Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell surface retention sequence (CRS) binding protein-1 (CRSBP-1) is a newly identified membrane glycoprotein which is hypothesized to be responsible for cell surface retention of the oncogene v-sis and c-sis gene products and other secretory proteins containing CRSs. In simian sarcoma virus-transformed NIH 3T3 cells (SSV-NIH 3T3 cells), a fraction of CRSBP-1 was demonstrated at the cell surface and underwent internalization/recycling as revealed by cell surface 125I labeling and its resistance/sensitivity to trypsin digestion. However, the majority of CRSBP-1 was localized in intracellular compartments as evidenced by the resistance of most of the 35S-metabolically labeled CRSBP-1 to trypsin digestion, and by indirect immunofluorescent staining. CRSBP-1 appeared to form complexes with proteolytically processed forms (generated at and/or after the trans-Golgi network) of the v-sis gene product and with a approximately 140-kDa proteolytically cleaved form of the platelet-derived growth factor (PDGF) beta-type receptor, as demonstrated by metabolic labeling and co-immunoprecipitation. CRSBP-1, like the v-sis gene product and PDGF beta-type receptor, underwent rapid turnover which was blocked in the presence of 100 microM suramin. In normal and other transformed NIH 3T3 cells, CRSBP-1 was relatively stable and did not undergo rapid turnover and internalization/recycling at the cell surface. These results suggest that in SSV-NIH 3T3 cells, CRSBP-1 interacts with and forms ternary and binary complexes with the newly synthesized v-sis gene product and PDGF beta-type receptor at the trans-Golgi network and that the stable binary (CRSBP-1.v-sis gene product) complex is transported to the cell surface where it presents the v-sis gene product to unoccupied PDGF beta-type receptors during internalization/recycling.
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PMID:Cell surface retention sequence binding protein-1 interacts with the v-sis gene product and platelet-derived growth factor beta-type receptor in simian sarcoma virus-transformed cells. 1018 53

We report the unusual occurrence of Kaposi's sarcoma following asbestos-related malignant mesothelioma, in a human deficiency virus (HIV)-negative Italian man. Seropositivity to human herpes virus 8 (HHV8) was documented at the time of mesothelioma diagnosis and preceded the onset of Kaposi' sarcoma with a time lapse of 13 months. HHV8 DNA was detected by polymerase chain reaction in lesional Kaposi's sarcoma but not within mesothelioma. By immunostaining, mesothelioma cells expressed interleukin-6 and platelet-derived growth factor, which are important for survival of Kaposi's sarcoma cells. Besides the possibility of a casual association, we hypothesize that mesothelioma-linked factors may have contributed to the development of Kaposi's sarcoma in the presence of HHV8 infection.
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PMID:Kaposi's sarcoma following malignant mesothelioma. 1062 4

While platelet-derived growth factor, PDGF, is not regularly expressed in mesenchymal tissues, PDGF B mRNA is often found in tumors derived from these tissues. PDGF B protein is also present, but the protein levels in individual tumors do not appear to correlate well with those of the mRNA. PDGF B is homologous to the v-sis oncogene of simian sarcoma virus (SSV), and certain deletions confined to 3; and 5; non-coding sequences of PDGF B mRNA are consistently found in tumors induced by SSV and by a PDGF B retrovirus. Part of exon 1, including a non-coding GC-rich regulatory domain and the signal sequence as well as a 149 nucleotide long AU-rich stretch in the 3; non-coding region, are often lost. We hoped that this information could provide a clue to defective regulatory mechanisms present in human tumors and have searched for such mRNA variants in human sarcoma cell lines and soft tissue tumors. We identified a splice variant of PDGF B mRNA that, similar to v-sis, lacks the 149 nucleotide stretch and introduces an anomalous splice point between exons 6 and 7. This weakly abundant mRNA variant was co-expressed with the regular PDGF B mRNA, but its presence failed to show any association with increased levels of immunohistochemically detectable PDGF B protein. Instead, the highest levels of cellular PDGF B protein were found in samples with mRNAs showing exon 1 divergence. The changes in the 5; end of the mRNA were not accompanied by any genomic aberrations.
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PMID:PDGF B mRNA variants in human tumors with similarity to the v-sis oncogene: expression of cellular PDGF B protein is associated with exon 1 divergence, but not with a 3'UTR splice variant. 1062 80

Human epithelioid sarcoma (ES) is an extremely aggressive soft tissue tumour of unknown histogenesis. Although growth factor-dependent signalling cascades significantly affect the biological behaviour of malignant tumours, little is known so far about their role in human ES. The present investigation, therefore, analyses the coexpression and function of different growth factors and their receptors in the human ES cell line GRU-1 and its clonal subpopulations (GRU-1A, GRU-1B and GRU-1C). As shown by Northern blot, flow cytometry, immunocytochemistry and MTT assay, all ES cell lines expressed transforming growth factor (TGF)-alpha and the epidermal growth factor receptor (EGF-R). Although no response to exogenous TGF-alpha was observed, antagonistic anti-EGF-R antibodies (at 20 microg/ml) induced significant (P<0.05) growth inhibition in all cell lines. All cell lines showed coexpression of platelet-derived growth factor (PDGF)-A and the corresponding receptors. Neutralisation of ES-derived PDGF by anti-hPDGF antibodies resulted in significant (P<0.05) growth inhibition of all clonal subpopulations. Although all cell lines expressed TGF-beta(1) as well as TGF-beta type I and type II receptors (TGF-BI-R and TGF-BII-R), growth inhibition (P<0.05) by exogenous TGF-beta(1) was achieved in the clonal subpopulations only and not in the parental cell line. No ES cell line expressed acidic fibroblast growth factor (FGF) but stimulation of FGF type 3 and type 4 receptors (FGF-3R and FGF-4R) by exogenous acidic FGF (aFGF) resulted in a marked (P<0.05) acceleration of proliferation in all cell lines. In conclusion, our investigation suggests an intricate network of autocrine, juxtacrine and paracrine signalling between ES tumour cells and adjacent non-neoplastic stromal cells.
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PMID:Analysis of growth factor-dependent signalling in human epithelioid sarcoma cell lines. clues To the role of autocrine, juxtacrine and paracrine interactions in epithelioid sarcoma. 1085 51

The Tel gene (or ETV6) is the target of the translocation (12;22)(p13;q11) in myeloid leukemia. TEL is a member of the ETS family of transcription factors and contains the pointed protein interaction (PNT) domain and an ETS DNA binding domain (DBD). By contrast to other chimeric proteins that contain TEL's PNT domain, such as TEL-platelet-derived growth factor beta receptor in t(5;12)(q33;p13), MN1-TEL contains the DBD of TEL. The N-terminal MN1 moiety is rich in proline residues and contains two polyglutamine stretches, suggesting that MN1-TEL may act as a deregulated transcription factor. We now show that MN1-TEL type I, unlike TEL and MN1, transforms NIH 3T3 cells. The transforming potential depends on both N-terminal MN1 sequences and a functional TEL DBD. Furthermore, we demonstrate that MN1 has transcription activity and that MN1-TEL acts as a chimeric transcription factor on the Moloney sarcoma virus long terminal repeat and a synthetic promoter containing TEL binding sites. The transactivating capacity of MN1-TEL depended on both the DBD of TEL and sequences in MN1. MN1-TEL contributes to leukemogenesis by a mechanism distinct from that of other chimeric proteins containing TEL.
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PMID:The MN1-TEL fusion protein, encoded by the translocation (12;22)(p13;q11) in myeloid leukemia, is a transcription factor with transforming activity. 1109 79

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial sarcoma usually affecting the trunk, with significant risk of local recurrence. It is characterized by the presence of ring chromosomes or chromosomal translocations fusing the promoter of the collagen gene COL1A1 to the platelet-derived growth factor beta-chain gene PDGFB, increasing the production of PDGF locally and promoting autocrine or paracrine tumor growth. Fewer than 5% of patients with DFSP develop metastatic sarcoma, with a poor subsequent prognosis. Imatinib (STI-571) was developed as an inhibitor of the PDGF receptor tyrosine kinase and has proven clinical activity against chronic myelogenous leukemia (expressing bcr-abl) and gastrointestinal stromal tumors (expressing c-kit). We describe 2 patients with metastatic and unresectable metastases from DFSP treated with imatinib. After confirmation of negative CD117 status of 2 sarcomas arising from DFSP, patients were given imatinib 400 mg po qd and assessed at regular intervals for their tolerance and response to therapy. One patient had a transient response, then progressed rapidly and died of disease. Another patient showed a partial response to therapy after 2 months, with resolution of superior vena cava syndrome and shrinking of metastatic lung lesions. His response is ongoing after 6 months of therapy. These clinical data confirm findings from models of DFSP and support the use of imatinib in the rare setting of metastatic DFSP. Imatinib may be useful for patients with locally advanced DFSP, when other options for local therapy are limited.
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PMID:Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. 1220 98

Platelet-derived growth factors (PDGFs) are important for normal tissue growth and maintenance. Overexpression of the classical PDGFs, PDGF-A and PDGF-B, has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Recently, two novel PDGFs, PDGF-C and PDGF-D, were discovered. It has not yet been established whether PDGF-C and PDGF-D are linked to disease phenotypes like the classical PDGFs. PDGF-B, the cellular homologue of the viral simian sarcoma oncogene v-sis, is known to potently induce cellular transformation through activation of PDGF receptor (PDGFR)-beta. In this work, we have determined the transformation efficacy of PDGF-D in comparison with that of PDGF-C and PDGF-B. PDGF-D is a potent transforming growth factor for NIH/3T3 cells, and the transformed cells displayed stress fibre reorganization, increased proliferation rate, anchorage-independent growth in soft agar, ability to induce tumours in nude mice, and upregulation of vascular endothelial growth factor. Morphological analyses of the vasculatures from the PDGF-isoform-expressing tumours revealed marked differences suggesting differential signalling through the two PDGF receptors in tumour vessel development and remodelling. In summary, these results suggest that PDGF-D induce cellular transformation and promote tumour growth by accelerating the proliferation rate of the tumour cells, and by stimulation of tumour neovascularization.
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PMID:PDGF-D is a potent transforming and angiogenic growth factor. 1262 13

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

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

The platelet-derived growth factor (PDGF) family was for more than 25 years assumed to consist of only PDGF-A and -B. The discovery of the novel family members PDGF-C and PDGF-D triggered a search for novel activities and complementary fine tuning between the members of this family of growth factors. Since the expansion of the PDGF family, more than 60 publications on the novel PDGF-C and PDGF-D have been presented, highlighting similarities and differences to the classical PDGFs. In this paper we review the published data on the PDGF family covering structural (gene and protein) similarities and differences among all four family members, with special focus on PDGF-C and PDGF-D expression and functions. Little information on the protein structures of PDGF-C and -D is currently available, but the PDGF-C protein may be structurally more similar to VEGF-A than to PDGF-B. PDGF-C contributes to normal development of the heart, ear, central nervous system (CNS), and kidney, while PDGF-D is active in the development of the kidney, eye and brain. In adults, PDGF-C is active in the kidney and the central nervous system. PDGF-D also plays a role in the lung and in periodontal mineralization. PDGF-C is expressed in Ewing family sarcoma and PDGF-D is linked to lung, prostate and ovarian cancers. Both PDGF-C and -D play a role in progressive renal disease, glioblastoma/medulloblastoma and fibrosis in several organs.
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PMID:Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family. 1627 38


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