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

N-Nitrosomethylbenzylamine (NMBA) is a potent esophagus-specific carcinogen that has been utilized extensively in the study of esophageal carcinogenesis in rats. While many studies have focused on the pathogenesis of NMBA-induced esophageal tumors, the tumorigenicity of NMBA itself has not been thoroughly investigated in any single, systematic dose-response study. Therefore, in this study we evaluated NMBA tumorigenicity in rats following various short-term s.c. treatment regimens with the aim of developing an abbreviated treatment protocol which could be used in future studies. To assess the possible correlation of basal cell proliferation with NMBA tumorigenicity, we evaluated the expression of proliferating cell nuclear antigen (PCNA) in both control and NMBA-treated rats. In rats which received a cumulative NMBA dosage of 7.5 mg/kg over the course of 5 weeks, tumor incidence and multiplicity were as follows: 40% with 0.4 +/- 0.3 tumors/rat at week 10; 100% with 2.2 +/- 1.0 tumors/rat at week 20; and 100% with 2.3 +/- 1.0 tumors/rat at week 30. These rats exhibited marked increases in basal cell labeling, with indices that were 1.5- to 1.8-fold higher than controls. NMBA treatment regimens of shorter duration with equivalent or higher cumulative dosages were generally ineffective in producing esophageal tumors, even though significantly elevated levels of basal cell proliferation occurred. Together, these findings indicate that the duration of NMBA treatment is of critical importance in the tumorigenic potential of the carcinogen.
Carcinogenesis 1995 Feb
PMID:Evaluation of dose and treatment duration on the esophageal tumorigenicity of N-nitrosomethylbenzylamine in rats. 785 57

Six-week-old male F344 rats were divided into 4 groups. Rats in Groups 1 (n = 16) and 3 (n = 14) received a s.c. injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN) (2800 mg/kg) in experimental week 1 while rats in Groups 2 (n = 5) and 4 (n = 5) received saline. From weeks 2-20, all rats were given an iodine deficient (I-def) diet and tap water. Groups 1 and 2 were killed for the measurements of thyroid-stimulating hormone (TSH), thyroxine (T4), the maximum thyroid width (MTW), thyroid weight, morphology, morphometrics and proliferating cell nuclear antigen (PCNA) labeling index (LI). The thyroids of the rats in Group 3 and 4 were surgically exposed and the MTWs were measured. These latter rats were given basal diet for 6 weeks to recover from iodine deficiency, and then killed for the same measurements. Thyroid nodular lesions in Group 1 rats were classified into five categories (NL0, NL1, NL2, NL3 and NL4) based upon incremental cellular and structural atypia. Two types of regressive nodules (NL'0 and NL'1+2) were identified in the recovered rats as the regressed form of NL0, NL1 and NL2 lesions. NL3 and NL4 nodules were seen in Groups 1 and 3. The mean number of combined NL0, NL1 or NL2 lesions was 28.44 +/- 6.12 nodules per rat (NPR) in Group 1 rats and the mean number of NL'0 and NL'1+2 lesions was 28.07 +/- 13.05 NPR in Group 3 rats. The mean number of NL3 or NL4 lesions was 1.70 NPR in Group 1 rats and 3.42 NPR in Group 3 rats. The LIs were NL0 (6.4 +/- 2.5%), NL1 (7.7 +/- 4.4%), NL2 (0.7 +/- 0.3%), NL3 (7.5 +/- 1.3%) and NL4 (14.4 +/- 5.3%) in Group 1 rats and NL'0 (< 0.001%), NL'1 + 2 (< 0.01%), NL3 (9.0 +/- 4.4%) and NL4 (23.3 +/- 17.8%) in Group 3 rats. The thyroid weights of Group 4 rats were 41% of Group 2 rats. The volume fraction (VF) of the non-NL3, non-NL4 areas in Group 3 rats was 40% of that in Group 1 rats. However, the VF of NL3 or NL4 lesions in Group 3 rats was 520% of that of Group 1 rats. In summary, the growth of the NL0, NL1 and NL2 lesions was TSH-dependent, whereas NL3 and NL4 lesions were TSH-independent.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1993 Nov
PMID:Regressive and non-regressive thyroid lesions of the rat induced by single injection of N-bis(2-hydroxypropyl)nitrosamine and iodine deficient diet. 790 19

The effects of magnesium hydroxide were examined on methylazoxymethanol (MAM) acetate-induced c-myc expression and cell proliferation of colonic mucosal epithelium in rats. Rats were divided into four groups and treated as follows: MAM acetate alone (25 mg/kg i.p. injection, five times, once a week for 5 weeks), MAM acetate and feeding of 0.2% magnesium hydroxide in diet, magnesium hydroxide alone and non-treatment. At 4, 8 and 16 weeks after the start of experiment, 10 rats in each group were sacrificed. Magnesium hydroxide inhibited the MAM-induced expression of c-myc proto-oncogene, and also suppressed the increased bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA) labelling indexes induced by MAM acetate in colon mucosa in initiation and post-initiation phase. These results suggest that the anti-carcinogenic effect of magnesium hydroxide on rat colon carcinogenesis induced by MAM acetate may be related to the inhibition of the carcinogen-induced expression of c-myc proto-oncogene and cell proliferation.
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PMID:Inhibitory effects of magnesium hydroxide on c-myc expression and cell proliferation induced by methylazoxymethanol acetate in rat colon. 790 96

The proliferative activity of dysplasia and carcinoma in situ (CIS) in the uterine cervix was examined using proliferating cell nuclear antigen (PCNA) immunostaining and silver-binding argyrophilic nucleolar organizer region (AgNOR) staining. A significant difference in the labeling index of PCNA immunostaining obtained from dysplastic cells in each histopathologic category was demonstrated between severe dysplasia and CIS. There was no significant difference among each category of dysplasia. The frequency of mitotic figures was highest in CIS, followed in decreasing order by severe, moderate, and mild dysplasia, and was closely correlated with the histopathologic classification. There was an intimate correlation between the PCNA and mitotic indexes in severe dysplasia and CIS. However, the mean numbers of AgNORs in each category of dysplasia and CIS were not significantly different, and there was no apparent relationship with the histologic classification. The PCNA index seemed to be a useful means of evaluating proliferative activity in dysplasia and CIS, and especially in distinguishing CIS from severe dysplasia. In addition, the present PCNA index suggests that a considerable alteration of the biologic behavior involving genetic changes occurs during the progression of carcinogenesis from severe dysplasia to CIS. However, AgNOR staining did not appear to reliably represent the proliferative activity in these lesions.
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PMID:The proliferative activity in dysplasia and carcinoma in situ of the uterine cervix analyzed by proliferating cell nuclear antigen immunostaining and silver-binding argyrophilic nucleolar organizer region staining. 791 22

p53 is known to play a central role in the control of cell proliferation and carcinogenesis. In non-small cell lung cancer, however, the clinicopathological studies of p53 have yielded conflicting results. In the current study, we examined 123 non-small cell lung cancers with detailed clinical information, 71 primary and 52 metastatic tumors, using formalin-fixed and paraffin-embedded surgical specimens to show the clinicopathological correlation of the immunohistochemical (DO-7) overexpression of p53. Nuclear specific p53 overexpression appeared in 48 (39%; any number of tumor cells positive) of 123 tumors (35% of primary and 44% of metastatic tumors). The distribution and intensity of staining were variable. Ninety-eight % of all tumors also expressed nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA; PC 10) to a varying degree. In a univariate analysis, both p53 (> 10% of tumor cells positive; n = 11) and PCNA (> 50% of tumor cells positive; n = 32) were associated with shorter survival in the curative intent group (stages I, II, and IIIA) of 63 patients. In a multivariate analysis including all clinicopathological variables, the overexpression of p53 (but not PCNA) was found to be an independent prognostic factor (P2 = 0.0011) in the curative intent group. No correlation was detected between the immunoreactivities and patient characteristics, such as age, gender, or smoking. Double immunohistochemistry of both p53 and PCNA revealed a distinct pattern, whereas its clinicopathological correlation remained elusive. We conclude that p53 overexpression in non-small cell lung cancer (but not PCNA) is independently associated with a shortened survival and may be of prognostic significance in selected patients with earlier stage cancer.
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PMID:Relationship of p53 overexpression and up-regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer. 790 77

We have studied the occurrence and specific features of liver cell dysplasia (LCD) in Chinese patients showing liver cirrhosis with or without hepatocellular carcinoma (HCC). Three types of LCD (SLCD, LLCDo, LLCDe) were morphologically defined, and these types were further analyzed using karyometry, estimation of nucleic acid content and density, and PCNA immunostaining. Features found for three types of LCD were compared with those of normal hepatocytes (NLC), simple regenerating hepatocytes (SRLC), and cells of HCCs covering different grades. The results show that 1) karyometry and nucleic acid parameters allow an objective separation of LCD types both from NLC and SRLC; 2) karyometric features of LLCDe are most close to those of highly differentiated HCCs, whereas nuclear size and chromatin composition of SLCD closely reflect those of poorly differentiated HCCs; 3) the frequency of LCD clusters was higher in cirrhotic livers carrying HCC, being about double for all three LCD types; 4) the highest PCNA labelling occurred in the small cell group of LCD (SLCD), still, however, being smaller than that of simple regenerating hepatocytes. Based on these findings it is suggested that, similar to atypical adenomatous hyperplasia, LCDs of distinct morphotypes may represent precursor lesions for HCC, and some cellular forms may mimick cell types known to occur in experimental carcinogenesis.
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PMID:Three types of liver cell dysplasia (LCD) in small cirrhotic nodules are distinguishable by karyometry and PCNA labelling, and their features resemble distinct grades of hepatocellular carcinoma. 791 90

Expression of transforming growth factor alpha (TGF alpha) was investigated immunohistochemically in preneoplastic and neoplastic hepatocytes induced by the Solt-Farber regimen. Although TGF alpha was almost negative in early lesions comparing carcinogen-altered hepatocytes, it was expressed in approximately 65% of the late lesions. Growth factor localization was predominantly in the cytoplasm or at the bile canalicular membrane within individual lesions, both types being observed at various ratios. Hyperplastic nodules (HPN) predominantly consisting of cells with cytoplasmic type staining showed expansive growth with more abundant expression of EGF receptors (EGFR) and proliferating cell nuclear antigen (PCNA) than those with the membranous localization. The staining patterns of TGF alpha, EGFR and PCNA in hepatocellular carcinomas (HCC) were similar to those of cytoplasmic type growth factor-positive HPN. Western blotting analysis for TGF alpha demonstrated a single 30 kDa protein in lysates of HPN and HCC. Since this protein was broken down to the 6 kDa mature TGF alpha via 20, 16 and 14 kDa forms by treatment with bovine pancreatic elastase, it may represent a physiological precursor. No mature TGF alpha was detected in the conditioned medium of cultured HPN cells, although a small amount of the 30 kDa form was identified. These results suggest that this form of TGF alpha may have an important role in the growth of preneoplastic and neoplastic hepatocytes during rat hepatocarcinogenesis.
Carcinogenesis 1994 Aug
PMID:Abundant TGF alpha precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogen-induced preneoplastic and neoplastic hepatocytes in rats. 791 77

Recently, depressed adenomas (DA) of the colorectum have been frequently detected in Japan. The natural history and carcinogenesis of these DA remain unclear. The histological features and cell kinetics of 13 DA were analyzed, using proliferating cell nuclear antigen (PCNA), and compared with 24 non-depressed adenomas (NDA), 12 non-neoplastic mucosa and 12 adenocarcinomas. The DA had a characteristic architecture when compared with the NDA, as demonstrated by a crowded collection of adenomatous tubules with small diameters. The adenomatous tubules tended to occupy the full thickness of the lamina propria at the center with superficial growth to the periphery. The PCNA-positive cells were mostly restricted to the lower half of the crypts in the non-neoplastic mucosa, and were distributed predominantly across the upper half area of the crypts in both the DA and NDA, whereas they were randomly distributed across any area in the adenocarcinomas. The mean labeling index of PCNA in the DA (43.2%) was significantly higher than that in the non-neoplastic mucosa (26.5%) and NDA (29.3%), but lower than that in the intramucosal component of the adenocarcinomas (70.0%). The DA should be seriously considered as a precancerous lesion because of its unusual histologic architecture and high proliferative activity.
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PMID:Depressed adenoma of the colorectum: analysis of proliferative activity using immunohistochemical staining for proliferating cell nuclear antigen (PCNA). 792 Nov 96

Although the dysregulation of physiological signals and mechanisms controlling cell proliferation has been a major focus in cancer research, recent evidence suggests that explicit evaluation of apoptosis or physiological cell death may be equally important in understanding multistage carcinogenesis. Dietary restriction of rodents is well known to reproducibly retard development of spontaneous and chemically induced tumors. We reasoned that the decrease in metabolic and hormonal trophic factors induced with this intervention could promote selective cell deletion via apoptosis. To pursue this possibility, we quantified the spontaneous apoptotic rate in liver sections from diet-restricted (DR) and ad libitum-fed (AL) 12-month-old male C57BL/6 x C3H F1 mice, a murine strain known to develop a high incidence of spontaneous liver tumors by 18 months of age. The identification of hepatocyte apoptotic bodies was facilitated by in situ end-labeling immunohistochemistry. The basal rate of proliferation of hepatocytes was quantified utilizing proliferating cell nuclear antigen immunohistochemistry. The incidence of apoptotic bodies and total proliferating cell nuclear antigen-positive cells was enumerated in 14 mice/group by scoring 50,000 random hepatocytes/liver and expressed as the mean incidence/100 cells. When the comparison was made between diet groups, the apoptotic rate was significantly higher in the DR mice relative to the AL mice, while the proliferation rate was significantly lower (P < 0.01 and P < 0.05, respectively). The increase in spontaneous level of apoptosis and the decrease in proliferation rate in livers of DR mice were associated with a significantly lower rate of spontaneous hepatoma over a 36-month period. In summary, the results suggest that caloric intake may modulate the basal turnover rates of cell death and proliferation in a direction consistent with a cancer-protective effect in the DR mice and a cancer-promoting effect in AL mice.
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PMID:Rates of apoptosis and proliferation vary with caloric intake and may influence incidence of spontaneous hepatoma in C57BL/6 x C3H F1 mice. 792 85

The role of the retinoblastoma gene (RB1) in human gastric carcinogenesis is yet to be clarified. We report on the analysis of RB1 structure and protein (pRB) expression in gastric carcinomas using Southern blotting, Western blotting and immunohistochemistry. The relationship between pRB expression and cell proliferation was assessed by a proliferation marker (PCNA) in a subset of cases. Non-neoplastic mucosas were studied, as controls, by the same methodology. We found a close relationship between pRB expression and PCNA in non-neoplastic mucosas as well as in gastric carcinomas. All tumours were immunohistochemically positive for pRB, although with a variable proportion of non-immunoreactive cells. Carcinomas of the diffuse type showed absence of pRB expression in a larger proportion of neoplastic cells than carcinomas of the intestinal type (P < 0.05). Analysis of the RB1 structure using probe p68RS2.0 revealed allelic imbalance in 29% of informative cases. No homozygous deletions and/or rearrangements were detected with p68RS2.0 and cDNA probes. Western analysis revealed no abnormal patterns of pRB. Our data therefore suggest that major alterations affecting the RB1 gene are rather infrequent in human gastric carcinomas.
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PMID:Retinoblastoma gene structure and product expression in human gastric carcinomas. 794 78


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