Expression in rat fibroblasts of a human transforming growth factor-α cDNA results in transformation

Rosenthal, Arnon; Lindquist, Patricia B.; Bringman, Timothy S.; Goeddel, David V.; Derynck, Rik

doi:10.1016/0092-8674(86)90747-6

Cited by 324 publications

(139 citation statements)

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“…Hepatocyte proliferation in rats and humans is typically associated with increased TGF-a expression, especially during liver development and regeneration (9,12,13,16,20,26,32,44,46,57). Similar increases in TGF-a occurred in replicating hepatocytes from mice treated with PB (40).…”

Section: Discussionmentioning

confidence: 99%

“…TGF-a is regulated during fetal and neonatal development, decreased in adult liver, and enhanced in regenerating rat and human liver and in hepatocytes proliferating in vitro (9,16,25,32,46,57). TGF-a is one of the most consistently altered growth regulators in the transformation of hepatocytes in vitro (5, 12, 25, 28, 44), and TGF-a antisense genes inhibited the tumorigenecity of chemically transformed rat hepatocytes (23). Increased TGF-a is strongly implicated in rat and human liver carcinogenesis (2-4, 6, 7, 9, 20, 22, 52, 54, 57).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

1997

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Modulations in the positive hepatocyte growth factor, transforming growth factor-alpha (TGF-α) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of this study was to determine if TGF-α and EGFR are altered in basophilic and acidophilic preneoplastic and neoplastic liver lesions generated in DEN-initiated mice exposed to a variety of hepatocarcinogens. Female B6C3F1 mice were initiated with N -nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline vapor (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenobarbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antibodies for TGFα and EGFR. In all treatment groups, basophilic hepatic foci were negative for TGF-α immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were immunoreactive for TGF-α (107/108, 99%). There was no significant difference in mean hepatic labeling index as measured by the incorporation of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmunoreactive for TGF-α. The incidence of immunoreactivity for TGF-α increased in hepatocellular tumors that were predominantly of the basophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20%) were immunoreactive for TGF-α, while 17/29 (59%) of hepatocellular carcinomas stained positive for TGF-α. A similar increased incidence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophilic foci (11/367, 3%), suggesting an autocrine mechanism for the development of mouse liver tumors. The increased incidence of TGF-α immunoreactivity in basophilic liver tumors suggests that TGF-α is a marker of tumor progression in mouse liver. Furthermore, TGF-α modulations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-α in basophilic and acidophilic hepatic lesions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

1997

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“…Both TGFx and EGF can act as potent mitogens in a number of epithelial cell systems (Carpenter & Cohen, 1979). It has been postulated that TGFa plays an important role in neoplastic transformation, since it is highly expressed along with its receptor in many TGFa growth responsive tumour cells (Bates et al, 1988;Derynck et al, 1987;Rosenthal et al, 1986;Watanabe et al, 1987). The results of studies with transgenic CD-1 mice, in which chronic overexpression of TGFa is directed by the metallothionein (MT) promotor to multiple tissues throughout their life (Jhappan et al, 1990;Sandgren et al, 1990), have shown that male mice bearing a TGFa transgene develop a high incidence of spontaneous hepatocarcinomas at the age of 10-15 months (Jhappan et al, 1990).…”

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confidence: 99%

Opposing behavioural alterations in male and female transgenic TGFα mice: association with tumour susceptibility

Hilakivi‐Clarke

Arora²,

Clarke³

et al. 1993

Br J Cancer

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Summary Psychosocial factors are thought to influence risk and survival from cancer. We have previously studied specific behaviours in transgenic male CD-1 MT42 mice, which overexpress the gene encoding human transforming growth factor a (TGFa) in multiple tissues, and which Transforming growth factor a (TGFa) is a polypeptide which exhibits approximately 35% sequence homology to epidermal growth factor (EGF), and interacts with cells through the EGF receptor. Both TGFx and EGF can act as potent mitogens in a number of epithelial cell systems (Carpenter & Cohen, 1979). It has been postulated that TGFa plays an important role in neoplastic transformation, since it is highly expressed along with its receptor in many TGFa growth responsive tumour cells (Bates et al., 1988;Derynck et al., 1987;Rosenthal et al., 1986;Watanabe et al., 1987). The results of studies with transgenic CD-1 mice, in which chronic overexpression of TGFa is directed by the metallothionein (MT) promotor to multiple tissues throughout their life (Jhappan et al., 1990;Sandgren et al., 1990), have shown that male mice bearing a TGFa transgene develop a high incidence of spontaneous hepatocarcinomas at the age of 10-15 months (Jhappan et al., 1990). Other abnormalities in these animals (stomach, pancreas, etc.) have emerged as studies have proceeded.Human and animal data suggest that an ability to cope with stress influences vulnerability to develop cancer (Hilakivi-Clarke et al., 1993b;Holland, 1989;Sklar & Anisman, 1981). Perturbations in natural killer (NK) cell activity (Chuang et al., 1990;Saibara et al., 1989;Shirai et al., 1990) and steroid hormone levels (d' Arville & Johnson, 1990;Yager & Shi, 1991) may mediate the effects of psychosocial factors in cancer. We have utilised transgenic male MT42 TGFax mice in studies assessing those behaviours associated with tumourigenesis (Hilakivi-Clarke et al., 1992a). When compared with age matched non-tran sgenic control CD-1 mice, 2-3-month-old male transgenic TGFa mice spent significantly longer times immobile in Porsolt's swim test, and in aggressive behaviour (Hilakivi-Clarke et al., 1992a). The male TGFa mice also exhibited a 25% lower NK cell activity, and a 4-fold increase in the plasma levels of 17p-estradiol (E2) than the controls (Hilakivi-Clarke et al., 1992 al., 1990). This is surprising, since TGFa appears to play a significant role in mammary tumourigenesis (Bates et al., 1988;Liu et al., 1987;Sandgren et al., 1990), and female mice in other transgenic TGFa models exhibit an increased incidence of mammary tumours (Matsui et al., 1990;Sandgren et al., 1990;Stuart, 1984). The expression of TGFoa mRNA appears equally elevated in both sexes of MT42 mice (Hilakivi-Clarke et al., 1993a;Jhappan et al., 1990). To investigate behavioural changes associated with the overexpression of TGFa in the female mice, we utilised (i) Porsolt's swim test, which is thought to measure both depressive behaviour and an animal's ability to cope with stress (Garcia-Marquez & Armario, 1987;Hilakivi et al., 19...

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“…9 Overexpression of TGF-␣ alone, or in combination with EGFR, leads to colony formation in soft agar and tumor formation in nude mice, thus linking TGF-␣ to transformation. 10 TGF-␣ transgenic mice display evidence of epithelial hyperplasia, pancreatic metaplasia and carcinoma of the breast. 11 Co-expression of TGF-␣ and EGFR has also been implicated in the pathophysiology of human cancer.…”

Section: Introductionmentioning

confidence: 99%

TGF-α antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo

et al. 2000

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Expression in rat fibroblasts of a human transforming growth factor-α cDNA results in transformation

Cited by 324 publications

References 47 publications

Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

Opposing behavioural alterations in male and female transgenic TGFα mice: association with tumour susceptibility

TGF-α antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo

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