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

The discrimination of atypical (premalignant) cells from invasive neoplastic cells in primary bladder lesions is a major diagnostic problem in cytopathology and surgical pathology. We have used an animal model of urinary bladder carcinogenesis to determine the specific changes which occur in the expression of certain cytokeratins (CK) during the progression of lesions from regenerative hyperplasia and carcinoma in situ to transitional cell carcinomas. At sequential time points following exposure of the rat bladder epithelium to N-methyl-N-nitrosourea in vivo, immunohistochemical staining of CKs was evaluated in ethanol-fixed samples from the induced urothelial lesions using commercially available anti-CK mouse monoclonal antibodies. Specific changes were found in the expression of CKs 13, 18, and 19 during the neoplastic progression of induced urothelial lesions in the rat. These changes included the reciprocal loss of expression of CK 19 and the reappearance of CK 18 as malignant tumors developed. Invasive cells also did not express CK 13. Our results, based on the rat model, are similar to those reported by others on CK expression in human bladder tumors. Because these changes in CK expression occurred at specific points in the progression of urothelial lesions, the antibodies utilized in this study may be helpful in predicting the invasive potential of cells present in cytopathological specimens and tissue biopsies from human urothelial lesions.
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PMID:Correlation of cytokeratin patterns with histopathology during neoplastic progression in the rat urinary bladder. 169 8

The early stages of the carcinogenic process induced by aflatoxin B1 (AFB1) in rat liver during 24 weeks of feeding and the resulting tumours have been studied with respect to cytokeratin (CK) expression. A previously uncharacterized monoclonal antibody, MRCTU/J1, has been shown to recognize rat CK18 and together with antibodies against human CK8, 18 and 19, has been used to examine the possible lineage of tumour cells and also to identify the altered foci that might be most relevant to tumorigenesis. Results suggested that AFB1-induced transformation in liver may occur in more than one cell type, since tumours with the normal hepatocyte CK pattern and those with bile duct or oval cell CK phenotype were identified. Additionally, hepatocytes with a bile duct CK phenotype appeared during the early stages of carcinogenesis. The in vivo pattern of CK expression also appeared to be maintained in one normal and one hepatoma-derived cell line. Overexpression of CKs (particularly of CK19) was a much more selective marker for altered foci, compared to gamma-glutamyltranspeptidase, and was more consistently expressed at high levels in tumours, suggesting that it might be a more reliable way of identifying those cells involved in the transformation process.
Carcinogenesis 1990 Jul
PMID:Cytokeratin expression during AFB1-induced carcinogenesis. 169 54

Male outbred Sprague-Dawley rats were fed a choline-deficient diet containing 0.10% DL-ethionine for up to 30 weeks. Liver slices from rats killed 4, 6, 10, 14, 22 and 30 weeks after starting the treatment were histochemically analyzed for the following parameters: basophilia, expression of cytokeratin 19 (which in the liver is bile duct epithelial cell-specific), glycogen content and activities of glycogen synthetase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6PASE), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycerin-3-phosphate dehydrogenase (G3PDH), 'malic enzyme' (MDH), alkaline phosphatase (ALKPASE) and gamma-glutamyltranspeptidase (GGT). The diet induced necrosis of single parenchymal cells and a massive proliferation of oval cells within 4-6 weeks; thereafter cholangiofibroses, cystic cholangiomas and some cholangiofibromas, but no cholangiocarcinomas, were observed. Oval cells, cholangiofibroses, cystic cholangiomas and cholangiofibromas expressed cytokeratin 19, whereas parenchymal cells, foci of altered hepatocytes and hepatocellular adenomas did not; this observation does not support a precursor-product relationship between oval and parenchymal cells. SYN, PHO, G6PASE, G6PDH, GAPDH, G3PDH, MDH, ALKPASE and GGT activities were detected in oval cells; cholangiofibrotic lesions, cystic cholangiomas and cholangiofibromas stained strongly for GAPDH, G3PDH and MDH. In livers from rats fed the diet for 10 weeks, single hepatocytes storing high amounts of glycogen appeared in the parenchyma. There was no indication of a transition from the oval cell population to hepatocytes storing glycogen in excess. Foci of glycogen-storing cells were scattered all over the lobes after 14 and 22 weeks; they had increased G6PASE, G6PDH, ALKPASE and GGT activities. Mixed cell foci and hepatocellular adenomas developed within 22-30 weeks and exhibited a remarkable decrease of G6PASE activity, a strong increase of G6PDH, GAPDH, G3PDH and MDH activities as well as extremely high ALKPASE and GGT activities. The data support the concept that during hepatocarcinogenesis, a number of sequential changes in the activities of various enzymes involved in carbohydrate metabolism occur and that a correlation between morphology and enzyme pattern in the focal lesions does in fact exist. Furthermore, our results suggest that two different cell lineages are involved in the development of cholangiocellular tumors from oval cells and hepatocellular tumors from hepatocytes.
Carcinogenesis 1991 Feb
PMID:Enzyme histochemical and immunohistochemical characterization of oval and parenchymal cells proliferating in livers of rats fed a choline-deficient/DL-ethionine-supplemented diet. 170 20

Primary human ovarian surface epithelial (HOSE) cells were immortalized by a retroviral vector (LXSN-16E6E7) expressing HPV-E6E7 open reading frames (ORF). Immortalizations of primary ovarian epithelial cells were achieved in three of three attempts. Detailed analysis was carried out in one line, HOSE 6-3, selected on the basis of its epithelial morphology. The immortalized line (HOSE 6-3) was nontumorigenic in nude mice when examined at subculture number 20. Cytogenetic analysis confirmed its human origin and detailed karyotypic analysis revealed a mixed karyotype made up of about 60% of diploid and 40% of near-tetraploid cells. Clonal chromosomal aberration was observed in a subpopulation of cells involving a ring chromosome number 9. Immunofluorescence and two-dimensional gel electrophoresis revealed the presence of vimentin and several species of cytokeratin (K7, K8, K18, K19). The profile of the cytoskeletal filaments of HOSE 6-3 cells is largely identical with that of normal ovarian epithelial cells before immortalization. The immortalized ovarian epithelial cells have a lower sensitivity to TGF-beta 1 inhibition compared to normal ovarian epithelial cells. The immortalized line, HOSE 6-3, has altered growth properties including a higher proliferation rate, plating efficiency, and saturation density. The establishment of a continuous line of human ovarian epithelial cells may provide an in vitro model for study of carcinogenesis in human ovarian cancers.
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PMID:Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV-E6E7 ORFs). 779 85

Head and neck cancer is occurring in younger patients in certain areas of the world. The factors that contribute to this process remain poorly defined, emphasizing the need for continued investigations into head and neck carcinogenesis. One potential determinant of disease development may relate to the significance of the host's intrinsic capacity to detoxify carcinogens, ie, through the phase II enzyme family, glutathione-S-transferases. Those patients with deficient GST activity may be at greatest risk. Additionally, genetic studies have suggested that certain chromosomes may be more susceptible to tobacco-induced damage. Chromosome 3p has now been identified as frequently altered both within head and neck cancers as well as within tobacco-induced malignancies. Over the past year numerous reports have addressed potential biologic determinants of not only cancer development, but also its continued progression. These factors may include altered growth factors and their receptors, changes in cellular intermediate filaments such as increased cytokeratin 19, and the production of matrix metalloproteinases. Finally, investigations continue to provide new insight into mechanisms by which abnormal gene expression may govern response to therapy. Our growing understanding of the complexity of head and neck cancer biology reinforces the need for preventive strategies, including the role of both nutritional and behavioral interventions.
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PMID:Head and neck oncology research. 808 Aug 55

In head and neck squamous cell carcinoma a reliable serum marker of carcinogenesis should be of predictive value for the development of recurrent disease or a second primary tumour. At the moment, such a tumour marker is not available. Recently, elevated levels of cytokeratin 19-fragments (Cyfra 21-1) have been detected in the serum of patients with lung cancer, in particular with squamous cell carcinoma. Cytokeratin 19 is an intermediate cell filament protein expressed in simple epithelia and their malignant counterparts. Therefore, in this prospective study, a standardized sandwich enzyme-linked immunosorbent assay for soluble cytokeratin 19 fragments was tested in the serum of 20 patients with a previously untreated head and neck squamous cell carcinoma. The results were compared with that of 20 control individuals. Our results showed significantly higher Cyfra 21-1 concentrations in the serum of patients with cancer (10.21 +/- 3.03 ng/ml) than the controls (7.2 +/- 2.63 ng/ml). After radical treatment the marker levels dropped significantly to 1.65 +/- 1.07 ng/ml. Cyfra 21-1 appears to be of value as a circulating tumour marker for head and neck squamous cell carcinoma especially in monitoring disease control.
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PMID:Circulating fragments of cytokeratin 19 in patients with head and neck squamous cell carcinoma. 858 85

Small non-epithelial cells with morphological features of blast-like cells are found within a proliferating intrahepatic biliary system after institution in rats of a diethylnitrosamine, 2-acetylaminofluorene, partial hepatectomy carcinogenesis protocol. Two to three days after the partial hepatectomy step of the carcinogen protocol, the small blast-like cells are evident beneath a layer of bile ductule epithelial cells that line the walls of the bile ductules. The basally located small cells are not exposed to the bile ductule lumen or to the surrounding basal lamina. They ranged in size from 3.0 to 5.0 microns, exhibit an undifferentiated phenotype, including a high nucleus-to-cytoplasm ratio and no to minimal differentiated cytoplasmic and surface structures. Mitosis of blast-like cells are evident, and their nuclei express proliferating nuclear cell antigen. The ductal blast-like cells do not express cytokeratin 19, oval cell antigen 270.38, or actin immunoreactivity, in contrast to bile ductule epithelial cells. The basal cells, as well as bile ductule epithelial cells, are negative for a panel of T and B lymphocyte surface markers in contrast to lymphocytes present in the connective tissue stroma surrounding the bile ductules and throughout the hepatic parenchyma. Within some segments of the biliary system, some of the ductal blast-like cells increased in size to approximately 10 microns and showed increased amounts of cytoplasmic organelles and plasma membrane filapodia but did not develop the polarized phenotype of bile ductule epithelial cells (ie, apical microvilli, desmosomes, connections to bile ductule cells, and exposure to duct lumen); however, their nuclear morphology was essentially similar to the smaller basal cells. We also found bile ductules to contain two types of polarized epithelial cells, one with the characteristic oval nucleus of the oval/bile ductule epithelial cells and the other, transitional epithelial cells with a rounder nucleus and prominent nucleoli. The transitional cells exhibit a similar apical-basal polarity and antigenic phenotype as the oval/bile ductule epithelial cells. However, transitional cells are larger and have an overall less dense cytoplasm than the bile ductule epithelial/oval cells, and some show apical microvilli changes and small catalase-positive peroxisomes. These observations indicate that a greater diversity of cell types exist within intrahepatic bile ductules of rats treated with carcinogens. Furthermore, the nonpolarized ductal blast-like cells undergo proliferation and are significantly different in phenotype from other hepatic cells previously reported as candidates for liver progenitor cells.
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PMID:Blast-like cell compartment in carcinogen-induced proliferating bile ductules. 862 18

This study supports the existence of a pluripotent liver stem cell population which has the potential to differentiate into hepatocytes and bile ductular cells. We compared the expression of hepatocyte-specific and bile ductular-specific markers in fetal and preneoplastic rat liver. L-pyruvate kinase (L-PK) and alpha glutathione S-transferase (GST) were used as adult hepatocyte-specific markers, while cytokeratin 19 (CK19) was used as a bile ductular-specific marker. pi GST and M2-pyruvate kinase (M2-PK), which are fetal hepatocyte-specific and expressed at high levels in the oval and duct-like cells, were also used. We characterized fetal liver derived from 13-21 days of gestation (E13-E21). pi GST was detected in the E18 hepatoblasts, which form the intrahepatic bile ducts, while CK19 was detected at E19. Some of these cells express alpha GST and L-PK from E19 to E21. Oval, duct-like and bile ductular cells in rats treated with a choline-deficient diet containing 0.07% ethionine (CDE diet) for up to 8 weeks were characterized by double immunocytochemistry. L-PK and alpha GST are absent from bile ductular cells in the normal adult liver and up to 3 weeks of CDE treatment. After 4-5 weeks on CDE treatment, the majority of bile ductular cells express L-PK, while at 6 weeks some co-express L-PK and alpha GST. There are two populations of oval cells, a major population expressing only the fetal hepatocyte markers, while a minor population expresses the fetal hepatocyte, adult hepatocyte and bile ductular markers. There are at least three different duct-like cell populations which co-express different markers and have characteristics of fetal hepatocytes at sequential stages of differentiation. One population co-expresses pi GST and M2-PK and is similar to fetal hepatocytes derived from E13-E14 fetuses. The second expresses the two fetal markers and L-PK, and this reflects characteristics of E15 hepatocytes. The third expresses pi GST, M2-PK, L-PK and alpha GST which is characteristic of E16-E19 hepatocytes. Upon withdrawal of the CDE diet, autoradiography using tritiated thymidine shows that oval and duct-like cells differentiate into hepatocytes. This study demonstrates that oval and duct-like cells express both hepatocytic and bile ductular markers, and have the capacity to differentiate into hepatocytes, characteristics similar to hepatoblasts in the developing rat liver.
Carcinogenesis 1996 Feb
PMID:Dual phenotypic expression of hepatocytes and bile ductular markers in developing and preneoplastic rat liver. 862 46

Malignant transformation is often associated with alterations in the expression of normal differentiation markers, which may serve as intermediate end points in carcinogenesis and cancer prevention. To identify early changes in differentiation markers during head and neck cancer development, we examined the expression of cytokeratins (CK1, CK8, CK13, and CK19) and involucrin by immuohistochemical methods in surgical specimens from 29 head and neck squamous cell carcinoma patients that included, in addition to carcinoma, adjacent dysplastic lesions (17 cases), hyperplastic lesions (21 cases), and adjacent histologically normal tissues (15 cases) and in specimens from 31 subjects with premalignant oral lesions (e.g, oral leukoplakia) without cancer, CK13 and involucrin were detected in all specimens from the cancer patients, and no differences in their expression were found among the different histopathological group. CK8 was detected in only 2.7% (1 of 36) of adjacent normal and hyperplastic tissues but in 58.8% (10 of 17) and 75.9% (22 of 29) of dysplastic and carcinoma tissues. The corresponding figures for CK19 expression in adjacent normal, hyperplastic, dysplastic, and carcinoma tissues were 13.3, 70, 71.4, and 82.1%, respectively. The expression of CK1 was not related to the progression from normal to malignant. In the leukoplakia lesions, CK8 CK13, CK19 and involucrin were detected in 13.8, 100, 74.2 and 100% of the specimens, respectively. These results demonstrate that CK19 expression increases in hyperplastic lesions and continues to be expressed in dyplastic and malignant lesions, whereas CK8 expression in low in adjacent normal and hyperplastic tissues and increases only in dysplastic and malignant lesions. Thus, CK19 and CK8 could be markers of sequential premalignant changes in head and neck carcinogenesis.
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PMID:Increased expression of cytokeratins CK8 and CK19 is associated with head and neck carcinogenesis. 863 60

It is widely believed that abnormal production of polypeptide growth factors, together with other molecular alterations, play an important role in neoplastic development. Transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major growth factors that contribute to liver regeneration occurring via both hepatocyte replication and oval cell proliferation. It is not clear, however, whether and to what extent these growth factors are also involved in hepatocarcinogenesis. In the present study, the gene expression of TGFalpha, HGF and aFGF and their corresponding receptors was examined by Northern blotting and in situ hybridization during hepatocarcinogenesis induced by the Solt-Farber protocol. All three growth factor/receptor systems, TGFalpha/epidermal growth factor receptor (EGFR), HGF/c-met and aFGF/FGF receptors (flg and bek) were significantly elevated at early time points when oval cells were proliferating. Their respective expression decreased after 1 month and remained at a low level until the development of liver tumors. In all hepatocellular carcinomas (HCC) examined, the transcripts of TGFalpha and aFGF were highly expressed, while those of HGF were low. With regard to the receptor expression in the tumors, EGFR was present at varying levels, c-met was expressed at higher levels and flg increased significantly, whereas bek remained at low levels. These data suggest that TGFalpha and aFGF are the major growth factors involved in the progression of HCC, and that the signal of aFGF is mainly transduced by the receptor flg in HCC. Furthermore, HCC cells were phenotypically very similar to oval cells with regard to the gene expression of growth factor/receptor systems. These results, along with the finding that all the HCC cells are positive for the oval cell antigen OV6, and that cytokeratin 19 is heavily expressed in both tumor and oval cells, strongly suggest that at least some of the HCC induced by the Solt-Farber protocol may be derived from oval cells.
Carcinogenesis 1996 May
PMID:Expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis. 864 Sep 40


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