UMLS:C0029463 - FACTA Search

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Query: UMLS:C0029463 (osteosarcoma)
16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteosarcoma is the most common primary malignant bone tumor, with high rates of metastasis. Here, we examined the expression of human epidermal growth factor receptor-2 (HER-2) in osteosarcoma cell lines with different metastatic potential, finding that the expression was correlated with metastasis of implanted tumors. We then introduced an expression vector encoding the e23sFv-PEA II-Bid Delta1-60 gene, composed of a HER2-specific single-chain antibody fused with domain II of Pseudomonas exotoxin A (PEA) and the carboxy end of truncated active Bid. We demonstrated that the e23sFv-PEA II-Bid Delta1-60 molecule selectively recognized and killed HER2-overexpressing osteosarcoma cells in vitro. Subsequently, we introduced the e23sFv-PEA II-bid Delta1-60 gene into BALB/c athymic mice bearing HER2-positive osteosarcomas using i.m. injections of liposome-encapsulated vector. Expression of the e23sFv-PEA II-Bid Delta1-60 gene suppressed tumor growth, significantly prolonged animal survival and inhibited metastasis, thereby suggesting it may represent a competitive approach to treating HER2/neu-positive osteosarcoma.
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PMID:scFv-mediated delivery of truncated BID suppresses HER2-positive osteosarcoma growth and metastasis. 1902 93

Sarcomatoid carcinoma (carcinosarcoma) of the upper urinary collecting system is a rare aggressive malignancy composed of malignant epithelial and stromal components. Because of the paucity of reported cases, the clinical behavior, molecular alterations, and potential therapies for this malignancy are not well understood. Eight cases of sarcomatoid carcinoma involving the upper urinary tract were studied. Clinicopathologic characteristics were reviewed. Immunohistochemical expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)/neu, c-kit, and p53 was analyzed in each case. Evaluation for amplification of EGFR and HER2 genes was performed by interphase fluorescence in situ hybridization (FISH). Each tumor was also examined for gains of chromosomes 3, 7, and 17 and for loss of chromosome 9p21 by UroVysion FISH (Vysis, Downers Grove, IL). The patients we studied were 5 females and 3 males, ranging in age from 56 to 78 years (mean age, 69 years). Presenting symptoms included gross hematuria, flank mass, urinary obstruction, fever, or sepsis. Radical nephroureterectomy was performed on all patients. Tumor size ranged from 2 to 13 cm. Coexisting urothelial carcinoma was present in all 8 cases. Heterologous osteosarcoma was identified in 2 cases. Pathologic stage was pT4 in 5 cases and pT3 in 3 cases. Lymph node metastases were present in 5 patients at the time of surgery. Of 8 patients, 7 died within 2 years after surgery. EGFR immunostaining had moderately to strongly positive results in 6 of 8 cases. Both HER2/neu and c-kit immunostaining had negative results in all cases. p53 immunostaining had positive results in 5 of 8 cases. The EGFR polysomy was demonstrated in 7 of 8 cases. No amplification of HER2/neu was present in any case. UroVysion FISH showed abnormalities typical of urothelial carcinoma in all 8 cases. In conclusion, the prognosis of sarcomatoid carcinoma of the upper urinary tract is extremely poor, most patients died within 2 years (7/8 patients). Gains of chromosome 3, 7, and 17 and loss of chromosome 9p21 were commonly observed in these tumors. Our findings suggest that targeted therapy may be a rational strategy in the management of these patients.
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PMID:Sarcomatoid carcinoma of the upper urinary tract: clinical outcome and molecular characterization. 1879 88

Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (>120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell-specific molecule-1, 5'-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy strategies.
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PMID:Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. 1917 81

The value of epidermal growth factor receptor (EGFR) and its downstream signaling molecules as prognostic factors have been studied in many tumor types. The aim of this study was to investigate whether these molecules have prognostic value in osteosarcoma. We evaluated the immunostaining of EGFR and its downstream signaling molecules, p-EGFR, Akt, Stat-3, survivin and Erk in 47 osteosarcomas. In addition, three osteosarcoma cell lines were used to evaluate EGFR expression levels and mutation status by real-time PCR and nucleotide sequence analysis. Using tissue microarray of samples from 47 paraffin-embedded osteosarcoma cases, 26, 17, 20 and 12 cases showed positive immunostaining of EGFR, Stat-3, survivin and Erk, respectively. Survivin and Erk were statistically correlated with survival (p=0.005 and p=0.002, respectively, log-rank test). Furthermore, we found that EGFR expression was correlated with Erk expression. In addition, we also observed a significant association of survivin expression with Stat-3 and Erk activation (p=0.006 and p=0.000, Fisher's exact test). p-EGFR and Akt immunostaining were not detected in any of the cases. Two out of three osteosarcoma cell lines showed increased EGFR levels as detected by real-time PCR. One of these cell lines had a CAA to CAG mutation at exon 20 of the amplified EGFR gene, but this did not change the amino acid sequence. These results support the idea that Erk is a downstream signaling molecule of EGFR. Moreover, our data indicate that survivin and Erk could be used as prognostic factors in patients with osteosarcoma.
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PMID:The expression of epidermal growth factor receptor and its downstream signaling molecules in osteosarcoma. 1921 84

In previous studies on HeLa cells we demonstrated estrogen-responsiveness of the epidermal growth factor receptor (EGFR) gene, as 17beta-estradiol (E(2)) and selective estrogen receptor modulators (SERMs) genistein (G), daidzein (D), and 4-hydroxytamoxifen (4OH-T) modulated its transcription in a ligand- and estrogen receptor (ER) isoform-specific way. This study describes further investigations into the role of ERs in mediating the effects induced by E(2) and SERMs on EGFR expression, and the relationship between the actions of ERs and EGFR in U2OS osteosarcoma cells stably expressing ERalpha or ERbeta. Cell number and DNA content determination revealed that E(2), G, and D inhibited proliferation and cell cycle progression and promoted apoptosis in both cell lines. In parallel, changes in cell morphology typical of osteoblast maturation were observed via optical microscopy. Consistently, quantitative PCR and Western blot analysis showed an up-regulation of markers of osteoblast differentiation and bone repair, and a decrease in EGFR expression. The transfection of specific antisense (AS) oligonucleotides strengthened our hypothesis that EGFR reduction caused changes in the proliferation/differentiation pattern comparable to those induced by ER ligands. The link between the ER and EGFR pathways was confirmed by treatment with 4OH-T, which decreased the EGFR level and produced differentiation effects via ERalpha, but induced both EGFR expression and proliferation effects via ERbeta. In conclusion, we show that also in U2OS cells, E(2) and SERMs are able to modulate the expression of the EGFR gene and can affect events strictly controlled by its signaling pathway, such as the maturation of osteoblasts.
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PMID:Down-regulation of epidermal growth factor receptor induced by estrogens and phytoestrogens promotes the differentiation of U2OS human osteosarcoma cells. 1934 70

Human epidermal growth factor receptor 2 (HER2) is expressed by the majority of human osteosarcomas and is a risk factor for poor outcome. Unlike breast cancer, osteosarcoma cells express HER2 at too low, a level for patients to benefit from HER2 monoclonal antibodies. We reasoned that this limitation might be overcome by genetically modifying T cells with HER2-specific chimeric antigen receptors (CARs), because even a low frequency of receptor engagement could be sufficient to induce effector cell killing of the tumor. HER2-specific T cells were generated by retroviral transduction with a HER2-specific CAR containing a CD28.zeta signaling domain. HER2-specific T cells recognized HER2-positive osteosarcoma cells as judged by their ability to proliferate, produce immunostimulatory T helper 1 cytokines, and kill HER2-positive osteosarcoma cell lines in vitro. The adoptive transfer of HER2-specific T cells caused regression of established osteosarcoma xenografts in locoregional as well as metastatic mouse models. In contrast, delivery of nontransduced (NT) T cells did not change the tumor growth pattern. Genetic modification of T cells with CARs specific for target antigens, expressed at too low a level to be effectively recognized by monoclonal antibodies, may allow immunotherapy to be more broadly applicable for human cancer therapy.
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PMID:Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. 1953 39

The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer.
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PMID:Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response. 2080 83

Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level of GAK expression and its correlation to prognosis was analyzed in osteosarcoma tissue microarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor-mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAK knockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.
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PMID:Cyclin G-associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. 2088 Dec 69

Immunotherapy is a promising strategy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive tumors. Previously, we constructed an immuno-carboxy terminal fragment of Bid (immuno-tBid) and reported its specific and effective destruction of HER2-positive tumor cells. In this study, in order to further reduce the immunogenicity of the previous immuno-proapoptotic protein, we constructed a novel immuno-tBid by replacing domain II of Pseudomonas exotoxin A with a short furin cleavage sequence from the diphtheria toxin. In order to explore the possible application of this novel immuno-tBid in the treatment of osteosarcoma, we first examined the expression of the HER2 protein in a subclone of a human osteosarcoma cell line with relatively high metastatic potential (SOSP-9607-E10), as well as in clinical specimens of osteosarcoma. Quantitative real-time PCR and Western blot analysis revealed that the expression of HER2 was up-regulated in the SOSP-9607-E10 cells, while immunohistochemical analysis revealed that HER2 was overexpressed in 37% of the tissue specimens examined. Both HER2-positive SOSP-9607-E10 and SKBR-3 cells, as well as HER2-negative HeLa cells were transiently transfected with the novel immuno-tBid in order to study its specific pro-apoptotic effect. We demonstrate here that this novel immuno-tBid induces the specific destruction of HER2-overexpressing SOSP-9607-E10 cells through the release of cytochrome C. These results suggest that the novel immuno-tBid with a minimized exogenous fragment could represent a competitive approach for the treatment of HER2-positive osteosarcoma.
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PMID:A novel recombinant immuno-tBid with a furin site effectively suppresses the growth of HER2-positive osteosarcoma cells in vitro. 2115 67

Human epidermal growth factor receptor 2 expression in osteosarcoma and its relationship to prognosis have been the subject of several conflicting reports, most of them relying on immunohistochemical studies. Because the urgent need of prognostic markers and effective new treatment options for osteosarcoma patients, we evaluated the role of human epidermal growth factor receptor 2 in 2 well-characterized sets of pretherapeutic osteosarcoma samples (46 paraffin-embedded and 46 fresh-frozen biopsy samples) using immunohistochemistry with 2 different antibodies [DAKO A0485 (Glostrup, Denmark) and Novocastra CB11 (Newcastle, UK)] as well as fluorescence in situ hybridization, real-time polymerase chain reaction, and SNP array analyses and correlated our findings with clinicopathological parameters. However, our study failed to detect unequivocal evidence of human epidermal growth factor receptor 2 gene amplification or overexpression of human epidermal growth factor receptor 2 messenger RNA or protein in any of the investigated tumors. Only in a small subset of samples, a moderate increase in messenger RNA levels (13.6%) or focal membranous immunoreactivity (8.7%; A0485) was detected but did not correlate with survival or response to chemotherapy. Cytoplasmic staining was identified more frequently (63%; CB11) but again did not show any association with clinicopathological parameters. In conclusion, our study does not support a role for human epidermal growth factor receptor 2 as a prognostic marker in osteosarcoma.
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PMID:Aberrant expression of the human epidermal growth factor receptor 2 oncogene is not a common feature in osteosarcoma. 2129 4

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