER2/neu and to validate the assessment methods of amplification of the HER2/neu oncogene, the authors have employed quantitative real-time PCR and fluorencent in situ hybridization analysis (FISH) in 21 low-grade osteosarcomas. We calculated the quantification of HER2/neu oncogene amplification as the ratio of measured HER2/neu gene/beta-globin reference gene in real-time PCR. All 21 cases had amplified signals in the quantitative real-time PCR. However, in the FISH analysis, HER2/neu oncogene amplification was only identified in 26% (5/19). The exact reasons for the discordance between these two methods are unknown; however, variable histological features might play a potential role. In conclusion, as our study showed amplification of HER2/neu oncogene in low-grade osteosarcoma, we assume that expression of HER2/neu is not a poor prognostic factor in low-grade osteosarcoma.
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PMID:Quantitative assessment of HER2/neu expression by real-time PCR and fluorescent in situ hybridization analysis in low-grade osteosarcoma. 1520 72

Vesicular stomatitis virus (VSV) is a candidate for development for cancer therapy. We created a recombinant replicating VSV (rrVSV) with an altered surface protein that targeted preferentially to breast cancer cells. The rrVSV genome contained a single glycoprotein (gp) gene derived from Sindbis virus. This gene expressed a chimeric Sindbis E2 binding gp and the native Sindbis E1 fusion gp. The chimeric E2 binding gp, called Sindbis-SCA-erbb2, was modified to reduce its native binding function and to contain a single chain antibody (SCA) with specificity for the human epidermal growth factor receptor Her2/neu protein, erbb2. These viruses selectively infected, replicated in and killed cells expressing erbb2. The titer of rrVSV on SKBR3 cells, a human breast cancer cell line which highly expresses erbb2 was 3.1 x 10(7)/ml compared with a titer of 7.3 x 10(5)/ml on 143 cells, a human osteosarcoma cell line which does not express erbb2. The titer of rrVSV on D2F2/E2 cells, a mouse mammary cancer cell line stably transfected to express human erbb2 was 2.46 x 10(6)/ml compared with a titer of 5 x 10(4)/ml on the parent D2F2 cells which do not express erbb2. When titered on erbb2-negative cells, non-replicating pseudotype VSV coated with Sindbis-SCA-erbb2 had <3% the titer of pseudotype VSV coated with wild type Sindbis gp indicating that the chimeric Sindbis gp had severely impaired binding to the natural receptor. Analysis of the protein composition of the rrVSV found low expression of the modified Sindbis gp on the virus.
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PMID:Preferential targeting of vesicular stomatitis virus to breast cancer cells. 1552 31

Her-2/neu is a tumor-associated antigen that has been targeted with both antibodies and cytotoxic T lymphocytes (CTL). Despite the isolation of Her-2/neu-reactive CTL in vaccinated patients, their therapeutic use has been limited by the observation that they often do not robustly recognize Her-2/neu(+) tumors. We sought to determine the mechanism for this escape using Ag201P and Ag201M cells, which are murine osteosarcoma tumor lines that express a functional HLA-A2/K(b) molecule. We now demonstrate that Ag201P and Ag201M express low levels of murine Her-2/neu, and that Ag201M was modestly and inconsistently recognized by an HLA-A2-restricted, Her-2/neu-reactive human CTL clone. In order to determine whether inefficient antigen processing might account for the weak recognition, COS-A2 cells were transfected with a short Her-2/neu minigene coding for the immunodominant Her-2/neu:369 epitope that did not require antigen processing or a long Her-2/neu minigene that did require antigen processing. Her-2/neu-reactive CTL clones only recognized COS-A2 cells transfected with the short minigene, indicating that lack of proper antigen processing could be responsible for the poor recognition of target cells. To confirm these results, it was demonstrated that following treatment with interferon-gamma, both Ag201P and Ag201M robustly and consistently stimulated the CTL clones. Furthermore, CTL clone recognition was enhanced following interferon-gamma treatment using another murine tumor line that expressed low levels of Her-2/neu (B16-A2/K(b)). The enhanced recognition of Ag201P and Ag201M in the presence of interferon-gamma was not due to an upregulation of Her-2/neu protein expression. Collectively, these results suggest that inefficient antigen processing of Her-2/neu can contribute to the lack of tumor recognition by CTL. These results also suggest that even tissues that express low levels of Her-2/neu might become CTL targets under conditions in which antigen processing is enhanced.
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PMID:Interferon-gamma renders tumors that express low levels of Her-2/neu sensitive to cytotoxic T cells. 1615 8


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