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

The sensitivity of outbred SENCAR mice and inbred SENCAR (SSIN) mice to multistage carcinogenesis was studied. Tumors were induced using either 7,12-dimethylbenz[a]anthracene or N-methyl-N'-nitro-N-nitrosoguanidine as initiators and 12-O-tetradecanoylphorbol-13-acetate or benzoyl peroxide as promoting agents. Although the number of papillomas per mouse was higher in SSIN than in outbred SENCAR mice, the number of carcinomas observed in the SSIN strain was significantly lower regardless of the initiator or promoter used. It was also observed that the expression of markers of premalignant progression (i.e., dysplasia, expression of keratin K13, and loss of keratin K1 expression) was markedly suppressed in SSIN papillomas. After 50 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate, the pattern of expression of K13 and K1 in SSIN mice was comparable to the pattern observed in outbred SENCAR mice after 10 to 20 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate. It was also observed that 67% of the tumors induced in SSIN mice by initiation with 7,12-dimethylbenz[a]anthracene exhibited a mutation in codon 61 of the Ha-ras-1 gene. This latter finding suggests that the differences observed in tumor progression between the inbred strain and the outbred stock are not related to a genetic alteration in the Ha-ras-1 gene but rather to an independent event that we have postulated to involve a putative suppressor gene. The data reported here suggest that the putative gene(s) that confers susceptibility to tumor promotion was segregated from the gene(s) involved in tumor progression during selection and inbreeding of the SENCAR mouse stock.
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PMID:Dissociation of sensitivities to tumor promotion and progression in outbred and inbred SENCAR mice. 137 69

In normal epidermis, the expression of keratins 1 and 10 is associated with the loss of proliferative capacity and the onset of terminal differentiation. Keratins 1 (K1) and 10 (K10) are commonly expressed in the differentiating layer of benign tumors, but are lost during progression from the benign to the malignant state in skin carcinogenesis. Active gene constructs of mouse K1 and K10 were introduced into papilloma and carcinoma cell lines derived from keratinocytes to analyze the consequences of the expression of these keratins on the organization of the endogenous cytoskeletal network and on the mitotic activity of the recipient cells. Exogenous K1 integrated into the preexisting keratin K5/K14 network of both SLC-1 carcinoma and 308 papilloma cells. The formation of a recombinant cytoskeleton was more restricted for K10 than for K1 and appeared to be related to a requirement for cessation of cell division before K10 could integrate. The integration of exogenous K1 filaments into the endogenous keratin network was compatible with sustained proliferation of SLC-1 carcinoma cells in vitro. However, the exogenous gene was not expressed in tumor grafts in vivo. In contrast, stable K1 or K10 transfectants could not be selected in 308 cells, suggesting that benign tumor cells expressing suprabasal keratins cannot sustain proliferation.
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PMID:Relationship between the expression of differentiation-specific keratins 1 and 10 and cell proliferation in epidermal tumors. 138 Feb 47

Keratins have been demonstrated to be suitable markers of changes taking place during epithelial neoplasia. Therefore, we analyzed 18 mouse skin tumors (nine papillomas and nine squamous cell carcinomas), induced either by two-stage carcinogenesis with 7,12-dimethylbenz[a]anthracene(DMBA)/12-O-tetradecanoylphorbol-13-acetat e or complete carcinogenesis with DMBA, by immunofluorescence with a monoclonal antibody to keratin (K) 8 (TROMA-1). Immunoperoxidase staining and immunoblotting were also used on selected tumor samples to further explore for the presence of K8. All of the papillomas tested were negative for the presence of K8, whereas the carcinomas were positive. The level of K8 expression in carcinomas showed a positive correlation with the degree of malignancy. Northern blot analysis using a K8 cDNA probe suggested that control of K8 expression in mouse skin tumors occurs at the transcriptional level. Double-label immunofluorescence staining using TROMA-1 and RK13 antibodies demonstrated that K8 did not generally colocalize with K13, a keratin normally found in internal stratified epithelial but aberrantly expressed in mouse epidermal tumors. Furthermore, tumors expressing high levels of K8 showed a reduced expression of K13. Histological examination of immunoperoxidase-stained tumors demonstrated that K8-positive cells were mainly found in anaplastic areas, whereas K13 foci were restricted to well-differentiated regions. Our results demonstrate that K8 expression is a marker of late stages of carcinoma progression in the mouse skin carcinogenesis model.
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PMID:Aberrant expression of the simple epithelial type II keratin 8 by mouse skin carcinomas but not papillomas. 138 41

In previous experiments, pretreatment of CD-1 mouse skin with prostratin (12-deoxyphorbol 13-acetate) inhibited hyperplasia, induction of ornithine decarboxylase and edema in response to acute treatment with phorbol 12-myristate 13-acetate (PMA). We report here that prostratin inhibits biological responses induced by multiple (chronic) PMA treatment. A typical chronic treatment schedule consisted of five applications of 3.2 nmol (2 micrograms) PMA at 48 h intervals. Most effective inhibition could be achieved when the first PMA treatment was preceded 48 h before by a lower dose of prostratin (256 nmol = 100 micrograms) and each PMA treatment was preceded 15 min before by a higher dose (2.56 mumol = 1 mg) of prostratin. Under this schedule hyperplasia was completely blocked, as was keratin K6 expression (a marker of hyperproliferative epidermis), whereas myeloperoxidase activity (a marker of neutrophil granulocyte infiltration) was reduced to 36%. 12-Deoxyphorbol 13-phenylacetate (dPP), a non-promoting 12-deoxyphorbol derivative that binds to protein kinase C with two orders of magnitude higher potency than does prostratin, showed the same pattern of inhibition as did prostratin for a single PMA treatment but with a corresponding two orders of magnitude higher potency. In the case of chronic PMA treatment, however, dPP failed to inhibit hyperplasia fully, though it reduced keratin K6 expression and inflammation. Dissociation of K6 expression from hyperplasia was unexpected, since expression of these two responses was thought to be closely coupled. We conclude that 12-deoxyphorbol 13-monoesters are functional antagonists for a class of protein kinase C-mediated responses closely correlated to tumor promotion.
Carcinogenesis 1992 Nov
PMID:Non-promoting 12-deoxyphorbol 13-esters as potent inhibitors of phorbol 12-myristate 13-acetate-induced acute and chronic biological responses in CD-1 mouse skin. 138 2

The Wnt-1 and int-2 proto-oncogenes are transcriptionally activated by mouse mammary tumor virus insertion mutations in virus-induced tumors and encode secretory glycoproteins. To determine whether these two genes can cooperate during carcinogenesis, we have crossed two previously characterized lines of transgenic mice to obtain bitransgenic animals carrying both Wnt-1 and int-2 transgenes under the control of the mouse mammary tumor virus long terminal repeat. Mammary carcinomas appear earlier and with higher frequency in the bitransgenic animals, especially the males, than in either parental line. Nearly all bitransgenic males develop mammary neoplasms within 8 months of birth, whereas only 15% of Wnt-1 transgenic males and none of the int-2 transgenic males have tumors. In virgin bitransgenic females, tumors occur approximately 2 months earlier than in their Wnt-1 transgenic siblings; int-2 transgenic females rarely exhibit tumors. Preneoplastic glands from the bitransgenic animals of either sex demonstrate pronounced epithelial hyperplasia similar to that seen in Wnt-1 transgenic virgin females and males, and both transgenes are expressed in the hyperplastic glands and mammary tumors. RNA from the int-2 transgene is more abundant in mammary glands from bitransgenic animals than from int-2 transgenic animals; the increase is associated with high levels of RNA specific for keratin genes 14 and 18, suggesting that Wnt-1-induced epithelial hyperplasia is responsible for the observed increase in expression of the int-2 transgene.
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PMID:Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice. 153 Aug 75

The majority of renal cancers are thought to arise from the proximal tubule epithelium, but little is known about their etiology. In this investigation, we have established an in vitro model to study the transformation of these target cells using rat kidney proximal tubule epithelial cells (RPTE) transformed in defined medium with SV40-viral DNA. Selection by passaging cells onto plastic surfaces yielded a population of cells (SV-RPTE) that expressed keratin and vimentin along with SV40 large-T antigen. The cells were morphologically transformed and lost their differentiated character as determined by several RPTE markers. SV-RPTE cells grew in soft agar in serum-supplemented medium containing insulin, epidermal growth factor, and cholera toxin, but were unable to grow when serum and growth factors were not combined. Acidic and basic fibroblast growth factors (aFGF and bFGF) were unique since they were the only single factor that induced anchorage-independent growth in the presence of serum alone. Transforming growth factor-beta 1 (TGF-beta 1) was a potent inhibitor of anchorage-independent growth, but the inhibition was partially overcome by a combination of growth factors. The growth factor responses of SV-RPTE in monolayer cultures differed from those in soft agar; the cells were more sensitive to growth stimulation by insulin and insulin-like growth factor, neither of which stimulated anchorage-independent growth. SV-RPTE cells in monolayer cultures had also lost the sensitivity to growth inhibition by TGF-beta 1 characteristic of normal RPTE. The RPTE transformation model described here will be very useful for investigating the molecular basis and etiology of renal cancers. Furthermore, the data suggest that maintenance of the transformed phenotype by aFGF and bFGF and loss of negative growth regulation by TGF-beta 1 could play a role in renal carcinogenesis.
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PMID:Altered growth regulation of rat kidney proximal tubule epithelial cells transformed in vitro by SV40 viral DNA: fibroblast growth factors (heparin-binding growth factors) are potent inducers of anchorage-independent growth. 164 62

XB2 cells, a teratocarcinoma derived cell line of keratinocyte lineage, have been shown to proliferate and differentiate in low calcium medium (0.03 mM Ca2+) at a density of 500 cells/9.6 cm2 without the need for fibroblast feeder layers or conditioned medium. The degree of differentiation can be assessed by measurements of keratin production and stratification of colonies of cells. Both of these parameters, as well as the proliferative capacity of the cells, can be altered by treatment of the cultures with various promoting agents and non-genotoxic carcinogens. Treatment with teleocidin and 12-O-tetradecanoyl phorbol-13-acetate induced large increases in proliferation, stratification and keratinization; mezerein-treated cells showed increased stratification at higher doses; butylated hydroxyanisole treatment resulted in hyperkeratinization and hyperstratification to lower levels than that seen with the phorbol-ester-like promoters; butylated hydroxytoluene had purely hyperproliferative effects. We suggest that this culture system may provide a useful model for studies of the mechanism of promotion and non-genotoxic carcinogenesis in epithelial tissues.
Carcinogenesis 1990 Mar
PMID:Effect of tumour promoters and non-genotoxic carcinogens on terminal differentiation and proliferation in mouse teratoma XB2 cells cultured in low calcium medium. 169 90

This study was undertaken to explore the expression of keratins in the hamster cheek pouch carcinogenesis model, using monospecific keratin antibodies and a technique that allows immunoblotting analysis of tissues embedded in paraffin. Changes in keratin expression were correlated with histopathological changes and with the expression of the enzyme gamma-glutamyl transpeptidase. The right cheek pouch of 20 male golden Syrian hamsters was treated with 0.5% 7,12-dimethylbenz[a]anthracene for 16 weeks. As previously described by other laboratories, this treatment resulted in hyperplastic and dysplastic lesions and benign and malignant tumors. The keratins assayed in this study were K14 (Mr 55,000), K1 (Mr 67,000), and K13 (Mr 47,000). The normal hamster cheek pouch epithelium expressed K14 in the basal layer and K13 in the suprabasal and differentiated layers, whereas K1 was not detected by either immunohistochemistry or immunoblotting. Concomitant with 7,12-dimethylbenz[a]anthracene-induced hyperplasia, there were some topographical alterations in the distribution of K14. In this case, K14 was no longer restricted to the basal layer but was also expressed in differentiated cells. The same pattern was also observed in dysplastic lesions and in squamous cell carcinoma. Furthermore, expression of the K13 differentiation-associated keratin was preserved in this hyperplastic epithelium during all the stages of carcinogenesis, including either anaplastic or differentiated areas. In contrast, after 2 weeks of 7,12-dimethylbenz[a]anthracene treatment, K1 expression started as a weak and patchy pattern in suprabasal cells, becoming stronger and more homogeneous at 8 and 16 weeks of treatment. However, K1 was almost absent in squamous cell carcinoma, where only small very well differentiated areas were stained. We also observed gamma-glutamyl transpeptidase-positive foci in earlier stages of carcinogenesis, concomitant with the expression of the K1 keratin. However, it was not possible to find a perfect topographical correspondence between the two events. Alterations in the pattern of keratin expression appear to be a common feature during the development of squamous cell carcinoma in different systems and could be an excellent tool to study carcinogenesis and chemoprevention.
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PMID:Changes in keratin expression during 7,12-dimethylbenz[a]anthracene-induced hamster cheek pouch carcinogenesis. 169 22

The BNLF-1 gene of Epstein-Barr virus (EBV) encodes the latent membrane protein (LMP), one of the putative oncogene products of the virus. This gene has been expressed from two different enhancer-promoter constructs in transgenic mice, to determine its biological activity and possible contribution to oncogenesis. While transgenic mice expressing LMP in many tissues demonstrated poor viability, expression of LMP specifically in the epidermis induces a phenotype of hyperplastic dermatosis. Concomitant with the expression of LMP in this tissue (and in the esophagus) is an induction of the expression of a hyperproliferative keratin, K6, at aberrant locations within the epidermis. The epithelial hyperplastic phenotype caused by the LMP-encoding transgenes implies that the LMP plays a role in the acanthotic condition of the tongue epithelium in the human EBV- and HIV-associated syndrome oral hairy leukoplakia, as well as possibly predisposing the nasopharyngeal epithelium to carcinogenesis.
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PMID:Expression of the BNLF-1 oncogene of Epstein-Barr virus in the skin of transgenic mice induces hyperplasia and aberrant expression of keratin 6. 169 24

The premalignant evolution of chemically induced mouse skin papillomas is characterized by dysplastic changes, aneuploidy, induction of gamma-glutamyl transpeptidase (GGT), and changes in the expression of keratins, especially differentiation-associated K1. This keratin, which is expressed in normal epidermis and early papillomas, is no longer present in more advanced dysplastic and aneuploid papillomas and in fully invasive carcinomas. More recently, it has been shown that K13, a keratin normally present in internal epithelia but not in epidermis, is aberrantly expressed in epidermal tumors. In the present study, the timing of expression of K13 and its correlation with other markers of premalignant evolution were investigated. Papillomas were induced by SENCAR mice by a single initiating dose of 20 nmol of 7,12-dimethylbenz[a]-anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) (2 micrograms twice a week). Tumors were randomly harvested at 10, 20 and 35 weeks of promotion. K13 and K1 expression in papillomas was studied using immunoblotting and immunostaining of consecutive sections, as previously described. As expected from previous studies, the distribution of K1 in papillomas collected at 10 weeks of promotion was restricted to differentiated cells and was uniform throughout the section of the papilloma. Conversely, K13 was expressed only as small foci in 10 out of 21 papillomas (48%). Papillomas of 20 weeks were also positive for K1. Staining for K13 was positive in these papillomas with the exception of only one that was essentially negative, presenting only one small positive focus. Some of the papillomas collected at week 35 were negative for K1, but immunostaining with K13 showed uniform staining of suprabasal cells in all the papillomas studied. In all cases, immunohistochemical results were confirmed by immunoblotting with proteins extracted from 7 microns sections from each paraffin block. These results indicate that keratins K1 and K13 are coexpressed in most papillomas from 10 to 35 weeks of promotion. However, analysis of adjacent sections showed that K13 positive areas are topographically located in the K1 negative areas of the papillomas, suggesting a shift in the differentiation program from epidermal to mucosal types of keratinization. Based on these and previous studies from our laboratory, we conclude that K13 is an early marker of papillomas progression, which occurs before gross chromosomal abnormalities are present in the stem line of the tumors, and precedes dysplastic changes and the onset of GGT expression, and is probably concomitant at the individual cell level with loss of K1.
Carcinogenesis 1990 Nov
PMID:Early expression of type I K13 keratin in the progression of mouse skin papillomas. 169 81


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