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

The present study addressed links between progestin and heregulin (HRG) signaling pathways in mammary tumors. An experimental model of hormonal carcinogenesis, in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female Balb/c mice, was used. MPA induced an in vivo up-regulation of HRG mRNA expression in progestin-dependent (HD) tumor lines. Mammary tumor progression to a progestin-independent (HI) phenotype was accompanied by a high constitutive expression of HRG. The HRG message arose from the tumor epithelial cells. Primary cultures of malignant epithelial cells from a HD tumor line were used to investigate HRG involvement on cell proliferation. HRG induced a potent proliferative effect on these cells and potentiated MPA mitogenic effects. Blocking endogenous HRG synthesis by antisense oligodeoxynucleotides (ASODNs) to HRG mRNA inhibited MPA-induced cell growth, indicating that HRG acts as a mediator of MPA-induced growth. High levels of ErbB-2 and ErbB-3 expression and low ErbB-4 levels were found in HD cells. Treatment of these cells with either MPA or HRG resulted in tyrosine phosphorylation of both ErbB-2 and ErbB-3. Furthermore, both HRG and MPA proliferative effects were abolished when cells were treated with ASODNs to ErbB-2 mRNA, providing evidence for a critical role of ErbB-2 in HRG-induced growth. Finally, blocking type I insulin-like growth factor receptor (IGF-IR) expression with ASODN resulted in the complete inhibition of HRG proliferative effect, demonstrating that a functional IGF-IR is required for HRG mitogenic activity. These results provide the first evidence of interactions between progestins and HRB/ErbB signal transduction pathways in mammary cancer and the first demonstration that IGF-IR is required for HRG proliferative effects.
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PMID:Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas. 1059 37

Many dietary constituents are chemopreventive in animal models, and experiments with cultured cells are revealing various potential mechanisms of action. Compounds classified as blocking agents can prevent, or greatly reduce, initiation of carcinogenesis, while suppressing agents affect later stages of the process by reducing cell proliferation. Many compounds have both types of activity. Blocking mechanisms include alteration of drug metabolising activities and scavenging of reactive oxygen species. Mechanisms which suppress tumorigenesis often involve modulation of signal transduction pathways, leading to altered gene expression, cell cycle arrest or apoptosis. As our knowledge of how these dietary components affect cell biochemistry improves, so the likelihood of success in chemoprevention trials and in provision of dietary advice to the general population to optimise the chances of preventing disease is increased.
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PMID:Blocking and suppressing mechanisms of chemoprevention by dietary constituents. 1072 Jul 72

We have established a female Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis. Based on the previous finding that the dose of testosterone affects only the latency period of mammary cancer, not the final incidence and that androgen upregulates apoptotic activity in pre-malignant mammary glands, we hypothesised that estrogen is the initiator and androgen the promoter for hormonal mammary carcinogenesis of the rats. In the present study, rats were treated with the sex hormones together with flutamide and tamoxifen for both short term (7 and 13 weeks) and long term (12 months) durations. We showed that tamoxifen could totally inhibit mammary carcinogenesis while flutamide cause a delay and reduction in tumour incidence in the 12 months treatment term. Blocking effect of flutamide and tamoxifen on T + E2 (testosterone and 17beta-estradiol) short-terms treatment was demonstrated by the similar histological changes identified in the mammary glands of the T + E2 and drug treated rats to that of the age matched E2 and T controls, respectively. These findings give further support for the role of estrogen and androgen in mammary carcinogenesis. Autopsy of the tumour bearing rats showed presence of pituitary macroadenoma causing compression and atrophy of the brain stem. Immunohistochemical staining of these adenomas showed a predominance of prolactin-secreting cells. Serum assay also showed a corresponding increase in circulatory prolactin level. Tamoxifen was also effective in blocking the formation of pituitary adenoma in the sex hormone treated rats. Pituitary size and level of prolactin were higher in the T + E2 + flutamide group than the T + E2 group in both short-term and long-term treatments. It suggests that testosterone may have a role in counteracting estradiol stimulation on the pituitary lactotropes although it is synergistic to estrogen in mammary carcinogenesis. Pituitary adenomas were found in all rats that developed mammary adenocarcinoma but not vice versa suggesting that prolactin level elevation alone cannot lead to mammary tumorigenesis. The animal model, in addition to mammary carcinogenesis, may be useful for investigation of anti-estrogen therapy in pituitary adenomas.
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PMID:The effect of flutamide and tamoxifen on sex hormone-induced mammary carcinogenesis and pituitary adenoma. 1203 6

Breast and prostatic carcinomas, melanoma, and endothelial cell lines are chemoattracted by medium conditioned by mature osteoblasts. The chemoattractant for endothelial cells was identified with C3, carboxyl-terminal trimer of pro-collagen type I. We report that C3 induces directional migration and proliferation, the expression of tissue inhibitor of metalloproteinases-2, pro-metalloproteinase-2 and -9, and their activation in MDA MB231 cells, without changing the expression of tissue inhibitor of metalloproteinases-1 and of metalloproteinase-14. Antiserum against metalloproteinase-2 or -9 or -14, tissue inhibitor of metalloproteinases-1, or GM6001 inhibits the C3-induced migration. Urokinase and its receptor are detected and unchanged upon exposure to C3. The antibody against urokinase or addition of plasminogen activator inhibitor inhibits migration. Blocking antibodies to integrins alpha(2), alpha(6), beta(1), and beta(3) inhibit chemotaxis and do not change urokinase and urokinase receptor expression. Blockage of alpha(2), beta(1), and beta(3) integrins affect differently the induction by C3 of pro-metalloproteinase-2 and -9 and of tissue inhibitor of metalloproteinases-2. Chemotaxis to C3 is also inhibited by genistein, by pertussis toxin, which also inhibits C3-induced pro-metalloproteinase -2 and -9, but not urokinase expression. Wortmannin partially inhibits C3-induced cell migration. Other, but not all, breast carcinoma lines tested responded to C3 with migration and pro-metalloproteinase-2 induction. Presently C3 is the only agent known to induce migration specifically of both endothelial and breast carcinoma cells. The mitogenic and motogenic role of C3 in vitro might prefigure a role in in vivo carcinogenesis and in the establishment of metastasis.
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PMID:Pro-collagen I COOH-terminal trimer induces directional migration and metalloproteinases in breast cancer cells. 1244 53

The molecular mechanisms potentially responsible for cadmium carcinogenesis were investigated by differential gene expression analysis of Balb/c-3T3 cells morphologically transformed with cadmium chloride. Differential display analysis of gene expression revealed overexpression of mouse Translation Initiation Factor 3 (TIF3; GenBank Accession Number AF 271072) and Translation Elongation Factor-1delta (TEF-1delta; GenBank Accession Number AF 304351) in the transformed cells compared with the control cells. The full length cDNAs for TIF3 and TEF-1delta were cloned and sequenced. Transfection of mammalian cells with an expression vector containing either TIF3 or TEF-1delta cDNA resulted in overexpression of the encoded protein. Overexpression of the cDNA-encoded TIF3 and TEF-1delta proteins in NIH3T3 cells was oncogenic as evidenced by the appearance of transformed foci capable of anchorage-independent growth on soft agar and tumorigenesis in nude mouse. Blocking the translation of TIF3 and TEF-1delta proteins using the corresponding antisense mRNA resulted in a significant reversal of the oncogenic potential of cadmium transformed Balb/c-3T3 cells as evidenced from the suppression of anchorage-independent growth on soft agar and diminished tumorigenesis in nude mouse. These findings demonstrate that the up-regulation of expression of TIF3 and TEF-1delta is a novel molecular mechanism responsible, at least in part, for cadmium carcinogenesis.
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PMID:Up-regulation of expression of translation factors--a novel molecular mechanism for cadmium carcinogenesis. 1497 50

NF-kappaB activation is required for TNF-alpha-induced transformation of JB6 mouse epidermal cells. Deficient activation of p65 contributes to the lack of NF-kappaB activation in transformation-resistant (P-) cells. We hypothesized that the differential NF-kappaB activation involves differential p65 phosphorylation arising from enzyme activity differences. Here we show that TNF-alpha induces greater ERK-dependent p65 phosphorylation at S536 in transformation sensitive (P+) cells than in P- cells. Our results establish that limited ERK content contributes to a low IkappaB kinase (IKKbeta) level, in turn resulting in insufficient p65 phosphorylation at S536 upon TNF-alpha stimulation in P- cells. Phosphorylation of p65 at S536 appears to play a role in TNF-alpha-induced p65 DNA binding and recruitment of p300 to the p65 complex as well as in release of p65 bound to HDAC1 and 3. Blocking p65 phosphorylation at S536, but not at S276 or S529, abolishes p65 transactivational activity. Over-expression of p65 but not p65 phosphorylation mutant (S536A) in transformation-resistant P- cells renders these cells sensitive to TNF-alpha-induced transformation. Over-expression of p65 phosphorylation mimics p65-S536D or p65-S536E in P- cells and also rescues the transformation response. These findings provide direct evidence that phosphorylation of p65 at S536 is required for TNF-alpha-induced NF-kappaB activation in the JB6 transformation model. The lack of NF-kappaB activation seen in P- cells can be attributed to an insufficient level of p65 phosphorylation on S536 that arises from insufficient IKKbeta that in turn arises from insufficient ERK. Thus, p65 phosphorylation at S536 offers a potential molecular target for cancer prevention.
Carcinogenesis 2004 Oct
PMID:Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-kappaB activation and transformation in resistant JB6 cells. 1519 14

Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-IR reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-IR/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma.
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PMID:Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy. 1556 29

Small molecule inhibitors of signaling pathways have proven to be extremely useful for the development of therapeutic strategies for human cancers. Blocking the tumor-promoting effects of transforming growth factor-beta (TGF-beta) in advanced stage carcinogenesis provides a potentially interesting drug target for therapeutic intervention. Although very few TGF-beta receptor kinase inhibitors (TRKI) are now emerging in preclinical studies, nothing is known about how these inhibitors might regulate the tumor-suppressive or tumor-promoting effects of TGF-beta, or when these inhibitors might be useful for treatment during cancer progression. We have investigated the potential of TRKI in new therapeutic approaches in preclinical models. Here, we demonstrate that the TRKI, SB-431542, inhibits TGF-beta-induced transcription, gene expression, apoptosis, and growth suppression. We have observed that SB-431542 attenuates the tumor-promoting effects of TGF-beta, including TGF-beta-induced EMT, cell motility, migration and invasion, and vascular endothelial growth factor secretion in human cancer cell lines. Interestingly, SB-431542 induces anchorage independent growth of cells that are growth-inhibited by TGF-beta, whereas it reduces colony formation by cells that are growth-promoted by TGF-beta. However, SB-431542 has no effect on a cell line that failed to respond to TGF-beta. This represents a novel potential application of these inhibitors as therapeutic agents for human cancers with the goal of blocking tumor invasion, angiogenesis, and metastasis, when tumors are refractory to TGF-beta-induced tumor-suppressor functions but responsive to tumor-promoting effects of TGF-beta.
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PMID:A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. 1596 3

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation and survival/or apoptosis of many cells. Knock-out experiments in mice for the three isoforms of TGF-beta have demonstrated their importance in regulating inflammation and tissue repair. TGF-beta is implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. TGF-beta receptors act through multiple intracellular pathways. Upon binding of TGF-beta with its receptor, receptor-regulated Smad2/3 proteins become phosphorylated and associate with Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of specific genes. Negative regulation of TGF-beta/Smad signalling may occur through the inhibitory Smad6/7. Furthermore, TGF-beta-activated kinase-1 (TAK1) is a component of TGF-beta signalling and activates stress-activated kinases: p38 through MKK6 or MKK3 and c-Jun N-terminal kinases (JNKs) via MKK4. In the brain TGF-beta, normally expressed at the very low level, increases dramatically after injury. Increased mRNA levels of the three TGF-beta isoforms correlate with the degree of malignancy of human gliomas. TGF-betas are secreted as latent precursors requiring activation into the mature form. TGF-beta may contribute to tumour pathogenesis by direct support of tumour growth and influence on local microenvironment, resulting in immunosuppression, induction of angiogenesis, and modification of the extracellular matrix. TGF-beta1,2 may stimulate production of vascular endothelial growth factor (VEGF) as well as plasminogen activator inhibitor (PAI-I), that are involved in vascular remodelling occurring during angiogenesis. Blocking of TGF-beta action inhibits tumour viability, migration, metastases in mammary cancer, melanoma and prostate cancer model. Reduction of TGF-beta production and activity may be a promising target of therapeutic strategies to control tumour growth.
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PMID:TGF beta signalling and its role in tumour pathogenesis. 1599 Sep 18

Cytokines such as IL-1 and TNF are primarily pro-inflammatory. The inflammation induced by these cytokines is reflected in the type of genes they induce. In the pathogenesis of carcinogenesis as well as tumor growth and spread, cytokines such as IL-1 and TNF induce chemokines that attract neutrophils. Neutrophils are key players in the production of reactive oxygen species and carcinogenesis. Another aspect of pro-inflammatory cytokines is the induction of adhesion molecules and metalloproteinases, both of which provide mechanisms for tumor invasion. Blocking cytokines, however, will reduce tumor growth and spread if administered at sufficient concentrations and will require parenteral therapy. However, blocking cytokines will not kill tumor cells nor prevent carcinogenesis. Blocking cytokines is best as an adjunct therapy together with tumorocidal drugs.
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PMID:The paradox of pro-inflammatory cytokines in cancer. 1702 30


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