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)

Decorin is a multifunctional molecule of the extracellular matrix. Among the multitude of assigned functions the most intriguing is the ability to inhibit the growth and the metastasis of a wide range of cancer cells in vitro. Decorin was established to directly interact with EGFR and erb2, inducing protracted receptor internalization, which results in attenuation of the receptor-mediated intacellular signaling and induction of apoptosis. Studies by our group of osteosarcoma cells described the first exception to the established decorin-mediated growth suppression model. Osteosarcoma cells constitutively produced decorin and they were not sensitive to decorin-induced growth arrest. On the contrary, decorin seemed to be beneficial to osteosarcoma cells, since it was necessary for cell migration and acted as mediator, counteracting the TGFbeta2-induced cytostatic function. Importantly, decorin did not induce p21 expression whereas EGFR appeared to be overexpressed and continuously phosphorylated in our osteosarcoma model. These data provide new insight on pathways that cancer cells might employ to overcome the established decorin-induced growth suppression.
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PMID:Decorin-mediated effects in cancer cell biology. 1866 52

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

Osteoprotegerin (OPG) is a major regulator of osteoclastogenesis, bone resorption and vascular calcification. OPG is produced by various cell types including mesenchymally derived cells, in particular, osteoblastic cells. Here we show OPG production by osteoblastic cells was stimulated by platelet-derived growth factor (PDGF) in two human osteosarcoma cell lines (MG63, Saos-2), a mouse pre-osteoblastic cell line (MC3T3-E1) and human bone marrow stromal cells (hMSC) by 152%, 197%, 113% and 45% respectively over 24 h. OPG was measured in the cell culture medium by immunoassay. PDGF isoforms AA, BB and AB show similar stimulation of OPG production. Message for OPG was also increased similarly to the increased secretion into the culture medium. Using specific inhibitors of cell signalling we demonstrate that PDGF acts through the PDGF receptor, PKC, PI3K, ERK and P38 and not via NF-kB or JNK. The importance of PDGF in fracture healing suggests a role for OPG production in countering bone resorption during the early phase of this process.
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PMID:Platelet-derived growth factor stimulates osteoprotegerin production in osteoblastic cells. 1881 41

The maintenance of bone mass requires a strict balance between bone formation by osteoblasts and bone resorption by osteoclasts. In tumoral bone environment, tumor cells frequently disturb this balance by interaction with bone cells to create a favorable site for tumor growth, and promote pathological bone changes. Thus, elucidation of the mechanisms underlying interaction between tumor cells and bone cells might eventually lead to a more rational strategy for therapeutic intervention for bone tumors and better understanding of bone biology. In the present study, the effects of mouse osteosarcoma cells on mouse preosteoblastic cells were determined by assessment of cell viability, osteoblastic differentiation and signal transduction pathways. MOS-J/POS-1 conditioned media (CM) significantly induced MC3T3-E1 cell proliferation in a dose-dependent manner and reduced both alkaline phosphatase activity and mineralized nodule formation. Piceatannol, AG490, LY294002 and rapamycin significantly abrogated this up-regulated cell proliferation; however, UO126 and STAT3 inhibitor peptide did not affect this up-regulated cell proliferation. MOS-J/POS-1 CM activated ERK 1/2, STAT3 and Akt signal transduction pathways; however, pro-proliferating signal induced by MOS-J/POS-1 CM was transmitted via Akt not ERK 1/2 and STAT3 pathways. Furthermore, Western blot analyses clearly revealed novel signal crosstalk between JAKs and PI3-K/Akt in osteoblastic cells. The specific factor(s) involved in MOS-J/POS-1 CM-induced MC3T3-E1 cell proliferation that use JAKs/PI3-K/Akt/mTOR pathway remain(s) to be determined. Determination of the specific factor(s) responsible for JAKs and PI3-K/Akt signal crosstalk that results in up-regulated preosteoblast proliferation will offer new insight into the pathology of osteosarcoma as well as other bone-related diseases.
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PMID:Conditioned media from mouse osteosarcoma cells promote MC3T3-E1 cell proliferation using JAKs and PI3-K/Akt signal crosstalk. 1895 57

The Met receptor tyrosine kinase (RTK) is aberrantly expressed in human osteosarcoma and is an attractive molecular target for cancer therapy. We studied spontaneous canine osteosarcoma (OSA) as a potential pre-clinical model for evaluation of Met-targeted therapies. The canine MET oncogene exhibits 90% homology compared with human MET, indicating that cross-species functional studies are a viable strategy. Expression and activation of the canine Met receptor were studied utilizing immunohistochemical techniques in 39 samples of canine osteosarcoma, including 35 primary tumours and four metastases. Although the Met RTK is barely detectable in primary culture of canine osteoblasts, high expression of Met protein was observed in 80% of canine osteosarcoma samples acquired from various breeds. Met protein overexpression was also concordant with its activation as indicated by phosphorylation of critical tyrosine residues. In addition, Met was expressed and constitutively activated in canine osteosarcoma cell lines. OSA cells expressing high levels of Met demonstrated activation of downstream transducers, elevated spontaneous motility, and invasiveness which were impaired by both a small molecule inhibitor of Met catalytic activity (PHA-665752) and met-specific, stable RNA interference obtained by means of lentiviral vector. Similar to observations in human OSA, these data suggest that Met is commonly overexpressed and activated in canine OSA and that inhibition of Met impairs the invasive and motogenic properties of canine OSA cells. These data implicate Met as a potentially important factor for canine OSA progression and indicate that it represents a viable model to study Met-targeted therapies.
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PMID:met oncogene activation qualifies spontaneous canine osteosarcoma as a suitable pre-clinical model of human osteosarcoma. 1940 29

This study examined the effect of ketoconazole on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca(2+) levels in MG63 osteosarcoma cells. Ketoconazole at 20-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that ketoconazole induced phosphorylation of ERK and JNK, but not p38, MAPKs. Ketoconazole-induced cell death and apoptosis were partially reversed by the selective JNK inhibitor SP600125, but not by the selective ERK inhibitor PD98059, suggesting that ketoconazole's cytotoxic action was via JNK, but not via ERK and p38 MAPKs. Ketoconazole at a concentration of 100 microM induced [Ca(2+)](i) increases. Chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) totally inhibited ketoconazole-induced [Ca(2+)](i) increases without reversing ketoconazole-induced cell death. Collectively, in MG63 cells, ketoconazole induced cell death and apoptosis via evoking JNK phosphorylation in a Ca(2+)-independent manner.
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PMID:Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. 1963 32

For the control of tumor metastasis it is important to identify chemical compounds with antimigratory potency. Agents acting against single cell and cluster type migration are necessary for successful antimetastatic therapy. In the present study, the migration of HT-1080 fibrosarcoma cells and OSCORT osteosarcoma cells was compared in a Boyden chamber and in an extracellular matrix (ECM)-based three-dimensional cell culture (3-DCC) model system. The Boyden chamber offers a model of single tumor cell migration, whereas the 3-DCC model system demonstrates invasive growth in the form of a cluster. Since PD98059 (MEK inhibitor) exclusively reduced migration in the 3-DCC model, it may be plausible that the ERK/MAPK signaling pathway is essential for cluster type migration. Interestingly, single cell migration was stimulated upon blocking phosphatidylinositol 3-kinase (PI3K) and also p38-MAPK by treatment with LY294002 and SB203580 respectively. A remarkable reduction of single cell migration was observed following treatment with okadaic acid, a phosphatase 1 (PP1) and 2A (PP2A) inhibitor, which was rather intriguing. This study provided evidence that certain cytotoxic/cytostatic agents at appropriate concentrations were able to preferentially inhibit certain types of migration relative to cell proliferation. Single cell migration was selectively inhibited by taxol at very low subtoxic concentration, whereas 5-hexyl-2'-deoxyuridine (HUdR) exclusively inhibited the cluster type of migration. The borrelidin compound was able to inhibit both types of tumor cell migration, but single tumor cell migration was much less affected. It is interesting that migration was more reduced than proliferation by borrelidin, especially at the advanced growth stage. Taxol is recommended as an agent acting against single cell migration, as well as HUdR and borrelidin as leading compounds for developing antimetastatic drugs against cluster type migration.
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PMID:Differential inhibition of single and cluster type tumor cell migration. 1966 4

Identification of correlation pattern and signal pathway among biomarkers in patients has become increasingly interesting for its potential values in diagnosis, treatment and prognosis. EGFR and p-AKT signaling in osteosarcoma (OS) patients were analyzed for its relationship with cancer cell proliferation maker, Ki-67, using causal procedures and statistical tests. A total of 69 patients were collected who present to Vanderbilt University Medical Center with newly diagnosed, previously untreated osteosarcomas during the clinical study period 1994 through 2003. Tissue microarrays were constructed for EGFR, p-AKT and Ki-67. The mediation model was constructed with structural equation model (SEM) for the causal analysis of the three biomarkers in osteosarcoma patients. The results suggested a mediating effect of p-AKT for the causal relationship between EGFR and Ki-67. The study also found significant associations between EGFR and Ki-67 (p = 0.002), EGFR and p-AKT (p = 0.027), and p-AKT and Ki-67 controlling EGFR (p = 0.004). After the impact of EGFR on Ki-67 was accounted for by p-AKT, the relation between EGFR and Ki-67 was no longer significant (p = 0.381). The mediating effect was confirmed with Sobel test (p < 0.001) and Goodman (I) test (p < 0.001). The study indicated that a mediation model could be an approach to exploring the correlation pattern of EGFR and AKT signal pathway for cancer cell proliferation in OS patients in clinical study.
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PMID:An EGFR and AKT Signaling Pathway was Identified with Mediation Model in Osteosarcomas Clinical Study. 1966 27

In our previous work, biomimetic calcium phosphate-coated poly(caprolactone) nanofibre meshes (BCP-NMs) were demonstrated to be more effective for supporting cell attachment and proliferation under static conditions, when compared with poly(caprolactone) nanofibre meshes (PCL-NMs). In many applications, in vitro cultivation of constructs using bioreactors that support efficient nutrition of cells has appeared as an important step toward the development of functional grafts. This work aimed at studying the effects of dynamic culture conditions and biomimetic coating on bone cells grown on the nanofibre meshes. BCP-NM and PCL-NM were seeded with osteoblast-like cells (MG63--human osteosarcoma-derived cell line). The cell-seeded constructs were cultured within a rotating bioreactor that simulated microgravity, at a fixed rotating speed, for different time periods, and then characterized. Cell morphology, viability, and phenotype were assessed. PCL-NM constructs presented a higher number of dead cells than BCP-NM constructs. Under dynamic conditions, the production of proteins associated with the extracellular matrix of bone was higher on BCP-NM constructs than in the PCL-NM ones, which indicates that coated samples may provide cells with a better environment for tissue growth. It is suggested that improved mass transfer in the bioreactor in combination with the appropriate substrate were decisive factors for this highly positive outcome for generating bone.
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PMID:Dynamic culture of osteogenic cells in biomimetically coated poly(caprolactone) nanofibre mesh constructs. 1972 92

Bone sarcomas cause disproportionate morbidity and mortality and desperately need new therapies as there has been little improvement in outcomes in 20 years. Identification of critical signaling pathways, including type 1 insulin-like growth factor receptor (IGF-1R) for Ewing sarcoma and possibly osteosarcoma, and the ERBB and the Wnt signaling pathways for osteosarcoma, have emerged as receptors mediating vital signals for bone sarcoma. Akt, mammalian target of rapamycin (mTOR), phosphoinositide 3-kinases, mitogen-activated protein kinase kinase, extracellular signal-regulated kinases, and Ras pathway play key roles in at least some tumors, and inhibition of mTOR in particular will likely lead to improved survival, although clinical trials are still underway. The Notch pathway and ezrin are essential for osteosarcoma metastasis, and Fas downregulation is necessary for survival of metastases in lungs. As little is known about chondrosarcoma signaling, more preclinical work is needed. By defining vital signaling pathways in bone sarcomas, small molecule inhibitors can be applied rationally, leading to longer survival and reducing morbidity and late effects from intensive chemotherapy.
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PMID:Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions. 1984 May 22


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