Gene/Protein Disease Symptom Drug Enzyme Compound
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 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyalinizing spindle cell tumor with giant rosettes (HSCTGR) and low-grade fibromyxoid sarcoma (LGFMS) are 2 variants of fibrosarcoma, which share several clinicopathologic features. This study compares the light microscopic, immunohistochemical, and ultrastructural features of 2 examples of HSCTGR and 3 of LG FMS to determine the degree of overlap of these 2 tumors. HSCTGR were composed of bland spindle cells within hyalinized to myxoid stroma. Scattered throughout the lesions were characteristic rosette-like structures, formed by a central collagenous core surrounded by spindled neoplastic cells. LGFMS consisted of a mixture of fibrous and myxoid areas, composed of fibroblast-like cells arranged in a swirling, whorled growth pattern. Immunohistochemical analysis showed diffuse positivity for vimentin in all cases, while few scattered tumor cells stained for CD57, CD34, factor XIIIA, and actin. The extracellular matrix showed intense positivity for type IV collagen, laminin, and fibronectin, with the exception of myxoid areas of LGFMS and the central core of the giant rosettes in HSCTGR. Ultrastructurally, both tumor types were composed of cells with the features of fibroblasts, embedded in a collagenous stroma with irregular deposits of amorphous basal lamina-like substance. In conclusion, HSCTGR and LGFMS share similar immunophenotypic and ultrastructural features, and together with other fibrosing fibrosarcomas, like sclerosing epithelioid fibrosarcoma, may constitute a subset of fibrosarcomas formed by fibroblasts capable of producing large amounts of basal lamina-like material.
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PMID:Hyalinizing spindle cell tumor with giant rosettes and low-grade fibromyxoid sarcoma: an immunohistochemical and ultrastructural comparative investigation. 1470 26

Feline vaccine-associated sarcoma (VAS) is a biologically aggressive soft-tissue sarcoma that can develop at sites where inactivated feline vaccines have been administered. We showed that platelet-derived growth factor (PDGF) and its receptor (PDGFR) play a role in the growth of VAS cells. The presence of PDGFR-beta was confirmed in each of five VAS cell lines evaluated, one non-vaccine-associated feline fibrosarcoma (FSA) cell line and a feline fibroblast-derived cell line. The PDGF/PDGFR signaling pathway was inhibited in the VAS cell lines and the FSA cell line using the tyrosine kinase inhibitor imatinib mesylate (formerly called STI-571). Imatinib inhibited PDGF-BB-induced autophosphorylation of PDGFR in VAS cells and feline FSA cells in vitro in a dose-dependent manner. Imatinib also significantly inhibited growth of feline VAS tumors in a murine xenograft model. Imatinib reversed the protective effect of PDGF-BB on growth inhibition by doxorubicin and carboplatin. PDGF-BB protected VAS cells from serum starvation and doxorubicin-induced apoptosis but not carboplatin-induced apoptosis, and imatinib eliminated this protection. These observations suggest that imatinib inhibits PDGFR tyrosine kinase activity in feline soft tissue sarcomas in vitro and inhibits tumor growth in a xenograft model.
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PMID:Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma. 1510 21

Soft tissue sarcomas represent a heterogeneous group of tumors and include over 50 histotypes. Some of these tumor types are characterized by specific chromosomal translocations, whereas other types show complex genetic aberrations. The recent developments within gene expression technologies have now been applied to studies of soft tissue sarcomas (STS) and the first results indicate that genetic signatures are useful for classification and diagnosis. Distinctive expression profiles have been found in e.g. gastrointestinal stromal tumors (GISTs), synovial sarcomas, malignant peripheral nerve sheath tumors (MPNSTs), and in subsets of liposarcomas. The more pleomorphic tumor types, such as high-grade variants of leiomyosarcomas, malignant fibrous histiocytomas (MFHs), fibrosarcomas, and subtypes of liposarcomas, show a greater variability among the expression profiles, but interestingly subsets with distinctive expression profiles can be identified also among these tumors. The data available place many of the genes hypothesized to be involved in the development of a certain type of STS, such as the KIT gene in GIST development, among the top discriminating genes. Thereby expression profiling provides novel insights into the pathogenesis of STS. Although much work remains to be done to validate the data and to define optimal discriminating gene lists, the current lessons from gene expression studies in STS are encouraging and imply that genetic signatures may serve as diagnostic and prognostic markers and may help identify novel therapeutic strategies.
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PMID:Lessons from genetic profiling in soft tissue sarcomas. 1518 64

KIT expression is a key diagnostic feature of gastrointestinal stromal tumors (GISTs), and virtually all of the GISTs express oncogenic forms of the KIT or PDGFRA receptor tyrosine kinase proteins, which serve as therapeutic targets of imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). However, KIT expression can be low in PDGFRA-mutant GISTs, increasing the likelihood of misdiagnosis as other types of sarcoma. We report that the signaling intermediate protein kinase C theta (PKCtheta) is a diagnostic marker in GISTs, including those that lack KIT expression and/or contain PDGFRA mutations. PKCtheta is strongly activated in most GISTs and hence may serve, along with KIT/PDGFRA, as a novel therapeutic target.
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PMID:Protein Kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). 1528 15

Myxoid/round cell liposarcomas (MLS/RCLS) are characterized by chromosome translocations that result in formation of FUS-CHOP or EWSR1-CHOP fusion oncogenes. More than 95% of the tumors carry one of these fusion genes. FUS-CHOP transforms 3T3 cells and causes MLS/RCLS-like tumors in transgenic mice. The fusion oncoproteins act as abnormal transcription factors and are believed to induce abnormal expression of growth controlling genes as part of their transforming activities. The aim of this study was to search for recurrent abnormal expression patterns of cell cycle regulating proteins and growth factor receptors. A series of 14 MLS/RCLS, 2 MLS/RCLS derived cell lines and a FUS-CHOP transfected human sarcoma cell line were analyzed using immunohistochemistry, Western blotting, and cDNA microarray based screening. The results revealed a highly abnormal expression pattern of several growth controlling proteins. The G1 cyclins D1 and E and their associated kinases CDK4 and CDK2 were strongly overexpressed in all of the tumors. High expression levels were also found for Cdk4/6 inhibitor P16 and CDK2 inhibitors P27 and P57. The growth factor tyrosine kinase receptors PDGFRB and EGFR were present in most cells of all investigated tumors. We conclude that deregulation of G1 controlling proteins is common in MLS/RCLS and that aberrant expression of these proteins is of importance in the pathogenesis of this tumor type.
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PMID:Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas. 1549 25

The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing's sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Most other high-grade (grading >I), so-called 'adult type', soft tissue sarcomas such as fibrosarcoma, liposarcoma, pleomorphic and synovial sarcomas are treated with an anthracycline-based regimen with or without ifosfamide as front-line therapy. In relapsed 'adult type' soft tissue sarcomas, trofosfamide, gemcitabine and trabectedin (ecteinascidin 743) appear to be drugs associated with some activity and an acceptable toxicity profile. A high activity has been reported for the taxanes, in particular for paclitaxel, in vascular sarcomas located in the scalp or face and in Kaposi's sarcoma. It is interesting to note that the different drugs have particular effects in distinct subtypes of soft tissue sarcoma; however, it should be taken into account that the number of patients included in the phase II trials is limited. The role of the newer agents (e.g. epothilones, brostallicin) is currently undefinable. Targeted therapy inhibiting vascular endothelial growth factor receptor, epidermal growth factor receptor, RAF kinase, c-KIT or platelet-derived growth factor receptors will continue to be tested in GIST patients refractory to imatinib and in other sarcoma histologies.
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PMID:Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma. 1563 40

A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.
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PMID:Low-grade sarcomas with CD34-positive fibroblasts and low-grade myofibroblastic sarcomas. 1576 78

Gastrointestinal stromal tumor (GIST), a form of soft-tissue sarcoma, is the most common noncarcinomatous tumor of the gastrointestinal tract. Despite its high incidence of recurrence, the malignant potential of GIST has been under-recognized. Advances in diagnostic technology since 2000 have led to increased diagnoses of GIST, suggesting that GIST is more common than previously suspected. Historically, the only treatment for GIST was surgical resection, but recent advances in the understanding of the pathogenesis of the disease have led to the development of a new treatment. A key factor in the growth and survival of cancerous GIST cells is the uncontrolled activation of a signaling enzyme known as KIT, a receptor tyrosine kinase, which becomes locked in an activated state. The abnormal signaling from the overactive KIT enzyme causes GIST cells to survive and proliferate uncontrollably. Imatinib mesylate is an oral drug designed to inhibit the kinase enzyme activity of KIT. Imatinib has been proven in several clinical trials to be effective against GIST and is currently the firstline medical therapy for malignant metastatic or recurrent GIST. Imatinib is administered as an outpatient oral drug and warrants nursing management with particular attention to potential side effects, significant drug interactions, monitoring, and patient education. This article--based on published trials and clinical experience--summarizes the nursing implications, clinical efficacy, and safety of imatinib as an effective and rationally targeted treatment for GIST.
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PMID:Nursing implications of imatinib as molecularly targeted therapy for gastrointestinal stromal tumors. 1585 60

Role of R-(-)-deprenyl in adhesion of neuronal and non-neuronal cells. The beneficial effect of the anti-parkinsonian monoamine oxidase-B inhibitor, R-(-)-deprenyl has been shown in a number of different diseases, such as Parkinson's and Alzheimer's disease, atherosclerosis or tumor formation. The role of the cytoskeleton, the main component of cell adhesion, has been suggested in the development of these diseases. Nevertheless, the effect of the drug on cell adhesion has never been examined. In the present study, the authors studied the effect of R-(-)-deprenyl on cell-cell adhesion of neuronal (PC12, rat phaeochromocytoma) and non-neuronal (NIH3T3, NIH3T3/EGFR, NIH3T3/EGFR-e3B1 mouse embryo fibroblasts, and 5180 mouse sarcoma) cells using cell association assay. R-(-)-deprenyl treatment resulted in a cell type- and concentration-dependent increase in cell-cell adhesion of PC12 cells, which contain no monoamine oxidase-B, and we observed the same effect in NIH3T3 cells at concentrations lower than those needed for monoamine oxidase-B inhibition. Interestingly, R-(-)-deprenyl increased cell-cell adhesion of tumor cell lines as well. The effect of R-(-)-deprenyl was not reversible during a 24-hour recovery period. At the same time, the monoamine oxidase-B inactive isomer of the drug, S-(+)-deprenyl had no effect on cell-cell adhesion in PC12 and NIH3T3 cells. In this study, the authors described a new, monoamine oxidase-B independent effect of R-(-)-deprenyl on cell-cell adhesion both in neuronal and non neuronal cells. The authors' results with S-(+)-deprenyl suggest that the sterical structure of the drug is an important factor of the observed effect, which is probably a consequence of an irreversible change in the cells.
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PMID:[Role of R-(-)-deprenyl in adhesion of neuronal and non-neuronal cells]. 1585 24

Vascular endothelial growth factor (VEGF) is a potent signalling molecule that acts through two tyrosine kinase receptors, VEGFR1 and VEGFR2. The upregulation of VEGF and its receptors is important in tumour-associated angiogenesis; however, recent studies suggest that several tumour cells express VEGF receptors and may be influenced by autocrine VEGF signalling. Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, and is dependent on autocrine signalling for its growth. The alveolar subtype of RMS is often characterized by the presence of a PAX3-FKHR translocation, and when introduced into non-RMS cells, the resultant fusion protein induces expression of VEGFR1. In our study, we examined the expression of VEGF and its receptors in RMS, and autocrine effects of VEGF on cell growth. VEGF and receptor mRNA and protein were found to be expressed in RMS cells. Exogenous VEGF addition resulted in extracellular signal-regulated kinase-1/2 phosphorylation and cell proliferation, and both were reduced by VEGFR1 blockade. Growth was also slowed by VEGFR1 inhibitor alone. Treatment of RMS cells with all-trans-retinoic acid decreased VEGF secretion and slowed cell growth, which was rescued by VEGF. These data suggest that autocrine VEGF signalling likely influences RMS growth and its inhibition may be an effective treatment for RMS.
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PMID:Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid. 1611 81


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