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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogenic activity of several growth factors on androgen responsive LNCaP human prostate tumor cells was studied. A two-fold stimulation of cell proliferation was observed after a culture period of 6 days in 1 ng EGF/ml, 10 ng TGF-alpha/ml or 20 ng basic FGF/ml. TGF-beta (0.02 ng/ml), which did not affect cell proliferation when added alone to the culture medium, inhibited the EGF- and TGF-alpha-induced growth. The synthetic androgen R1881 (0.1 nM) stimulated cell proliferation three-fold and increased the number of EGF receptors from 11500 to 28500 sites/cell. One of the mechanisms involved in androgen action on these cells is therefore an increased EGF receptor expression and increased sensitivity to EGF. TGF-beta did not directly affect androgen-responsive growth but inhibited the synergistic effect of EGF. A considerable expression of TGF alpha (precursors) could be demonstrated on the cells by immunohistochemical staining. However the staining intensity was not affected by androgens. These results make it less likely that androgen-responsive growth is mediated by regulation of secretion of an EGF- or TGF alpha-like activity, which in turn acts in an autocrine manner to stimulate growth. Estrogens, progestagens and antiandrogens do not inhibit androgen responsive growth of LNCaP cells but have striking growth stimulatory effects, increase EGF receptor level and increase acid phosphatase secretion. LNCaP cells contain a modified androgen receptor system with respect to both steroid specificity and antiandrogen sensitivity. It has recently been shown that the stimulatory effects are due to a mutated amino acid in the steroid binding domain of the androgen receptor.
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PMID:Regulation of growth of LNCaP human prostate tumor cells by growth factors and steroid hormones. 195 20

The chronic administration of estradiol or diethylstilbestrol to male Syrian hamsters induces kidney tumors. The effect of vitamin C treatment on estrogen-induced carcinogenesis has been studied to elucidate the mechanism of tumor induction by estrogen. Vitamin C decreases the tumor incidence by approximately 50% but does not influence hormone-dependent growth of kidney tumors. Moreover, vitamin C lowers the concentration of diethylstilbestrol-4',4"-quinone, the genotoxic metabolite of diethylstilbestrol, in vitro and in Syrian hamsters treated with stilbene. Vitamin C also decreases the levels in hamsters of diethylstilbestrol-DNA adducts formed by the quinone metabolite. Estrogens may thus initiate tumors by their metabolic oxidation to corresponding quinone metabolites, which bind covalently to cellular macromolecules. Vitamin C may inhibit tumorigenesis by decreasing concentrations of quinone metabolites and their DNA adducts. Lowering quinone metabolite concentrations may also inhibit free radical generation by decreasing redox cycling between estrogens and their corresponding quinones.
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PMID:Vitamin C reduces the incidence and severity of renal tumors induced by estradiol or diethylstilbestrol. 196 79

Estrogens are associated with several cancers in humans and are known to induce tumors in rodents. In this review a mechanism of carcinogenesis by estrogens is discussed which features the following key events: (1) Steroid estrogens are metabolized by estrogen 2- and 4-hydroxylases to catecholestrogens. Target organs of estrogen-induced carcinogenesis, hamster kidney or mouse uterus, contain high levels of estrogen 4-hydroxylase activity. Since the methylation of 4-hydroxyestradiol by catechol-O-methyltransferase is inhibited by 2-hydroxyestradiol, it is proposed that a build up of 4-hydroxyestrogens precedes estrogen-induced cancer. (2) The catecholestrogen or diethylstilbestrol (DES) are oxidized to semiquinones and quinones by the peroxidatic activity of cytochrome P-450. The quinones are proposed to be (the) reactive intermediates of estrogen metabolism. (3) The quinones may be reduced to catecholestrogens and DES and redox cycling may ensue. Redox cycling of estrogens has been shown to generate free radicals which may react to form the organic hydroperoxides needed as cofactors for oxidation to quinones. (4) The quinone metabolites of catechol estrogens and of DES bind covalently to DNA in vitro whereas DNA binding in vivo has only been examined for DES. When DES is administered to hamsters, the resulting DES-DNA adduct profile in liver, kidney, or other organs closely matches that of DES quinone-DNA adducts in vitro. In vitro, DES-DNA adducts are chemically unstable and are generated in incubations with organic hydroperoxide as cofactor. It is proposed that the instability of adducts and the lower sensitivity of previous assay methods contributed to the reported failures to detect adducts. Steroid estrogen-DNA adducts in vivo are currently under investigation. (5) Tumors are postulated to arise in cells rapidly proliferating due to the growth stimulus provided by the estrogenic activity of the primary estrogen or of hormonally potent metabolites such as 4-hydroxyestradiol. The covalent modification of DNA in these cells is temporary because of the chemical instability of adducts and will result in altered genetic messages in daughter cells, whereas in non-proliferating cells there may be no lasting genetic damage. The sequence of events described above is a plausible mechanism for tumor initiation by estrogens and is partially substantiated by experimental evidence obtained in vitro and/or in vivo.
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PMID:Genotoxic effects of estrogens. 216 Jun 7

Estrogens inhibit tumor growth and modify PRL and GH expression in the MtT/W15 transplantable rat pituitary tumor. The effects of estradiol (E2) and diethylstilbestrol (DES) on PRL and GH mRNA levels were investigated. Estrogens increased GH mRNA levels and decreased PRL mRNA levels as detected by in situ hybridization and Northern blot hybridization with oligonucleotide probes, while inhibiting tumor growth. Similar changes in immunoreactive GH and PRL were seen in the tumor cells. The pituitary glands of tumor-bearing rats treated with estrogen for 3 weeks were increased in weight with a concurrent increase in pituitary PRL mRNA when analyzed by dot blot hybridization. These results indicate that estrogens have an inhibitory effect on the growth of the MtT/W15 tumor and increase GH protein and mRNA levels, while causing PRL protein and mRNA levels to decrease. The pituitaries of tumor-bearing rats concomitantly undergo PRL cell hyperplasia with an increase in PRL mRNA. These results also demonstrate a paradoxical effect of estrogens on different pituitary tissues.
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PMID:The effects of estrogens on tumor growth and on prolactin and growth hormone mRNA expression in rat pituitary tissues. 246 Oct 92

Primary well-differentiated dimethylbenzene alpha-anthracene (DMBA)-or nitrosomethylurea (NMU)-induced rat mammary adenocarcinomas that are estrogen dependent possess biologically active and immunoreactive transforming growth factor alpha (TGF alpha), which can be detected in a sort agar growth-promoting assay and by a specific liquid-phase competitive RIA, respectively. In contrast, tissue extracts prepared from transplantable undifferentiated DMBA-I and NMU-II rat mammary carcinomas that are estrogen independent and metastatic exhibit low or undetectable levels of TGF alpha. In addition, the primary DMBA- and NMU-induced rat mammary adenocarcinomas express a specific 4.8-kilobase TGF alpha mRNA species, whereas little or no TGF alpha mRNA can be detected in the transplantable DMBA-I and NMU-II tumors. Primary tumors synthesize type IV basement membrane collagen, whereas the transplantable tumors elaborate very little type IV collagen. Either TGF alpha or estrogens can differentially enhance the synthesis of type IV collagen by 0.5- to 4-fold over total protein synthesis in primary cultures of normal mouse mammary epithelial cells or in primary NMU-induced tumor cells, respectively. Therefore, TGF alpha could function as an estrogen-inducible autocrine growth factor for well differentiated rat mammary tumor cells by its ability to selectively regulate type IV collagen synthesis. Estrogens can modulate TGF alpha production in vivo in primary DMBA-induced rat mammary tumors, because ovariectomy results in a rapid decline (within 6 h) of TGF alpha mRNA levels. This response to estrogens can also be observed in vitro. Primary DMBA- or NMU-induced rat mammary tumor cells cultured in the presence of 17 beta-estradiol (10(-8) M) for 4 days show an increase in the level of TGF alpha mRNA over cells not treated with estrogen. This increase in TGF alpha mRNA is paralleled by a 2- to 3-fold increase in the levels of immunoreactive TGF alpha that can be detected and in the conditioned medium from estrogen-treated cells. These results suggest that TGF alpha may be an adjunct marker for those mammary tumors that are well differentiated adenocarcinomas and estrogen dependent and that estrogen-independent tumors do not constitutively produce TGF alpha or express TGF alpha mRNA.
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PMID:Expression of transforming growth factor alpha (TGF alpha) in differentiated rat mammary tumors: estrogen induction of TGF alpha production. 248 11

Estrogens have previously been shown to induce covalent DNA modifications specifically in the hamster kidney, the target organ of estrogen-inducible and -dependent renal carcinoma. The DNA adducts, formed by yet unknown mechanisms, have been postulated to mediate hormonal carcinogenesis in this animal model. In an attempt to study a possible involvement of estrogen receptor mechanisms in the formation of DNA adducts, 17 beta-estradiol and the antihormone tamoxifen were concomitantly administered as s.c. implants to male Syrian hamsters. 17 beta-Estradiol-treated and tamoxifen-treated animals served as positive and negative controls, respectively. The tumor incidence decreased from 100% in 17 beta-estradiol-treated controls to 25% in the group receiving tamoxifen in addition to hormone. Tamoxifen-treated animals did not develop kidney tumors and did not show any detectable DNA damage. DNA adduct levels were comparable in hamsters treated with 17 beta-estradiol and 17 beta-estradiol plus tamoxifen for 5 or 7 months. In hamsters inoculated with H-301 cells, which are derived from the estrogen-induced hamster renal carcinoma and are estrogen dependent for growth, tamoxifen decreased estrogen-dependent H-301 tumor growth. However, in cell culture, neither 17 beta-estradiol nor tamoxifen influenced H-301 cell division. It was concluded that tamoxifen inhibited the growth of estrogen-induced renal carcinoma but did not interfere with tumor initiation since it did not inhibit the formation of DNA adducts. Moreover, receptor mechanisms were most probably not involved in the induction of DNA modifications by estrogens.
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PMID:Inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by tamoxifen without decrease in DNA adduct levels. 333 75

Sixteen steroids with different endocrine activities were administered to female rats for 6 or 7 days, in a broad range of doses. Liver growth was recorded by measuring weight and DNA contents and monooxygenase activity by assaying the turnover of five different substrates. According to their effects on these parameters steroids were assigned into one of the following three groups: (a) Estrogens estradiol and ethinylestradiol, as well as the progestins norethynodrel and norethisterone (norethindrone) which have estrogenic activity in rats. These agents induced pronounced liver growth and excessive DNA increase which was not associated with major monooxygenase induction. (b) A different type of response consisted of liver growth and DNA increase associated with a pronounced induction of monooxygenase(s) in a characteristic pattern. This response was elicited by pregnenolone-16 alpha-carbonitril, by progestins progesterone, cyproterone acetate, and medroxyprogesterone (but not gestoden and levonorgestrel), by the antimineralocorticoid spironolactone and by the glucocorticoids cortisol and dexamethasone. Apparently, this response pattern was not related to any specific endocrine action but to certain structural features, in particular to the presence of a saturated, at least two-membered alkyl substituent at C17 of the steroid ring system. (c) No or small effects were observed after gestoden, levonorgestrel and the androgens testosterone and methyltestosterone. Dose-response stuides revealed that estrogens estradiol and EE2 induced hepatic effects more potently by four orders of magnitude than progestins. The response patterns observed may be relevant to the tumor-promoting activity of some of the steroids tested.
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PMID:Quantitative structure-activity studies on effects of sixteen different steroids on growth and monooxygenases of rat liver. 335 10

Estrogens provide the major hormonal support for endocrine-dependent human mammary neoplasms. In postmenopausal women, the extraglandular aromatization of the adrenal prehormone, androstenedione to estrone is the major pathway for estrogen biosynthesis. Estrone can then be converted into estradiol or into an inactive conjugate, estrone sulfate. Recent data suggest that the estrogens may also be synthesized in situ by human breast tumors, either from androstenedione via aromatase, or from estrone sulfate via the enzyme, sulfatase. Our enzyme kinetic studies support the predominance of the sulfatase pathway for in situ estrogen biosynthesis. The ability of estrone sulfate to stimulate colony formation of the nitrosomethylurea-induced rat mammary tumor in the clonogenic assay, suggests that this in situ pathway has biologic relevance. Aromatase inhibitors can be used to suppress the levels of circulating estrone, estrone sulfate, and estradiol in postmenopausal women. Aminoglutethimide, the major inhibitor currently used clinically, acts in a competitive fashion and blocks cholesterol side chain cleavage and 11 beta-hydroxylase as well as aromatase. Clinical studies indicate that the combination of aminoglutethimide plus replacement glucocorticoid causes breast tumor regression with the same frequency and for the same duration as surgical ablative therapies such as adrenalectomy or hypophysectomy. Aminoglutethimide also induces a similar rate of tumor regression as achieved with the antiestrogen, tamoxifen. However, because tamoxifen is associated with fewer side effects, this antiestrogen is to be preferred over use of aminoglutethimide as first-line hormonal treatment for women with breast cancer. Several specific suicide inhibitors of aminoglutethimide such as 4-hydroxy-androstenedione are being developed and have proven effective in early clinical trials with breast cancer patients. Further development of active aromatase inhibitors should allow precise control of estradiol levels in women with breast cancer. This ability to perform an 'estrogen clamp' may allow new strategies to be developed in which hormone depletion followed by repletion can produce a synchronization of tumor cell DNA synthesis. If achievable, such manipulations may allow potentiation of the effects of cytotoxic chemotherapy. This latter concept is currently being rigorously tested in basic and in clinical investigative studies.
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PMID:Aromatase inhibitors for treatment of breast cancer: current concepts and new perspectives. 352 4

Estrogens are known to induce tumors in several animal species. To understand the mechanism of hormonal carcinogenesis, estrogen-induced renal carcinoma in male Syrian hamsters was investigated using estradiol and 2-fluoroestradiol. The biological activities of the latter steroid were compared with those of the natural hormone, because of the reduced metabolic conversion of 2-fluoroestradiol to catechol estrogen metabolites. 2-Fluoroestradiol was administered to male Syrian hamsters at three times the dose (60 mg) of estradiol (20 mg, positive control) by s.c. implantation. After 7 months, 75% of the estradiol-treated hamsters had kidney tumors, while in animals exposed to 2-fluoroestradiol renal carcinoma could not be detected. The reduced tumor incidence by the fluorinated steroid is not due to a lack of estrogenic potency. In the test animals, pituitary LH concentrations matched those measured in estradiol-treated hamsters and the reduction in testes weights was comparable. Furthermore, in immature female rats, uterine wet weight increases illustrate that 2-fluoroestradiol is a potent estrogen. The observed increases in uterine weight were shown to be accompanied by increases in protein and DNA synthesis comparable to those observed in estradiol-treated animals. 2-Fluoroestradiol stimulated growth of H-301 cells in vivo. These cells are estrogen-dependent for growth and are derived from the primary hamster kidney tumor. The results indicate that hormonal activity and carcinogenicity of estrogens are separable properties.
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PMID:Hormonal carcinogenesis: separation of estrogenicity from carcinogenicity. 376 51

Development and differentiation of mammary gland are controlled by a large number of hormones. In embryo, foetal androgens induce a partial necrosis of mammary epithelium. This action is mediated by cells of the parenchyma which is the real target of androgens. Estrogens are not true growth factor in normal mammary gland: they deliver a message of unknown chemical nature, which allows growth factors to act. The growth factors of mammary cells are only partially known. Clones of the various mammary cell types have been obtained (fibroblasts, adipocytes, myoepithelial and epithelial cells). These clones are a good tool to determine growth factors specific of each cell type. Under the influence of GH, mammary fibroblasts are transformed into preadipocytes which secrete a growth factor (PGE2) which specifically stimulates multiplication of mammary epithelial cells. Other growth factors induced by oestrogens or prolactin have been identified but their exact role remains unknown. Induction of milk synthesis is under the strict dependency of prolactin. The action of this hormone is strongly stimulated by glucocorticoids and insulin at high concentrations and it is inhibited by progesterone and EGF. Prolactin stimulates transcription of milk protein genes and this stimulation is modulated by glucocorticoids and progesterone. Induction of casein and DNA synthesis by prolactin can be mimicked by polyclonal and monoclonal anti-prolactin receptor antibodies. Collagen is necessary for isolated epithelial mammary cells to respond to prolactin signal. The role of other components of the extracellular matrix (proteoglycans, glycoproteins) is partially known. Specific peripheral markers corresponding to the different cell types and to the various stages of mammary gland development have been identified. All these cellular and molecular parameters are compared in normal and tumor mammary cells to point out possible differences.
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PMID:[Hormonal regulation of the normal mammary gland]. 389 Sep 87


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