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

The purpose of this study was to assess the effect of alcohol on oral epithelium by quantifying epithelial compartment thicknesses after chronic alcohol ingestion with the use of a computerized planimetry system. A 10% solution of absolute alcohol in water was given as the sole source of drinking fluid to young adult Syrian hamsters over a period of 9 months. Quantitative histologic analysis showed significant atrophy of the posterior lateral tongue epithelium. The epithelium of the dorsal tongue showed an increase in the thickness percentage of keratin. No significant change was found in the ventral aspect of the tongue epithelium. It was concluded that such alcohol-related atrophy may render the lateral margins of the posterior tongue more susceptible to carcinogenesis.
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PMID:Oral epithelial response to experimental chronic alcohol ingestion in hamsters. 828 79

We established a human osteoblastic cell line immortalized by simian virus 40 (SV40) in vitro, and designated it SV-HFO. Immunocytochemically, the cells were positive for SV40 large T-antigen, vimentin and osteocalcin, but negative for keratin and epithelial membrane antigen. The cells had characteristic morphologic and ultrastructural features of osteoblasts, produced alkaline phosphatase, and synthesized osteocalcin, the levels of which were elevated by treatment of the cells with 1a,25-dihydroxyvitamin D3. The cells proliferated and showed such osteoblastic properties even under serum-free conditions. The cells grew in soft agar, but did not form tumors when transplanted into athymic nude mice. Karyotypic analysis by the Q-banding technique showed that these cells were of human origin. The SV-HFO cell line is expected to serve as a suitable model for studying metabolism and carcinogenesis in human bone.
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PMID:Establishment and characterization of a simian virus 40-immortalized osteoblastic cell line from normal human bone. 838 78

7,12-Dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis of the hamster buccal pouch has been an excellent model for the study of squamous cell carcinogenesis in human head and neck cancer. Using a differential hybridization of cDNA cloning technique, we isolated a cDNA clone that is expressed in N-ras-transformed PA-1 cells but poorly expressed in non-tumorigenic PA-1 cells; the cDNA codes for the human ribosomal S2 gene product. To define the involvement of S2 gene expression during carcinogenesis in this animal model, we used in situ hybridization technique with non-radioactive digoxigenin-11-dUTP-labeled cDNA. S2 gene was expressed at low levels in basal and suprabasal cell layers of the epidermis in the control, but showed marked elevation throughout the epidermis other than the keratin layer in samples treated for 4 or 8 weeks; S2 was highly expressed in all malignant squamous cell carcinoma cells resulting from DMBA treatment for 16 weeks. As tumors progress from normal epithelium to squamous cell carcinomas, mRNA of the S2 gene was not only elevated sequentially, but also demonstrated the marked heterogeneity among transformed populations, particularly in dysplastic lesions and squamous cell carcinomas. The S2 gene was expressed in a stage-specific manner in the hamster tumor model; S2 could be useful as a neoplastic marker for the detection of certain epithelial origin of tumors and premalignant lesions as well.
Carcinogenesis 1993 Jan
PMID:Activation of ribosomal protein S2 gene expression in a hamster model of chemically induced oral carcinogenesis. 842 67

The effects of dehydroepiandrosterone (DHEA) with/without ribonucleoside (RNs) supplementation on butylated hydroxyanisole (BHA) bladder-tumor promotion and forestomach carcinogenesis were investigated. Male F344 rats were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and then received basal diet or diet containing BHA, DHEA, a mixture of RNs, BHA + DHEA or BHA + DHEA + RNs for 32 weeks. The occurrences of papillomas and carcinomas in the urinary bladder were increased in the groups given BHA or BHA + DHEA + RNs, as compared with control group values. In comparison with the BHA group, the BHA + DHEA group incidences and numbers of these tumors were decreased. However, the incidence and multiplicity of papillomas in the group given BHA + DHEA + RNs were again elevated. DNA synthesis levels in normal-appearing bladder epithelium, but not tumor cells, were closely correlated with the observed level of promotion in most groups. The case of DHEA alone proved exceptional in that DNA synthesis was markedly decreased without any significant influence on lesion development. In the forestomach, DHEA, which itself was associated with slight although non-significant hyperplasia, enhanced BHA-induced epithelial lesions, characterized by marked basal-cell proliferation and keratin-cyst formation, independently of additional RNs administration. Our results suggest that the anti-promoting effects of DHEA in the bladder depend on a deficiency in the pentose phosphates necessary for production of nucleosides. Organ-specific modulation is indicated by the enhancing effects of DHEA on BHA-induced forestomach hyperplasia.
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PMID:Inhibition by dehydroepiandrosterone of butylated hydroxyanisole (BHA) promotion of rat-bladder carcinogenesis and enhancement of BHA-induced forestomach hyperplasia. 844 7

Keratoacanthomas are benign skin tumors that grow rapidly but eventually regress. They occur most commonly in sun-exposed skin and are histologically remarkably similar to squamous cancers. Since mutations of the p53 tumor suppressor gene are found frequently in cutaneous squamous cell carcinomas, we hypothesized that p53 mutations might contribute to the development of keratoacanthomas. To address this question, we did p53 immunohistochemistry with a polyclonal rabbit antiserum, CM-1, that binds both mutant and wild-type p53 proteins. Although wild-type p53 protein degrades rapidly and is generally undetected by immunohistochemistry, mutant p53 protein has a longer half-life and accumulates to detectable levels. We tested 26 formalin-fixed keratoacanthomas and 4 normal skin biopsies. Positive nuclear staining was detected in 20 of 26 (77%) of the keratoacanthomas and in none of the normal skin samples. Nuclear staining occurred in the outermost layer of the neoplasms and not in the keratin-filled central cores. Since nuclear p53 protein within a cutaneous squamous cell carcinoma usually correlates with missense mutation, these data suggest that p53 mutations contribute to the development of this benign neoplasm. The histologic similarity to squamous cell carcinoma and the accumulation of p53 protein suggest progression toward malignancy, but the invariable regression of these tumors suggests an arrest at some point in multistage carcinogenesis. If this model is correct, then genetic analysis of keratoacanthomas may provide clues to the later stages of squamous carcinogenesis including local invasion and metastasis.
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PMID:Quantitative image analysis of p53 protein accumulation in keratoacanthomas. 860 Jul 91

High-risk human papillomaviruses (HPVs), including type 16, have been identified as factors in cervical carcinogenesis. However, the presence and expression of the virus per se appear to be insufficient for carcinogenesis. Rather, cofactors most likely are necessary in addition to viral gene expression to initiate neoplasia. One candidate cofactor is prolonged exposure to sex hormones. To examine the possible effects of estrogen on HPV-associated neoplasia, we treated transgenic mice expressing the oncogenes of HPV16 under control of the human keratin-14 promoter (K14-HPV16 transgenic mice) and nontransgenic control mice with slow release pellets of 17beta-estradiol. Squamous carcinomas developed in a multistage pathway exclusively in the vagina and cervix of K14-HPV16 transgenic mice. Estrogen-induced carcinogenesis was accompanied by an incremental increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-HPV16 mice. Expression of the HPV transgenes in untreated transgenic mice was detectable only during estrus; estrogen treatment resulted in transgene expression that was persistent but not further upregulated, remaining at low levels at all stages of carcinogenesis. The data demonstrate a novel mechanism of synergistic cooperation between chronic estrogen exposure and the oncogenes of HPV16 that coordinates squamous carcinogenesis in the female reproductive tract of K14-HPV16 transgenic mice.
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PMID:Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. 861 Jan 45

In a previous paper (Barboro et al., 1993, Biophys. J. 65, 1690-1699) we have shown that cancer development in the resistant hepatocyte model of Solt and Farber is characterized by the progressive unfolding of the higher-order structure of chromatin. A possible functional role of decondensation phenomena in cell transformation cannot be ruled out. Genetic activation involves the relaxation of the superstructure of chromatin, which may be, at least in part, modulated by its interaction with the nuclear matrix. Moreover, recent observations suggest that gene expression can be stimulated by alterations in the organization of the cytoskeleton. Therefore, we have characterized the changes in composition that the nuclear matrix-intermediate filament complex undergoes during the evolution of rat hepatocyte nodules. Dramatic changes in the expression of both the nuclear matrix and intermediate filament proteins occur during transformation; they are, however, related in a different way to the stages of carcinogenesis. Several new nuclear matrix proteins appear in early nodules, isolated 9 weeks after initiation. The subsequent evolution of persistent nodules is also characterized by discrete changes in the composition. Thus, the new synthesis of nuclear matrix proteins reflects the emergence of successive cellular populations, in line with the recent finding that a subset of components of the nuclear matrix is cell type-specific. In contrast, intermediate filament proteins undergo continuing changes. A new keratin with apparent molecular weight of 39 kDa, analogous to human keratin 19, appears in early nodules, and its expression steadily increases up to the 32nd week from initiation; at the same time, the amount of the proteolytic fragments of keratins A and D increases sharply. These findings suggest that the inappropriate expression of keratin 19 may be involved in the epigenetic activation of new cellular programs, through the rearrangement of the cytoskeleton which in turn may perturb nuclear matrix function.
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PMID:Changes in the cytoskeletal and nuclear matrix proteins in rat hepatocyte neoplastic nodules in their relation to the process of transformation. 866 Sep 20

Human papillomavirus (HPV) has been implicated in the etiology of oral and cervical cancers. Normal oral epithelial cells at passage two were infected with recombinant retrovirus containing the E6/E7 open reading frames of HPV type 16. The G418-selected cells that were immortalized and express HPV 16 E6/E7 have been in culture for over 4 years and 350 passages. In contrast, the normal oral epithelial cells did not survive the culture environment beyond 7 to 9 passages. Fifteen clones were selected from the pooled population. By Northern blot analysis all clones demonstrated the presence of E6solidusE7 genes. Keratin expression of both normal and immortalized oral epithelial cells was studied in organotypic culture. Both cell types were positive with antibodies AE1, AE3, and 34BE12. Both were focally positive with AE8, which stains for keratin 13 (specific for oral and esophageal epithelial cells). The normal control cells were focally positive for filaggrin, while the HPV 16-immortalized cells (IHGK cells-immortalized human gingival keratinocytes) were negative. The IHGK cells were strongly positive with KS19.1, which stains the embryonal keratin K19, an indicator of premalignant or malignant changes, while the normal control cells were only lightly and focally positive. In conclusion, we present an oral epithelial cell line successfully immortalized with HPV E6/E7 which will facilitate further research on the involvement of HPV in oral carcinogenesis.
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PMID:HPV immortalization of human oral epithelial cells: a model for carcinogenesis. 866 Sep 52

To investigate the effect of p53 tumor suppressor gene loss in the mouse skin model of multistage carcinogenesis, p53 knockout mice, generated by gene targeting (p53 -/-), were mated to transgenic mice expressing v-rasHa (HK1.ras), v-fos (HK1.fos), or human transforming growth factor alpha+HK1.TGFalpha) exclusively in the epidermis, by means of a keratin K1-based targeting vector (HK1). HK1-p53 transgenic progeny expressing wild-type p53 alleles (p53 +/+) or hemizygous for the p53 knockout allele (p53+/-) were identical to parental HK1 lines and exhibited neonatal epidermal hyperplasia or wound-associated hyperplasia in adults, together with spontaneous or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced benign papillomas. Mating to p53-/- did not lead to the expected tumorigenesis in adults. Instead, whereas HK1.ras or HK1.TGFalpha transgenic mice null for p53 (HK1.ras-p53-/- and HK1.TGFalpha-p53-/-, respectively) retained the neonatal epidermal hyperplasia phenotype, in adults, spontaneous and TPA-promoted papilloma formation was blocked. Similarly, wound-associated epidermal hyperplasia/hyperkeratosis, a hallmark of adult HK1.fos phenotypes, was completely absent in HK1.fos-p53 -/- mice. Histological, immunofluorescence, and bromodeoxyuridine labeling analysis of neonatal or adult epidermis in HK1-p53 transgenic genotypes +/+, +/-, and -/- for p53 revealed no obvious differences in morphology, expression of keratinocyte differentiation markers, or mitotic index attributed to p53 loss. To determine whether the paradoxical absence of papillomas centered on up-regulation of p53 target genes, WAF1/CIP1/p21 RNA expression levels were examined in TPA promotion experiments. WAF1/CIP1/p21 expression increased in response to TPA promotion in all HK1-p53 transgenic genotypes regardless of p53 status. However, in HK1-p53 null genotypes, although TPA-induced, p53-independent WAF1/CIP1/p21 expression was observed, no large increase in expression was associated with the observed paradoxical tumorigenesis block. These data suggest that epidermis is somewhat resistant to the neoplastic effects of p53 loss, possibly possessing several compensatory systems. Alternatively, there may be a requirement forp53 expression in response to TPA or a wound-promotion stimulus in mouse epidermis.
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PMID:Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha. 881 35

The aim of the present study was to investigate the sequential expression of placental glutathione S-transferase (GST-P) during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch squamous cell carcinogenesis. Both immunohistochemical and immunoblot analyses were employed to detect the epithelial GST-P in hamster buccal pouch mucosa over a 15-week treatment regimen. No GST-P positivity was demonstrated in the pouches of the control group. GST-P positive cells were first noted as early as 1 week after DMBA applications. A gradual increase in both the mean number and size of GST-P-positive foci was noted in the first 12 experimental weeks, but a plateau level was approached thereafter. The early GST-P-positive-area were located in the basal layer, or occasionally in the middle layer, of DMBA-treated hamster buccal pouch mucosa. Later, the stained sites became enlarged and were scattered randomly in different layers or in the whole thickness of the dysplastic and non-dysplastic epithelium. The keratin layer was only occasionally involved during the first 12 weeks of DMBA treatment but positive staining was more noticeable in the final stage of the experiment. Both exophytic (8-12 weeks) and invasive (13-15 weeks) squamous cell carcinomas showed GST-P positivity, in both cytoplasmic and nuclear components. Immunoblot analysis revealed no band in the crude tissue extracts of the control pouches whereas GST-P polypeptide of molecular weight approximately 26 kD was demonstrated in DMBA-treated pouches over the whole 15-week treatment regimen. Results of the present work indicate that GST-P is a stable and persistent label for almost all of the carcinogen-altered cells during DMBA-induced hamster buccal pouch carcinogenesis. Immunohistochemically detectable GST-P may be a potential marker throughout oral chemical carcinogenesis.
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PMID:Sequential expression of placental glutathione S-transferase (GST-P) during DMBA-induced hamster buccal pouch squamous cell carcinogenesis. 889 54


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