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

In this review, we focus on a number of developments pertaining to lung cancer diagnosis, entirely restricted to those parameters assessable by light microscopy. A number of discrete areas of interest stand out in 1996 related to the pathology of lung cancer. Aberrant p53 expression continues to be debated as an independent prognostic factor in nonsmall cell carcinoma. Neuroendocrine differentiation may be an independent prognostic factor in nonsmall cell carcinoma and new associations with the protein product of the bcl-2 oncogene have been described. Angiogenesis continues to arise as a predictor of metastatic potential in lung cancer. Finally, we review conceptual aspects of carcinogenesis from atypical adenomatous hyperplasia to bronchioloalveolar carcinoma, in addition to a variety of individual tumor-related issues associated with progression, response to chemotherapy, and survival.
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PMID:Pathology of lung cancer. 926 9

Overexpression of p53 is considered to be predictive of mutations of the p53 gene. Exposure-specific mutations of the p53 gene have been described for cancers at different sites. An association between p53 mutation/overexpression and smoking has been described in early stage bladder cancer, but results were conflicting. We have conducted a study on 131 bladder cancer cases, considering p53 expression and smoking habits in an area where the use of air-cured tobacco, rich in carcinogenic arylamines, is common. The study suggests that the use of air-cured tobacco induces p53 overexpression (possibly via mutation) in early stage-low grade bladder cancer, more frequently than flue-cured tobacco (odds ratios = 3.4, 95% confidence intervals 0.9-13 in stage 1; odds ratios = 24, 95% confidence intervals 1.1-519 in stage 1, grade 1). However, all the excess associated with air-cured tobacco was concentrated in recurrences. When available, the biopsies of recurrent cases with early-stage disease were re-examined and all showed p53 expression at first diagnosis (with 10-50% of cells positive) (n = 5). It is hypothesized that exposure to tobacco-related chemicals increases the risk of recurrences via p53 overexpression/mutation. Expression of the bcl-2 gene was detected in only 2 out of 13 p53-positive smokers.
Carcinogenesis 1997 Aug
PMID:Tobacco smoke, recurrences, and p53/bcl-2 expression in bladder cancer. 927 45

An organotypic, tridimensional cell culture, also called a raft system, was used to study the influence of fibroblasts on epithelial carcinogenesis in a cell line derived from laryngeal squamous cell carcinoma and harboring a mutated p53. Differences between the effects of normal fibroblasts and those of tumor-derived fibroblasts were compared by means of fibroblasts taken from the normal skin and from the tumor of a cancer patient and cultivated with epithelial carcinoma cells in an organotypic culture. To study cell contact-mediated changes, the fibroblasts were either simply embedded in collagen matrix or additionally brought into direct contact with epithelial cells. Control epithelial cells were cultivated without any fibroblasts in an organotypic model. A protein panel [p53, p21, PCNA, bcl-2, Ki67, total cytokeratin (CK), CK 8, CK 10, CK 17, CK 18, CK 19, vimentin] involved in cell cycling and epithelial differentiation was assessed immunocytochemically in all organotypic cultures with fibroblasts, in tumor cells cultivated as a monolayer, and in the original tumor sample. The most dysplastic phenotype was obtained when tumor-derived fibroblasts were used in direct contact with epithelial cells, whereas the most benign phenotype was seen when skin fibroblasts had no contact with them. The intensive staining seen for p53 can be explained by p53 mutations also reflecting the weak expression of p21 and abundant expression of PCNA. The intensive Ki67 staining seen in all sections paralleled that of PCNA and marked active cellular proliferation. The CK staining pattern seen in cultured epithelia toward embryonic CKs, CK 8 and CK 18, suggested a simple epithelial phenotype. CK 19 was found only in the epithelium where no direct contacts had occurred. Vimentin expression increased when the raft epithelium was shifting toward a more benign phenotype. The results stress the importance of the origin of fibroblasts as well as the role of direct cellular contacts in modifying the epithelial phenotype even when the epithelial cells are malignant.
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PMID:Fibroblasts can modulate the phenotype of malignant epithelial cells in vitro. 928 67

The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras-stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras-transfected intestinal epithelial cell clones (IEC-ras) to examine the role of epidermal growth factor (EGF)-related peptides in the behavior of IEC-ras. Overexpression of EGF family growth factors (transforming growth factor alpha, heparin-binding EGF-like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC-ras compared with control cells. IEC-ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG 1478, abolished the increased proliferation of IEC-ras. Heparitinase and chlorate also prevented increased proliferation of IEC-ras. Additionally, IEC-ras expressed more bcl-2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG 1478 suppressed bcl-2 expression and inhibited resistance to apoptosis of IEC-ras. Heparitinase and chlorate had effects similar to those of AG 1478. Our data indicate that heparin-binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras-stimulated intestinal epithelial cells.
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PMID:Role of heparin-binding EGF-related peptides in proliferation and apoptosis of activated ras-stimulated intestinal epithelial cells. 939 76

To gain insight into the neoplastic progression of Barrett's epithelium (BE), we assessed the expression of Ki-67 antigen and bcl-2 protein and the occurrence of apoptosis in metaplastic epithelium with and without regenerative atypia (RA), low-grade dysplasia, and high-grade dysplasia (HGD). To refine our understanding of the epithelial kinetics during the carcinogenic sequence, we performed separate analyses of four different mucosal regions, i.e., surface epithelium, upper and lower crypts, and glands. Expansion of the proliferative zone was noted in dysplasia and to a mild degree in epithelium with RA but not in BE. Expression of bcl-2 protein was seen in the proliferative zone in BE and showed a significant increase in RA but was essentially absent in HGD. Numerous apoptotic nuclei were seen in HGD, decreasing along the cellular gradient from gland to surface. We noted a positive correlation between Ki-67 and bcl-2 in the proliferative zone of BE and RA, whereas a negative correlation was present on the surface of RA. Ki-67 was positively correlated with apoptosis in the lower crypts of HGD. bcl-2 expression was negatively correlated with apoptosis in all regions except the proliferative zone of dysplastic areas. Our findings suggest that overexpression of bcl-2 protein is not an important step in the carcinogenesis of BE. We confirm the upward shift of cellular proliferation in dysplastic epithelia. Apoptosis that is increased in dysplasia might play a significant role in carcinogenesis by restraining increased cellular proliferation.
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PMID:Cellular kinetics in Barrett's epithelium carcinogenic sequence: roles of apoptosis, bcl-2 protein, and cellular proliferation. 943 64

Over 90% of all cervical carcinomas originate from hyperplastic reserve cells of the endocervix. When cell cycles of the pluripotent reserve cells are shortened or damaged by hormonal overstimulation or toxic chemicals, DNA repair after viral infection is no longer possible. The immortalized cells may then become malignant with precancerous and carcinomatous differentiation to squamous, adenosquamous or adenocarcinomas. To determine the type of HPV infection is clinically important for estimating prognosis and for planning further therapy. In recent years HPV 18-associated endocervical adenocarcinomas have increased considerably in number as compared with squamous cell carcinomas. In endometrial carcinomas the estrogen-stimulated endometrioid types must be distinguished from the gestagen-stimulated mucinous, clear-cell and serous-papillary types because prognosis as well as operative and adjuvant therapy differ considerably. The endometrioid carcinomas and their preceeding atypical hyperplasia are frequently associated with bcl-2, c-myk and c-ki-ras oncogenes. The mixed Muellerian types, in contrast, and their preceeding mucinous, clear-cell and serous-papillary metaplasias very often show genetic defects, LOH, mutations, amplifications and deletions, especially of p53. The endometrial carcinomas occurring in the reproductive age period are of endometrioid type and frequently present microsatellite instabilities. In rapidly proliferating tissues like the endometrium there appears to be a close correlation between functional and neoplastic changes. A simple explanation for that might be found in the greatly enhanced mitotic activity in a hormonally stimulated endometrium with shortening of cell cycles, leaving insufficient time for DNA repair. Since, however, carcinogenesis is a multi-factorial event, to correlate endometrial function with morphology can contribute only one aspect to the understanding of neoplastic change. In discussing hormonal function it is important to realize that the endocervix and the endometrium differ not only in their cellular structure, but they react antagonistically to hormonal stimulation: excessive (endogenous or exogenous) estrogen results in hyperproliferation of endometrial epithelial cells, but in the cervix in differentiation of the endocervical cells with mucus production. Extensive synthetic gestagens lead to hyperproliferation of endocervical epithelial cells (reserve cells as well as glandular epithelial cells), but in the endometrium cause atrophy (see Table 1).
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PMID:Histopathology of functional and neoplastic changes in cervix and endometrium. 947 76

Nonmelanoma skin cancers (NMSC) are among the most common malignancies in the world. Typically, these neoplasms grow slowly and are comparatively indolent in their clinical behavior. The most frequent molecular alterations implicated in the pathogenesis of these neoplasms involve genes known to be regulators of cell death including p53, Ha-ras and bcl-2. In order to evaluate the significance cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1.bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic HK1.bcl-2 protein was expressed at high levels specifically in the epidermis extending from the stratum basale through the stratum granulosum. The epidermis of HK1.bcl-2 mice exhibited multifocal hyperplasia without associated hyperkeratosis and aberrant expression of keratin 6. The rate of proliferation was similar in HK1.bcl-2 and control epidermis although suprabasal BrdUrd incorporating cells were present only in HK1.bcl-2 skin. Keratinocytes from the HK1.bcl-2 mice were significantly more resistant to cell death induction by U.V.-B, DMBA, and TPA, compared to control keratinocytes. Furthermore, papillomas developed at a significantly greater frequency and shorter latency in the HK1.bcl-2 mice compared to control littermates following initiation with DMBA and promotion with TPA. Together these results support a role for bcl-2 in the pathogenesis of NMSC.
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PMID:Human keratin-1.bcl-2 transgenic mice aberrantly express keratin 6, exhibit reduced sensitivity to keratinocyte cell death induction, and are susceptible to skin tumor formation. 948 76

Disordered balance between proliferation and apoptosis may contribute to carcinogenesis. Thirty-two oral biopsies were collected prospectively: 10 normal (N), 10 leukoplakia (dysplasia, D = 5; hyperplasia, H = 5) and 12 squamous cell carcinoma (C: 11). Distant normal tissue was also collected (HN, DN, CN). Based on counts of 1000 cells/slide, mitotic (MI), apoptotic (AI) and proliferating cell nuclear antigen (PCNA: PI) indices were calculated and bcl-2 expression recorded. AI correlated with MI (P < 0.001), but not PI or bcl-2 expression. PCNA was higher in H and HN than other groups (P < 0.0001). bcl-2 was reduced in C and CN (P < 0.001). Peak mitosis shifted basally in dysplasia, whilst peak apoptosis remained unaltered. These data confirm topographical alterations in proliferation relative to apoptosis in dysplasia of the oral cavity. Reduced bcl-2 in carcinoma and related 'normal' epithelium was unexpected, and may contribute to the high incidence of metachronous carcinomas in these patients.
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PMID:Apoptosis, mitosis, PCNA and bcl-2 in normal, leukoplakic and malignant epithelia of the human oral cavity: prospective, in vivo study. 950 26

In a previous paper, we suggested that tamoxifen (TAM)-mediated endometrial carcinogenesis may not involve estrogenic pathways because of random estrogen receptor positivity among endometrial carcinomas with and without TAM treatment for breast cancer. DNA adduct formation (reported in rat liver and human endometrium) was considered to be a more plausible mechanism for TAM-mediated carcinogenesis. To examine the reported correlation between DNA adduct formation and p53, the present study examined p53 expression in the endometrial carcinomas reported in the previous study. Seven endometrial adenocarcinomas associated with long-term TAM treatment for breast carcinoma and 4 carcinomas without TAM treatment but with history of breast carcinoma were immunohistochemically investigated for nuclear p53 expression. The bcl-2 product was also examined. Diffuse and intense nuclear reactivity for p53 protein was present in only one TAM-related case. Essentially, no differences were observed in the bcl-2 staining patterns of TAM-treated and -untreated patients with cancer. Thus, p53 overexpression in endometrial carcinomas occurring in patients with breast cancer seems to be not specific for TAM-treated patients, and, if DNA adduct formation has any role in this type of endometrial carcinogenesis, it may not be related preferentially to p53 gene alteration. Further studies are needed to understand the precise mechanism(s) of the endometrial carcinogenesis.
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PMID:Random nuclear p53 overexpression pattern in tamoxifen-mediated endometrial carcinoma. 955 10

Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.
Carcinogenesis 1998 Apr
PMID:Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. 960 Mar 37


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