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

Recent circumstantial evidence has implicated Insulin-like growth factor II in the genesis of several tumour types, notably developmental tumours (Scott et al., 1985; Schofield & Tate, 1987; Wilkins et al., 1989). This type of tumour, thought to originate during the defective differentiation of organ precursors (Miereau et al., 1987), often expresses greatly elevated levels of mRNA for IGF-II, a known mitogen for these cells and abundantly expressed in their presumed normal counterparts (Scott et al., 1985; Schofield & Tate, 1987; Gray et al., 1987). It has been proposed that continued, inappropriate expression of this gene drives tumour growth by an autocrine mechanism. In order to examine the potential role of IGF-II in the growth of tumour cells an IGF-II cDNA was introduced into a retroviral expression vector, and used to infect a cloned fibroblast cell line. Expression of IGF-II conferred a degree of serum independence of growth in cell culture, however, when cells were injected into nude mice as subcutaneous grafts, clones expressing IGF-II from the retrovirus were found to have a greatly increased (five fold) latency of sarcoma formation. After a prolonged lag all cell lines eventually gave rise to tumours in which the introduced IGF-II genes had either been lost or inactivated, suggesting that in this system IGF-II acts as a tumour suppressor gene.
 ...
PMID:Tumour suppression associated with expression of human insulin-like growth factor II. 203 93

A new radioreceptor assay for insulin-like growth factor-II (IGF-II), using receptors on ovine placental membranes, is described. Half-maximal displacement of specifically bound radioiodinated human IGF-II tracer was seen at 1.0 ng/tube of unlabelled IGF-II. The cross-reactivity of IGF-I was 1%, and insulin was entirely without effect. Measured on serum samples from 100 healthy adults, the mean IGF-II concentration (+/- SD) was 576 +/- 160 ng/ml. Identical mean values were seen for all adult age groups up to 65 years. The mean value for 10 acromegalic adults was 583 +/- 155 ng/ml, and for 9 GH-deficient subjects, 161 +/- 26 ng/ml (P less than 0.001 compared to normals). Of eight patients with chronic renal failure, none had an IGF-II level less than 2SD above the normal mean. No significant effect of renal dialysis was seen. In groups of patients with gastric, breast, lung, testicular, oat cell, ovarian, colonic and prostatic carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, sarcoma and teratoma (5-12 patients per group), mean IGF-II levels were in the lower part of the normal range. Thus this study does not provide evidence supporting a role for excessive IGF-II production in the growth of any of these tumour types.
 ...
PMID:Measurement of insulin-like growth factor-II by radioreceptor assay using ovine placental membranes. 301 20

Normal chicken heart mesenchymal cells at low density in monolayer culture in plasma-containing medium have a polygonal shape and are proliferatively quiescent. The combination of epidermal growth factor and insulin at hyperphysiological concentration, an insulin-like growth factor surrogate, causes these cells to assume a fusiform shape and to increase 40-fold in number during four days of incubation. These mitogenic hormones do not, however, induce normal chicken heart mesenchymal cells to form colonies in agarose suspension culture. Chicken heart mesenchymal cells infected with the Schmidt-Ruppin or Prague-A strains of Rous sarcoma virus or with the Fujinami or Y73 avian sarcoma viruses assume spindle and round shapes, increase 50-100 fold in number during four days of monolayer culture in the absence of mitogenic hormones and form macroscopic colonies during 3-4 days of agarose suspension culture. The autonomous (mitogenic hormone-independent) proliferation, in monolayer culture, of cells infected with temperature-sensitive transformation mutants of Rous sarcoma virus (tsNY68, tsNY72, tsLA24, tsLA29) is temperature-sensitive. Chicken heart mesenchymal cells infected with avian erythroblastosis virus assume spindle shapes and proliferate in monolayer culture at a rate comparable to that of sarcoma virus-infected cells but do not, however, form colonies in agarose suspension culture. Cells infected with the myelocytomatosis virus MC29 assume stellate shapes and increase 18-fold in number during four days of monolayer culture. Cells infected with the myelocytomatosis virus MH2 assume fusiform shapes and increase fourfold in number during four days of monolayer culture. Neither MC29 nor MH2 renders chicken heart mesenchymal cells capable of colony formation in agarose suspension culture. Infection with avian leukosis viruses (RAV-1, RAV-2, RPL-42) or with transformation-defective mutants of Rous sarcoma virus (tdNY105, 107, 109) does not affect the morphology or proliferative behavior of chicken heart mesenchymal cells. Monolayer culture of chicken heart mesenchymal cells in plasma-containing medium appears, therefore, to define the ability of onc genes of acute transforming avian retroviruses to induce autonomous (mitogenic hormone-independent) cell proliferation, the essential characteristic of neoplasia. The differences in transformed morphology and rates of autonomous proliferation between cells infected with different acute transforming retroviruses probably reflects differences in the modes of action of the transforming proteins encoded by the onc genes of the respective viruses.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Morphological transformation, autonomous proliferation and colony formation by chicken heart mesenchymal cells infected with avian sarcoma, erythroblastosis and myelocytomatosis viruses. 608 24

The physiological role of insulin-like growth factor (IGF) II (IGF-II) in adult humans is poorly understood. Rather high levels of IGF-II persist in adult human serum, whereas, in rodents, IGF-II levels are very low. To investigate the physiological and carcinogenic effects of persistently elevated IGF-II in adults, we have produced two lines of transgenic mice in which high levels of IGF-II (20- or 30-fold increase above normal) are persistently maintained in the blood. The transgene is driven by the major urinary protein promoter, and it is highly expressed in the liver and perputial glands in both lines. The adult transgenic mice are smaller than controls, and their body composition is altered. Their lean body mass is reduced by 5-8%, whereas fat mass is reduced between 44 and 77%. The mice expressing the highest level of IGF-II (30x) develop hypoglycemia and hypoinsulinemia and IGF-I levels are normal. Mice in the lower expression line (20-fold elevated IGF-II) develop hypoglycemia progressively over their lifetime. Mice from both lines also develop a diverse spectrum of tumors at a higher frequency than controls after 18 months of age, and the most frequent types of tumors are hepatocellular carcinomas and lymphomas. Squamous cell carcinoma, sarcoma, and thyroid carcinomas also occurred in our test group. The long latent period before tumors arise and the wide spectrum of tumor types suggest that IGF-II may function primarily as a tumor progression factor in mice via autocrine and endocrine mechanisms of action.
 ...
PMID:Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice. 751 93

A variety of bone and soft-tissue sarcoma cell lines have been shown to express receptors for insulin-like growth factor-1 (IGF-1) and to respond mitogenically to IGF-1 in vitro. We have recently demonstrated evidence of IGF dependency in murine MGH-OGS and RIF-1 sarcomas, which express relatively high and intermediate levels of IGF-1 receptors. Overexpression of IGF-1 receptors and/or IGF ligands might, therefore, be a mechanism by which human bone and soft-tissue sarcomas obtain a proliferative advantage over normal adjacent tissues. Therefore, we evaluated 29 human sarcoma specimens for expression of IGF-1 receptor, IGF-1, and IGF-2 by competitive binding and reverse-transcription polymerase chain reaction (RT-PCR) techniques. Twelve of 29 sarcomas examined by RT-PCR and 13 of 25 examined by affinity-binding studies expressed IGF-1 receptor levels equal to or greater than levels determined in the IGF-responsive MCF-7 breast carcinoma cell line. DNA amplification of the IGF-1 receptor gene was not identified in this group of sarcomas that expressed high levels of IGF-1 receptor. Evaluation of IGF ligand expression by RT-PCR revealed that 22 of 28 sarcomas expressed IGF-1 levels comparable to or above those of the RPMI 7666 control line, and 17 of 27 sarcomas expressed significant levels of IGF-2 compared with the NCI H69 control cell line. These results suggest that autocrine/paracrine regulatory mechanisms might be responsible for the growth of some sarcomas.
 ...
PMID:Insulin-like growth factor 1 (IGF-1) receptors, IGF-1, and IGF-2 are expressed in primary human sarcomas. 780 22

Recent studies indicate that insulin-like growth factor-II (IGF-II) acts as an autocrine differentiation factor for skeletal myoblasts in culture. IGF-II mRNA and protein are induced as early events in muscle differentiation, and the rate and extent of IGF-II secretion correlate with both biochemical and morphological differentiation. Here we show that IGF-II also functions as an essential survival factor during the transition from proliferating to differentiating myoblasts. Stably transfected C2 muscle cell lines were established in which a mouse IGF-II cDNA was expressed in the antisense orientation relative to the constitutively active Moloney sarcoma virus promoter. IGF-II antisense cells proliferated normally in growth medium containing 20% serum but underwent rapid death when placed in low serum differentiation medium. Death was accompanied by characteristic markers of apoptosis with more than 90% of cells showing DNA fragmentation within 12-16 h. Myoblast death was prevented by IGF-I, des [1-3] IGF-I, IGF-II, and insulin with a dose potency consistent with activation of the IGF-I receptor; death also could be blocked by the protein synthesis inhibitor, cycloheximide. Exogenous IGFs additionally stimulated passage through a single cell cycle and subsequently induced terminal differentiation. Cell survival and cell cycle progression also were enhanced by fibroblast growth factor-2 and platelet-derived growth factor-bb, but these peptides did not promote differentiation. Our results define a novel system for studying apoptotic cell death and its prevention by growth factors, underscore the importance of IGF action in minimizing inappropriate cell death, and indicate that shared signal transduction pathways may mediate myoblast survival in vitro.
 ...
PMID:Insulin-like growth factor-II is an autocrine survival factor for differentiating myoblasts. 862 86

The differentiation of small intestinal epithelial cells may require stimulation by microenvironmental factors in vivo. In this study, the effects of mesenchymal and luminal elements in nonmalignant epithelia] cells isolated from the human fetus were studied in vitro. Enterocytes from the human fetus were cultured and microenvironmental factors were added in stages, each stage more closely approximating the microenvironment in vivo. Four stages were examined: epithelial cells derived on plastic from intestinal culture and grown as a cell clone, the same cells grown on connective tissue support, primary epithelial explants grown on fibroblasts with a laminin base, and primary epithelial explants grown on fibroblasts and laminin with n-butyrate added to the incubation medium. The epithelial cell clone dedifferentiated when grown on plastic; however, the cells expressed cytokeratins and villin as evidence of their epithelial cell origin. Human connective tissue matrix from Engelbreth-Holm-Swarm sarcoma cells (Matrigel) modulated their phenotype: alkaline phosphatase activity increased, microvilli developed on their apical surface, and the profile of insulin-like growth factor binding proteins resembled that secreted by differentiated enterocytes. Epithelial cells taken directly from the human fetus as primary cultures and grown as explants on fibroblasts and laminin expressed greater specific enzyme activities in brush border membrane fractions than the cell clone. These activities were enhanced by the luminal molecule sodium butyrate. Thus the sequential addition of connective tissue and luminal molecules to nonmalignant epithelia] cells in vitro induces a spectrum of changes in the epithelial cell phenotype toward full differentiation.
 ...
PMID:Human fetal enterocytes in vitro: modulation of the phenotype by extracellular matrix. 875 42

The paraneoplastic production of pro-insulin-like growth factor-II (IGF-II) forms causes tumour hypoglycaemias and presumably also has an effect on tumour cell growth. We investigated the molecular weights of IGF-II forms and their ability to form complexes with IGF binding proteins (IGFBPs) in conditioned culture media (CM) from 12 paediatric soft tissue sarcoma (STS) cell lines and from two healthy fibroblast lines. Untreated CM were separated by size exclusion chromatography using biocompatible HPLC. Subsequently, IGF-II, IGFBP-2 and IGFBP-3 were determined in the HPLC fractions by specific RIAs. In the CM, IGF-II concentrations between 0.5 and 8.6 ng/10(6) cells were measured but no IGF-I was detectable. Parallel to this investigation, a high IGF-II mRNA level averaging 44.4 +/- 29.7% was measured by semi-quantitative RT-PCR. The STS cell lines secreted a higher proportion of big-IGF-II forms reaching 10-18 kD (10-33% of the total IGF-II secreted) compared to the healthy fibroblasts (2.5-5%). At the same time, the proportion of IGF-II bound with IGFBP in complexes of 35- 70 kD and 150 kD was reduced by up to 85% in CM from tumour cells. The tumour cell lines apparently secrete a different spectrum of IGF-II forms than healthy fibroblasts. The reduced ability to form complexes with IGFBP and the higher molecular weight of the IGF-II forms produced by the tumour cells indicate that these forms could in fact be the known tumour-associated pro-IGF-II forms. Due to these characteristics, the big-IGF-II forms probably have an altered biological effect on the tumour cells when compared to IGF-II.
 ...
PMID:Secretion of noncomplexed 'Big' (10-18 kD) forms of insulin-like growth factor-II by 12 soft tissue sarcoma cell lines. 1072 83

Chromosomal translocations that disrupt the molecular organization of transcription factors are typical of a variety of solid and hematopoietic cancers. Alveolar rhabdomyosarcoma (ARMS), a paediatric soft tissue malignant tumour, is characterized by the recurrent translocation t(2;13)(q35;q14) that fuses the 5' DNA binding domain-encoding sequences of the Pax3 gene with the 3' sequences of the FKHR gene. The insulin-like growth factor (IGF) system has an important role in muscle development as well as in the aetiology of paediatric sarcomas, including ARMS. In the present study the potential regulation of the IGF-I receptor (IGF-I-R) gene by PAX3-FKHR at the transcriptional level was investigated. PAX3-FKHR was able to transactivate the IGF-I-R promoter in sarcoma-derived cell lines, whereas PAX3 exhibited a reduced potency in comparison to the fusion protein. Furthermore, transfection of the chimera induced a significant increase in the endogenous levels of IGF-I-R protein, suggesting that the IGF-I-R gene is a physiologically-relevant molecular target for the PAX3-FKHR oncogene.
 ...
PMID:Transcriptional regulation of IGF-I receptor gene expression by the PAX3-FKHR oncoprotein. 1173 47

Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Rhabdomyosarcoma cell lines overexpress insulin-like growth factor-II (IGF-II), an autocrine growth factor that is inhibited by insulin-like growth factor binding protein-6 (IGFBP-6). IGFBP-6 is associated with myoblast quiescence, and expression in rhabdomyosarcoma cells is low. The effect of IGFBP-6 on 2 rhabdomyosarcoma cell lines, RD and Rh30, was studied. IGFBP-6 inhibited anchorage-dependent growth of RD and Rh30 cells in a dose-dependent manner (p < 0.0001). IGFBP-6 also inhibited anchorage-independent growth of RD cells in soft agar in a dose-dependent manner (p < 0.01). Anchorage-independent growth of RD cells on polyhydroxyethylmethacrylate-coated plates was decreased to a minimum of 48% of control after treatment with IGFBP-6 (p < 0.001). In this system, IGFBP-6 increased apoptosis 4-fold (p < 0.001). IGF-II partially reversed the IGFBP-6-induced decrease in growth and increase in apoptosis. Rh30 cells were stably transfected with an IGFBP-6 cDNA and subcutaneous xenografts established in BALB/c nude mice. After 18 days, sizes of 2 independent clones of IGFBP-6-overexpressing Rh30 cells were reduced to 12% and 26% of vector control-transfected tumors (p = 0.0006 and 0.002, respectively). IGFBP-6 therefore inhibits proliferation and promotes apoptosis of rhabdomyosarcoma in vitro and dramatically inhibits xenograft growth in vivo, at least in part by inhibiting IGF-II. Low expression of IGFBP-6 may therefore contribute to rhabdomyosarcoma growth and metastasis.
 ...
PMID:Overexpression of insulin-like growth factor binding protein-6 inhibits rhabdomyosarcoma growth in vivo. 1174 58


1 2 3 4 5 6 Next >>