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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of growth regulation by transforming growth factor-beta (TGF-beta) may be an important step in carcinogenesis. We have used a cell fusion system to show that inhibition of growth by TGF-beta can be restored to carcinoma cell lines that are unresponsive to the inhibitory effects of TGF-beta. In a previous study, the EJ bladder carcinoma line was fused to the SW480 colon adenocarcinoma line and found to produce nontumorigenic hybrid cells along with one hybrid cell clone of low tumorigenicity. Here we show that the capacity of the nontumorigenic hybrid cells to respond to either TGF-beta 1 or TGF-beta 2 has been restored, while the parental or tumorigenic hybrid cells show little or no inhibition of growth following TGF-beta treatment. Cross-linking analyses with labeled TGF-beta 1 demonstrated much higher levels of the type II (85 kDa) receptor in the hybrid cells compared with the parental tumor lines. Both the parental and tumorigenic hybrid cell lines were capable of responding to TGF-beta as evidenced by increased levels of mRNA for fibronectin, type IV collagenase, and plasminogen activator inhibitor after treatment with TGF-beta 1. These results suggest that the type II receptor is necessary for mediating the effects of TGF-beta on inhibition of growth but not on gene activation of the hybrid cells.
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PMID:Inhibition of growth by transforming growth factor-beta following fusion of two nonresponsive human carcinoma cell lines. Implication of the type II receptor in growth inhibitory responses. 137 Aug 26

There is substantial evidence to suggest that transforming growth factor-beta (TGF-beta) plays an important role in wound healing and tissue repair as well as in carcinogenesis. It has also been observed that naturally occurring bovine papillomavirus type 1 (BPV-1)-induced bovine fibropapillomas occur predominantly at traumatized sites of the body, suggesting that humoral factors released in wounds might be important for papillomavirus infection. We have therefore investigated the possible role of TGF-beta 1 in BPV-1 infections. Two antipeptide antibodies which recognize different epitopes in the N-terminus of TGF-beta 1 were used to localize TGF-beta 1 in bovine fibropapillomas and normal bovine skin using immunohistochemical methods. Staining by anti-LC(1-30) is intracellular in suprabasal keratinocytes of the epidermis as well as the hair follicles and sebaceous glands and correlates with known sites of TGF-beta 1 mRNA synthesis. Anti-CC(1-30) staining is extracellular in the immediately underlying dermis. Neither the pattern nor intensity of TGF-beta 1 staining was affected by BPV-1 infection. C127 cells and BPV-1-transformed C127 cells were compared for TGF-beta 1 mRNA expression and secretion of TGF-beta 1 peptide. Although the levels of messenger RNA and secreted TGF-beta 1 peptide were similar in both cell types, five- to six-fold greater amounts of TGF-beta-like activity per cell was detected in media conditioned by the uninfected cells. TGF-beta 1 treatment had no effect on the growth rate of either cell type or on BPV-1 gene expression in the transformed cells.
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PMID:Transforming growth factor-beta expression in fibropapillomas induced by bovine papillomavirus type 1, in normal bovine skin, and in BPV-1-transformed cells. 216 Feb 57

Since many chemical tumor promoters and some oncogenes have been shown to inhibit gap junction-mediated intercellular communication, the effect of various growth factors on gap junctional intercellular communication on normal human keratinocytes was examined. In order to measure the effect of the growth factors on gap junctional communication, the scrape loading/dye transfer technique was used on human keratinocytes grown in a serum-free medium in vitro. At 24 h after treatment epidermal growth factor (10 ng/ml), transforming growth factor-beta (1 ng/ml), whole bovine pituitary extract (70 micrograms/ml) and 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 ng/ml) inhibited intercellular communication. Treatment of these cells with transforming growth factor-beta (1 ng/ml) induced morphological changes in some of the cells and brought about selective intercellular communication within and between the nonaltered and altered cells. Epidermal growth factor and whole bovine pituitary extract, significantly enhanced [3H]thymidine uptake and also stimulated cellular proliferation under the experimental conditions used to inhibit intercellular communication. Both transforming growth factor-beta and TPA markedly inhibited [3H]thymidine uptake and induced differentiation of some of these cells. In order to study the possible mechanism by which the growth factors might inhibit intercellular communication, the effect of the growth factors on protein kinase C activation and alterations of intracellular free calcium was investigated. The results indicated that neither protein kinase C nor an increase in [Ca2+]i were involved in the modulation of gap junctional communication by epidermal growth factor or transforming growth factor-beta. The study suggests that in the human keratinocytes inhibition of intercellular communication may be involved (i) in the action of growth factors such as epidermal growth factor during cellular proliferation and (ii) in the differentiation of primary keratinocytes by transforming growth factor-beta.
Carcinogenesis 1989 Jan
PMID:Altered regulation of intercellular communication by epidermal growth factor, transforming growth factor-beta and peptide hormones in normal human keratinocytes. 246 13

Skin tumor-promoting agents, including the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, such as diterpine phorbol esters, teleocidin and aplysiatoxin, and a non-TPA-type tumor promoter (the newly described palytoxin, present in the coelenterate of the genus Palythoa), stimulated arachidonic acid metabolism by rat liver cells in culture. Palytoxin was 1000-3000 times more effective than TPA-type tumor promoters. The stimulations of arachidonic acid metabolism by palytoxin and the TPA-type tumor promoters were synergistic, whereas the stimulations among the TPA-type tumor promoters were not. The stimulation of arachidonic acid metabolism by palytoxin was synergistic with that of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta (TGF-beta). An antiserum to the EGF-receptor that blocks EGF binding partially inhibited the synergistic responses to palytoxin and EGF and palytoxin and TGF-alpha, whereas an antiserum to the EGF-receptor that does not block EGF binding or a non-immune rabbit serum did not.
Carcinogenesis 1985 Nov
PMID:Stimulation of arachidonic acid metabolism by different types of tumor promoters. 286 14

To understand the molecular mechanism of action of retinoids in control of differentiation and carcinogenesis, it is now necessary to consider the interactions of retinoids with oncogenes, as well as with peptide growth factors and their receptors. Experimental studies in these areas are described. In particular, it is shown that retinoic acid inhibits the proliferative effects of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) on fibroblasts that have been transfected with the c-myc oncogene. The ability of retinoic acid to induce differentiation in several types of human and murine tumor cells also is associated with the ability of retinoic acid to suppress the expression of either the c-myc oncogene, or the related N-myc gene.
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PMID:Suppression of carcinogenesis by retinoids: interactions with peptide growth factors and their receptors as a key mechanism. 391 93

Women with "apocrine" breast cysts (usually having intracystic Na/K < 3) may have a higher risk of developing breast cancer than women with breast cysts lined by flattened epithelium (usually having intracystic Na/K > 3). In this study the concentrations of basic fibroblast growth factor (bFGF), a potent mitogen, and transforming growth factor-beta 2 (TGF-beta 2), which exerts a growth inhibitory effect on epithelial cell types, were measured in breast cyst fluid and their relationship studied. Both growth factors were measured by "sandwich" enzyme immunometric assays. The concentrations of both bFGF and TGF-beta 2 were significantly higher (P < 0.001) in the Na/K > 3 group (median 444 fmol/L, range: < 56 fmol/L-7,890 fmol/L, n = 23 and median 1,776 pmol/L, range: 20.4 pmol/L-5,000 pmol/L, n = 19 respectively) than in the Na/K < 3 group (median < 56 fmol/L, range: < 56 fmol/L-2,722 fmol/L, n = 21 and median 176 pmol/L, range: 12 pmol/L-1,940 pmol/L, n = 23 respectively). Significantly positive correlations were found between bFGF and TGF-beta 2 (rS = 0.496, n = 37, P = 0.002), bFGF and Na/K (rS = 0.599, n = 44, P < 0.001) and TGF-beta 2 and Na/K (rS = 0.521, n = 42, P < 0.001). The significantly higher concentrations of the growth inhibitory TGF-beta 2 in the Na/K > 3 cyst group may provide an explanation for the lower risk of breast cancer which has been observed in this group of women. The role of bFGF in mammary carcinogenesis is unclear as lower levels of this growth factor are present in breast cancer tissue and breast cancer cell lines than in normal breast tissue and cell lines. The positive correlation between bFGF and TGF-beta 2 may indicate regulation by a common factor or that one of these growth factors may regulate the production of the other. This is the subject of further study.
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PMID:Relationship between basic fibroblast growth factor and transforming growth factor-beta 2 in breast cyst fluid. 785 41

Rat liver tumors initiated with N-nitrosodiethylamine (DEN) followed by promotion with phenobarbital (PB) were examined for expression of transforming growth factor-beta (TGF beta) type I, II and III receptors. RNase protection and TGF beta 1 affinity labeling assays were used to determine TGF beta receptor steady-state mRNA and protein levels, respectively. We have demonstrated that all three TGF beta receptors are expressed in both normal and malignant hepatic tissues. Long-term PB administration did not alter TGF beta receptor mRNA or protein levels in normal liver. However, type I, II and III TGF beta receptor mRNA and protein levels were decreased by approximately 50% in the DEN-initiated/PB-promoted liver tumors as compared to the receptor levels in normal liver tissue surrounding the tumors. In contrast, TGF beta receptor mRNA and protein levels were unchanged in liver tumors initiated with DEN but not PB-promoted. These data demonstrate that PB promotes the formation of a tumor phenotype that is characterized by a significantly reduced number of TGF beta type I, II and III receptors. This suggests that the down-regulation of TGF beta receptors in PB-promoted hepatic tumors may provide a selective growth advantage to the tumor cells by reducing the ability of TGF beta to inhibit their growth.
Carcinogenesis 1994 Dec
PMID:Transforming growth factor-beta receptors type I, II and III in phenobarbital-promoted rat liver tumors. 800 Dec 32

Cytokines such as transforming growth factor-beta (TGF-beta) are peptide factors that regulate embryogenesis, development, inflammation, tissue repair, and carcinogenesis. Growing evidence indicates that dysregulation of cytokine actions may underlie the pathogenesis of serious autoimmune, degenerative, and fibrotic diseases. Studies in a model of acute mesangial proliferative glomerulonephritis show that overproduction of TGF-beta is the cause of pathologic accumulation of extracellular matrix in the nephritic glomeruli. Transforming growth factor-beta acts to increase matrix production, inhibit matrix degradation, and modulate matrix receptors in the glomerulonephritic rats. It may also play a role in the glomerular matrix build-up that is a central feature of diabetic nephropathy. Elevated expression of TGF-beta mRNA and TGF-beta protein were found in the glomeruli of diabetic rats along with increased levels of proteoglycans and other matrix components that are known to be induced by TGF-beta. The study of human diabetic glomeruli has also showed markedly elevated levels of TGF-beta protein. Glomeruli from normal kidneys and nonprogressive kidney disorders were negative. The striking ability of TGF-beta to cause exuberant matrix formation may be due to the fact that TGF-beta can induce its own production by resident cells at a site of injury. Thus, the potential for TGF-beta to do harm may be due to this autoinduction mechanism whereby TGF-beta expression can become chronic, creating a vicious circle. As the role that TGF-beta plays in chronic fibrotic diseases becomes better understood, it is likely that TGF-beta inhibitors will become important future drugs for treating these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokines in kidney disease: the role of transforming growth factor-beta. 832 71

This study describes a new technique to separate transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta (TGF-beta) from culture supernatants using ion exchange chromatography; assays of competitive inhibition of ligand binding were used to quantify the amount of growth factor. The method was simple, inexpensive and did not require large volumes of culture medium. The autocrine production of TGF-alpha and TGF-beta was examined in oral keratinocyte cell lines derived from the palatal and lingual mucosa of rats painted with the carcinogen 4-nitroquinoline N-oxide (4NQO). Escape from cellular senescence (immortality) was associated with a marked increase in TGF-alpha production (cell line R2P) but tumour progression, as reflected by the development of anchorage independence in agarose gels and tumorigenicity in athymic mice, did not result in a consistent increase or decrease of TGF-alpha production compared to normals. Four cell lines (R8AP, R1T, R3T, R1P), with different functional cellular phenotypes, produced two to three times more TGF-alpha than normals. TGF-alpha production was inversely correlated to epidermal growth factor cell surface receptor expression. The autocrine production of TGF-beta was variable with the majority of cell lines producing markedly little TGF-beta; three cell lines (R4T, R8BP, R9T) produced more TGF-beta than normals. The production of TGF-beta was unrelated to tumour progression, the expression of TGF-beta cell surface receptors or TGF-alpha production. The results indicate that the autocrine production of TGF-alpha and TGF-beta are not accurate markers of tumour progression in the rat 4NQO model of oral carcinogenesis.
Carcinogenesis 1993 May
PMID:Autocrine production of TGF-alpha and TGF-beta during tumour progression of rat oral keratinocytes. 850 93

Chemoprevention is a new branch of oncology which aims to use chemical agents to reduce the incidence of malignant diseases in humans. On the basis of a growing mass of experimental data, it is now felt that the importance of early, precursor lesions of clinically symptomatic cancer should be recognized. Just as in cardiovascular disease, there is now major emphasis on the natural history of tumors and some authors believe that the actual disease process is carcinogenesis, rather than cancer. Indeed, as the chemoprevention of cardiovascular illness with pharmacological agents that either lower blood cholesterol or prevent platelet aggregation is widespread, the effectiveness of different chemical compounds in preventing cancer or, at least in delaying its onset, is presently under investigation. For breast cancer, various agents have been suggested as having chemopreventive effects: vitamins C and E, difluoromethylornithine, selenium, retinoids and antiestrogens. Among retinoids, 4-(N-hydroxyphenyl)retinamide, fenretinide, is at present the most promising molecule, due to its ability to concentrate in the mammary gland. Attention has recently been focussed on tamoxifen because of its effectiveness in reducing the incidence of contralateral tumors in breast cancer patients. Finally, the recent discovery of the steroid receptor superfamily is expected to stimulate further research into combination chemoprevention (the use of multiple agents to achieve synergistic effects while diminishing toxicity). As retinoids and tamoxifen both increase the synthesis or activity or transforming growth factor-beta, a cytokine which is a potent inhibitor of epithelial cell proliferation, tamoxifen and fenretinide are now proposed as the first model of combination chemoprevention in breast cancer.
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PMID:Retinoids and tamoxifen in breast cancer chemoprevention. 851 14


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