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

The SV40 T-antigen-transfected human thyroid cell line SGHTL-34 was used to investigate the effect of thyrotropin (TSH), insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) on c-fos and c-erbB/EGF receptor (EGF-R) mRNA expression and their role in human thyroid cell proliferation. EGF caused a transient 8- and 4-fold increase in c-fos mRNA level after 30 min in serum/hormone-deprived and in logarithmically growing cells, respectively. EGF was only mitogenic in the presence of serum, as measured by 3H-thymidine incorporation and cell counting. TSH had no detectable effect on c-fos mRNA expression and no mitogenic effect on the SGHTL-34 cells. IGF-1 showed no effect alone or in combination with EGF or TSH on either proliferation or c-fos mRNA expression. Our data suggest that increased c-fos mRNA levels are part of the mitogenic pathway, but are insufficient to engender a mitogenic response. SGHTL-34 cells produced high levels of transforming growth factor-alpha (TGF-alpha) and c-erbB/EGF-R mRNA, also seen in thyroid papillary carcinomas. The TGF-alpha protein was detected in conditioned medium from the SGHTL-34 cells, indicating that TGF-alpha may function as an autocrine growth factor. Our data show that the c-erbB/EGF-R mRNA level is regulated by growth factors and hormones in the SGHTL-34 cell line. The SGHTL-34 cells may therefore represent a useful model system for studying the role of TGF-alpha and EGF-R in thyroid carcinogenesis.
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PMID:Growth requirements and oncogene expression in the human thyroid cell line SGHTL-34. 790 43

In the study presented here, we examined the possible role of the transforming growth factor-alpha (TGF alpha)/epidermal growth factor receptor (EGFR) system during multistage carcinogenesis in mouse skin. In this regard, the expression (mRNA and protein) of both TGF alpha and EGFR was examined in primary papillomas and squamous cell carcinomas (SCCs) obtained from SENCAR mice treated with standard initiation-promotion regimens and compared with the levels of expression in normal epidermis. The level of a 4.8-kb TGF alpha transcript was elevated in 100% of the skin tumors examined (both papillomas and SCCs), including papillomas obtained 13 wk after the start of promotion, compared with normal epidermis. Immunohistochemical analyses detected elevated levels of TGF alpha protein in these skin tumors and in papillomas as early as 10 wk after the start of promotion. The levels of EGFR transcripts were also significantly elevated in most (90%) of the skin tumors examined, including again those harvested after 13 wk of promotion. Interestingly, multiple EGFR transcripts (10.5, 5.8, 2.8, and 1.8 kb) were detected in both papillomas and SCCs. The two smaller transcripts appeared to encode truncated versions of the EGFR, and the 1.8-kb transcript appeared to be unique to RNA samples isolated from skin tumors, based on comparative analyses of several normal tissues. As with TGF alpha, immunohistochemical analyses detected elevated levels of EGFR protein in these skin tumors (both papillomas and SCCs), including papillomas harvested as early as 10 wk after the start of promotion. Southern analyses of genomic DNAs for TGF alpha and EGFR failed to detect any cases of gene rearrangements or amplification as a possible explanation for the elevated levels of the transcripts of these two genes. These results support the hypothesis that a key step in the development of autonomous growth in mouse skin papillomas generated in SENCAR mice by an initiation-promotion regimen may involve alterations in the synthesis of TGF alpha and its cognate receptor.
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PMID:Altered expression of the epidermal growth factor receptor and transforming growth factor-alpha during multistage skin carcinogenesis in SENCAR mice. 791 86

The expression of mRNA for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), EGF receptor (EGFR) and c-erbB-2 genes and the immunoreactivity to these gene products were examined in 3 newly established human pancreatic carcinoma cell lines and their corresponding in vivo tumor lines using the Northern blot technique and the immunohistochemical method. All 3 cell lines expressed TGF-alpha, EGFR and 2 of the 3 lines expressed EGF and c-erbB-2 mRNAs. The immunohistochemical study showed immunoreactivity to EGF, TGF-alpha and EGFR in all these 3 cell lines and their corresponding in vivo tumor lines. These results indicate that the autocrine loop of EGF and/or TGF-alpha/EGFR in pancreatic carcinoma cells may be one of the important reasons for the uncontrolled growth of the pancreatic carcinoma. The c-erbB-2 overexpression in some of the cell lines may also contribute to the carcinogenesis or progression of this cancer.
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PMID:Expression of EGF, TGF-alpha, EGFR and c-erbB2 genes and their gene products in human pancreatic carcinoma cell lines. 794 34

The influence of the tumor promoter 2-acetylaminofluorene (2-AAF) on cell proliferation and on the epidermal growth factor receptor (EGFR) system was assessed in normal and nodular rat livers. DNA replication in vivo was inhibited below the detection level after 8d of dietary 2-AAF treatment of previously unexposed rats. The 2-AAF-induced growth inhibition was accompanied by downregulation of the number of epidermal growth factor (EGF)-binding sites and decreased levels of EGFR transcripts, whereas no changes in the transforming growth factor-alpha (TGF-alpha) mRNA levels were observed. The persistent liver nodules generated by intermittent 2-AAF-feeding had a 30- to 35-fold higher replicating cell fraction than normal liver. Treatment with 2-AAF in vivo reduced the replicating cell fraction to one third in nodules after 14 d of 2-AAF treatment. The initial EGFR mRNA levels and number of EGF binding sites in nodules before 2-AAF administration was about 605 that of control livers and was slightly reduced by 2-AAF feeding. The levels of EGFR mRNA after 14 d of 2-AAF feeding were thus similar in the nodules and in the 2-AAF-treated control livers, whereas the fraction of proliferating cells in nodules after the 2-AAF treatment was much larger than in normal liver. The TGF-alpha mRNA level in the nodules was found to be 1.4-fold and in malignant hepatomas 1.7-fold the level in normal liver. Primary hepatocytes isolated from control livers were four to five times more sensitive to replicative stimulation with EGF than with TGF-alpha, whereas nodular cells responded at lower concentrations than control cells and equally well to both EGF and TGF-alpha. We conclude that the decreased amounts of EGFR in the nodular cells with respect to proliferative stimulation could be more than compensated for by elevated synthesis of TGF-alpha combined with an increased TGF-alpha sensitivity. Collectively, these changes implicate TGF-alpha in sustaining cell proliferation during chemically induced rat liver carcinogenesis.
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PMID:Increased expression of and sensitivity to transforming growth factor-alpha: a promotive role during rat liver carcinogenesis. 803 70

The role of duct cells in the histogenesis of pancreatic carcinoma was studied using a propagable cultured pancreatic duct epithelial cell line derived from a Fischer-344 rat. Tumorigenic transformation was induced by treatment with two experimental pancreatic carcinogens, azaserine and streptozotocin, or spontaneously using a 'selective' culture condition. Tumors arising from spontaneously transformed cells were anaplastic carcinomas, while those from streptozotocin-transformed cells were well or moderately differentiated ductal adenocarcinomas. Azaserine-treated cells produced moderately to poorly differentiated adenocarcinomas. Ultrastructural evidence of acinar or endocrine differentiation was absent. The biochemical phenotypes of representative tumor cell lines established from these tumors were studied. As compared to the parental cell line which expressed high activity of carbonic anhydrase (CA) and negligible activity of gamma-glutamyl transpeptidase (GGT), the tumor cell lines displayed variably increased levels of GGT, and a diminution or loss of CA activity. The tumor cell lines also showed heterogeneity in proto-oncogene and growth factor/receptor expression. The transforming growth factor-alpha mRNA expression was increased in all tumor cell lines, especially in those induced by azaserine. In contrast, mRNA expression of epidermal growth factor receptor was markedly down-regulated in all tumor cell lines. All chemically induced tumor cell lines showed marked overexpression of the c-myc and c-Ki-ras mRNAs, whereas the spontaneously transformed tumor cell line showed only a significant overexpression of the c-Ki-ras. Point mutation of this proto-oncogene at codons 12, 13 or 61 was absent. The results show that azaserine and streptozotocin are potent carcinogens in vitro for cultured rat pancreatic duct epithelial cells, and the phenotype of the tumors is modulated by the method or agent used for their transformation.
Carcinogenesis 1993 May
PMID:Neoplastic transformation of propagable cultured rat pancreatic duct epithelial cells by azaserine and streptozotocin. 809 12

Cell lines derived from formaldehyde-induced nasal tumors in Fischer 344 rats were established. All of the lines were found to be epithelial and aneuploid and to express keratin, transforming growth factor-alpha, and epidermal growth factor receptor transcripts. Two of four lines were tumorigenic upon injection into nude mice, and these lines also contained point mutations in the p53 suppressor gene. The data indicate that these lines possess characteristics that make them a valuable tool for the study of chemically induced respiratory tract carcinogenesis.
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PMID:Characterization of cell lines derived from formaldehyde-induced nasal tumors in rats. 814 52

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are polypeptides which bind to the EGF receptor (EGFr) and may play a role in cell growth and carcinogenesis. Our study investigated the content of EGF, TGF-alpha, and EGFr in tumors of the stomach and the colon in comparison with the surrounding mucosa. EGF was detected in half of the stomach specimens with concentrations between 1 and 9 ng/g weight irrespective of histology. In the colon no EGF was found in the tumor or normal mucosa. In the stomach normal mucosa contained higher TGF-alpha concentrations (mean 22.4 ng/g) than the tumors (mean 11.8 ng/g), but the difference was not statistically significant because of a wide variation in mucosal values. By contrast, the colon mucosa displayed significantly higher TGF-alpha concentrations than the tumor tissues (33 ng/g versus 12 ng/g; P < 0.01). EGFr content in the gastric mucosa was lower compared to gastric carcinoma (48 fmol/g versus 75 fmol/g) yet not significantly different. In contrast, colorectal tumor specimens disclosed significantly higher concentrations than the mucosal tissues (mean of 155 fmol/g versus 80 fmol/g; P < 0.01). In conclusion, TGF-alpha should not be considered a tumorigenic but a physiological growth factor in the stomach and colon. An elevated EGFr content in colorectal tumors in comparison with the normal mucosa could lead to a growth advantage by an autostimulating mechanism.
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PMID:Epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor content in normal and carcinomatous gastric and colonic tissue. 831 82

This study was designed to determine whether hepatocytes from hepatic nodules are resistant to the mitoinhibitory effects of orotic acid. Hepatic nodules were initiated in Fischer 344 male rats with 1,2-dimethylhydrazine.2HCl (100 mg/kg ip) given 16 hr after two thirds partial hepatectomy and promoted by feeding a diet containing 1% orotic acid. Eight to 9 months later, when persistent nodules had developed, the rats were taken off the orotic acid diet and maintained on a semisynthetic basal diet for 2 to 5 weeks. The effect of orotic acid on the DNA synthesis in the hepatocytes isolated from hepatic nodules and from the surrounding nonnodular liver and from the age- and sex-matched control rats was studied. The results indicated that a dose of orotic acid (120 microM) that almost completely inhibited the transforming growth factor-alpha-induced DNA synthesis in hepatocytes from nonnodular surrounding liver and from age- and and sex-matched control liver could not inhibit the DNA synthesis in hepatocytes from hepatic nodules. These results are consistent with the postulate that orotic acid may promote liver carcinogenesis by a differential mitoinhibition of normal hepatocytes while permitting the initiated hepatocytes to respond to growth stimuli and form hepatic nodules. However, it needs to be determined whether differential mitoinhibition of normal hepatocytes is the mechanism by which orotic acid promotes liver carcinogenesis.
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PMID:Influence of orotic acid on multistage hepatocarcinogenesis in the rat: resistance of hepatocytes from nodules to the mitoinhibitory effects of orotic acid. 842 92

Sequential treatment of partially (two-thirds) hepatectomized rats with diethylnitrosamine and 2-acetylaminofluorene induces the emergence of diploid hepatocytes in rat liver. These carcinogen-induced diploid cell populations are thought to contain the progenitors of hepatocellular carcinoma (HCC), i.e., initiated, cells. In the study presented here, we addressed the question of whether putative mutations in carcinogen-induced diploid hepatocytes can cooperate with activated oncogenes in the process of transformation in vitro. Both carcinogenesis in vivo and transformation in vitro have been shown to be multistep processes requiring at least two independent transforming events. Diploid and polyploid rat hepatocytes were isolated by centrifugal elutriation. The purity of the elutriated fractions was 88 +/- 3% in the diploid fraction and 84 +/- 3% in the polyploid fraction. Hepatocytes from both the elutriated cell fractions and, for comparison, hepatocytes from untreated rats were transfected by electroporation with oncogene expression vectors containing the mutated human T24 c-Ha-ras gene and of the N-myc gene. Transient expression of transfected DNA was similar in both hepatocyte populations. No cell lines could be established by using the N-myc vector. In contrast, the carcinogen-induced diploid hepatocytes, but not polyploid hepatocytes, could be converted by transfection with the ras vector into permanent anchorage-independent growing cell lines with hepatocyte-like morphology and differentiation. These cell lines expressed the myc proto-oncogene and transforming growth factor-alpha constitutively. Thus, carcinogen-induced diploid hepatocytes are sensitive to transformation by the ras oncogene, suggesting cooperation between putative preexisting mutations in the diploid cells and the ras oncogene product in hepatocellular transformation.
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PMID:Carcinogen-induced diploid hepatocytes: sensitive target cells for transformation by mutated c-Ha-ras oncogene. 848 13

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


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