Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the synergistic effect of growth and transcription factor deregulation on carcinogenesis in vivo, mating experiments were performed between transgenic mice expressing human TGF alpha or v-fos exclusively in the epidermis by means of a human keratin K1-based targeting vector (HK1.fos, HK1.TGF alpha and HK1.fos/alpha). While HK1.TGF alpha mice exhibited mild epidermal hyperplasia resulting in a wrinkled appearance, this hyperplasia was significantly increased in HK1.fos/alpha mice which also exhibited a novel opalescent and peeling skin phenotype. HK1.fos/alpha keratinocyte differentiation was considerably deregulated with cornified cells appearing in the granular layer, granular cells in the spinous layer and a sixfold increase in BrdU labeling over normal. In addition, hyperplastic HK1.fos/alpha epidermis exhibited aberrant loricrin, filaggrin and novel K13 expression associated with v-fos expression. Unlike adult HK1.TGF alpha controls, hyperplasia persisted in HK1.fos/alpha adults which also rapidly developed autonomous squamous cell papillomas. These results demonstrate that v-fos and TGF alpha over-expression can cooperate to reprogram keratinocyte differentiation and elicit the early stages of neoplasia. Moreover, TGF alpha over-expression appeared to play an early, initiating role in HK1.fos/alpha papilloma etiology, and a promotion role in the accelerated appearance of v-fos wound-associated preneoplastic phenotypes. However, the stable persistence of HK1.fos/alpha papillomas for up to 12 months, suggests that additional events are required for malignant conversion.
 ...
PMID:TGF alpha and v-fos cooperation in transgenic mouse epidermis induces aberrant keratinocyte differentiation and stable, autonomous papillomas. 753 Aug 25

Retinoids are powerful regulators of epidermal cell growth and differentiation and are widely used in the prevention and treatment of skin disorders and cancers in humans. Since many of the effects of retinoids on cell growth and differentiation are mediated by nuclear retinoid receptors (RARs and RXRs), we were interested in determining RAR and RXR gene expression during mouse skin tumor progression. The two-stage system of mouse skin carcinogenesis was used to generate papillomas and carcinomas, and the different stages of malignant progression (papillomas, differentiated squamous cell carcinomas, undifferentiated squamous cell carcinomas, and spindle cell carcinomas) were characterized in each tumor by specific keratin expression prior to receptor characterization. Using in situ hybridization analysis, we show that the two major RAR isoforms (alpha 1 and gamma 1), which account for most of RARs in the skin, were expressed in both the basal and suprabasal layers in mouse epidermis. In contrast, RXR alpha transcripts were compartmentalized to the basal cell layers and concentrated in hair follicles. During skin tumor progression, RAR (alpha 1 and gamma 1) transcripts were down-modulated in malignant tumor cells, whereas RXR (alpha and beta) transcript expression was expanded in papillomas and carcinomas as the number of undifferentiated cells also increased. RXR gamma was not detected in the skin or at any stage during skin tumor progression. Spindle cell tumors lacked markers of the keratinocyte phenotype and lost RAR expression, yet retained expression of RXR alpha and beta. The increased abundance of transcripts for RXRs and decreased presence of RARs in skin tumor progression may favor other nuclear signal transduction pathways requiring RXR for heterodimer formation and contribute to phenotypic progression of cancer cells.
 ...
PMID:Mouse skin tumor progression results in differential expression of retinoic acid and retinoid X receptors. 754 Sep 49

Serum-free cultures of normal human buccal epithelial cells were transfected with a plasmid containing the SV40 T-antigen (SV40T) gene. Two major lines developed that showed extended lifespans (between 30 and 40 weeks) as compared with the controls (approximately 6 weeks). Continued growth through one or two crises generated several sublines. They expressed the epithelial marker keratin and also exhibited nuclear expression of SV40T. The lines showed abnormal karyotypes with both numerical and structural aberrations and variably responded to agents that normally inhibit growth and/or induce terminal differentiation, i.e. transforming growth factor-beta 1 and fetal bovine serum. One of the lines, termed SVpgC2a, developed into an apparently immortal line, since it had undergone more than 700 population doublings from over 2 years in culture. Further characterization of this line demonstrated its clonal origin, with integration of two copies of SV40T at the same site and the presence of both normal retinoblastoma and wild-type p53 proteins. This line showed high resistance to growth inhibition by transforming growth factor-beta 1 and serum similar to that shown by buccal carcinoma cell line SqCC/Y1. Neither SVpgC2a nor its parental lines were tumorigenic when injected into athymic nude mice, whereas the SqCC/Y1 cells induced tumors. The various lines with extended but finite lifespans, complemented by one immortalized line, which retained non-malignant properties upon extended culture, provide a battery of model systems that will be useful for studying mechanisms of human oral carcinogenesis.
Carcinogenesis 1995 Oct
PMID:Characterization of human buccal epithelial cells transfected with the simian virus 40 T-antigen gene. 758 60

The regulatory elements of the human keratin K1 gene have been used to target expression of the v-Ha-ras oncogene exclusively in the epidermis of transgenic mice. We developed 12 transgenic mouse lines that express the HK1.ras transgene, producing epidermal hyperplasia in neonates and hyperkeratosis in juveniles. Eventually this skin phenotype diminished but with time adult animals developed papillomas that could persist or regress. The rate and frequency of tumorigenesis appeared to be limited, which suggests that v-Ha-ras requires a second or even third event to elicit and maintain a benign phenotype in transgenic mice. Since in certain transgenic lines papillomas appeared at wound sites, it appears that the promotion stimulus from wounding may be a second event. We envision that such transgenic mice that express v-Ha-ras in the epidermis will become a powerful model for assessing how environmental and molecular factors affect the process of multistage skin carcinogenesis in vivo, as well as a model for evaluating novel therapeutic protocols.
 ...
PMID:Induction of epidermal hyperplasia, hyperkeratosis, and papillomas in transgenic mice by a targeted v-Ha-ras oncogene. 768 Dec 93

Squamous carcinomas of both human and rodent origin can undergo a transition to a more invasive, metastatic phenotype involving reorganization of the cytoskeleton, loss of cell adhesion molecules such as E-cadherin and acquisition of a fibroblastoid or spindle cell morphology. We have developed a series of cell lines from mouse skin tumors which represent different stages of carcinogenesis, including benign papillomas, and clonally related squamous and spindle carcinomas derived from the same primary tumor. Some spindle cells continue to express keratins, but with a poorly organized keratin filament network, whereas in others no keratin expression is detectable. All of the spindle cells lack expression of the cell adhesion molecule E-cadherin and the desmosomal component desmoplakin. Loss of these cell surface proteins therefore appears to precede the destabilization of the keratin network. At the genetic level, it is not known whether such changes involve activation of dominantly acting oncogenes or loss of a suppressor function which controls epithelial differentiation. To examine this question, we have carried out a series of fusion experiments between a highly malignant mouse skin spindle cell carcinoma and cell lines derived from premalignant or malignant mouse skin tumors, including both squamous and spindle carcinoma variants. The results show that the spindle cell phenotype as determined by cell morphology and lack of expression of keratin, E-cadherin, and desmoplakin proteins, is recessive in all hybrids with squamous cells. The hybrids expressed all of these differentiation markers, and showed suppression of tumorigenicity to a variable level dependent upon the tumorigenic properties of the less malignant fusion partner. Our results suggest that acquisition of the spindle cell phenotype involves functional loss of a gene(s) which controls epithelial differentiation.
 ...
PMID:The conversion of mouse skin squamous cell carcinomas to spindle cell carcinomas is a recessive event. 768 80

Proliferation of stromal cells is a common occurrence in experimentally induced hepatocarcinogenesis in fish. However, the role of these cells in fish hepatic injury and neoplasia is unknown. To better understand the biology of the cells comprising the hepatic stroma, livers from medaka (Oryzias latipes) experimentally induced by diethylnitrosamine or methylazoxymethanol acetate were labeled with keratin, actin, and desmin antibodies. The distribution of these proteins in hepatocellular carcinoma, cholangiocarcinoma, spindle cell proliferative lesions, and spongiosis hepatis was assessed, including three peritoneal sarcomas for comparison. Ductular epithelial cells in cholangiocarcinoma were positive for keratin, with desmin and actin positive ductular walls. Presumptive perisinusoidal cells in primarily trabecular and schirrous hepatocellular carcinoma were also actin positive. Only one spindle cell proliferative lesion was positive for any of the antibodies (desmin), and this lesion was morphologically distinct from others in the same category. Spongiosis hepatis, the peritoneal sarcomas, and normal perisinusoidal and other stromal cells were negative for these proteins. Since actin and desmin can be alternatively or coexpressed by mammalian perisinusoidal cells in association with hepatic fibrosis and neoplasia, the present studies suggest these proteins may serve as functional markers of hepatic stromal cells in fish as well.
Carcinogenesis 1995 May
PMID:Expression of actin and desmin in experimentally induced hepatic lesions and neoplasms from medaka (Oryzias latipes). 776 65

This study investigated the value of an immunohistochemical demonstration of placental glutathione S-transferase (GST-P) and a histochemical demonstration of gamma-glutamyl transpeptidase (GGT) for the detection of putative preneoplastic lesions and squamous cell carcinomas in the Syrian golden hamster buccal pouches treated with 7,12-dimethylbenz[a]anthracene (DMBA). The results showed that GST-P foci appeared earlier than GGT foci, that the GST-P foci were much more numerous than GGT foci and that most of the GGT positive foci were GST-P positive. All tumors stained strongly positive for GST-P. Only 62.5% of tumors stained for GGT and the staining was usually weak and involved only the superficial layer of the epithelium or keratin, suggesting that the enzyme activity in the basal cells had decreased with formation of neoplasms. The length percentage of basal cells that were GST-P positive increased rapidly during the experiment and by week 12, 25% of the basal cells exhibited GST-P staining. Such rapid expansion of the putative initiated cells may explain the early development of chemically induced invasive squamous cell carcinoma (weeks 10-12) in 100% of hamsters.
Carcinogenesis 1994 Jan
PMID:The value of placental glutathione S-transferase and gamma-glutamyl transpeptidase as markers of altered foci during hamster pouch carcinogenesis. 790 3

Transfection of primary human cervical epithelial (HCE) cells with full-length HPV type 16 and 18 DNAs resulted in cell lines that could grow continuously. Four HPV DNA-immortalized cell lines were established. Morphologically the immortalized cells resembled primary HCE cells. Electron microscopy showed that they contained desmosomes and keratin filaments, which are characteristic structural components of epithelial cells. Each cell line had a unique integration pattern of HPV DNA but the transcription patterns were similar in the 3 HPV 16 DNA-immortalized cell lines. The expression patterns of viral DNA in the HPV 18 DNA-immortalized cell line were similar to that in HeLa cells, suggesting transcription of mainly early viral genes. The cell lines, unlike HeLa and SiHa carcinoma cells, did not form tumors in nude mice or grow in soft agarose, but collagen raft culture indicated that the immortalized cell lines had lost the capacity of normal differentiation compared with primary HCE cells. Morphologically, the aberrant differentiation of the immortalized cells showed great resemblance to cervical intra-epithelial neoplasia. The altered pattern of growth and differentiation of human cervical epithelial cells transfected by HPV 16 and 18 DNAs is in agreement with the view that HPV types 16 and 18 play an important role at an initial step of human cervical epithelial carcinogenesis but that co-carcinogenic factors are necessary for full malignant transformation in vivo.
 ...
PMID:Altered growth behavior of human cervical epithelial cells transfected by HPV type 16 and 18 DNA. 807 58

Epidemiological studies have shown that inhalation of radon is associated with an increased risk for bronchogenic carcinoma in uranium miners. These alpha-emitting radon daughters also represent the largest component of background radiation to the general public. In the present study, the oncogenic transforming effects of single versus multiple doses of radon-simulated alpha-particles were examined using human papillomavirus-immortalized human bronchial epithelial cells. Endpoints such as growth kinetics, resistance to serum and 12-O-tetradecanoylphorbol-13-acetate-induced terminal differentiation, anchorage-independent growth and tumorigenicity in nude mice were used to assess the various stages of transformation in the bronchial epithelial cells. We show here, for the first time, that immortalized human cells in culture can be malignantly transformed by a single 30 cGy dose of alpha-particles. Transformed cells produced progressively growing subcutaneous tumors upon inoculation into athymic nude mice. Immunofluorescent staining of keratin and isozyme analysis of the cell lines subsequently generated from these tumors indicated that the cells were of human epithelial origin. Analysis of genomic DNA from the tumorigenic cell lines using PCR amplification and restriction enzyme analysis demonstrated no point mutation at either codon 12/13 or 61 in any of the ras oncogenes examined (K-, N- and H-ras). This system provides an opportunity to study the cellular and molecular changes at the various stages in radiation carcinogenesis involving human cells.
Carcinogenesis 1994 Mar
PMID:Malignant transformation of human bronchial epithelial cells by radon-simulated alpha-particles. 811 24

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.
 ...
PMID:Characterization of cell lines derived from formaldehyde-induced nasal tumors in rats. 814 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>