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

The adhesive properties and the expression of extracellular matrix receptors of the beta 1-integrin subfamily were analyzed in transformed epidermal keratinocyte cell lines of different stages of mouse skin carcinogenesis. One- and two-dimensional analyses of the immunoprecipitates obtained with anti-beta 1- and specific anti-alpha-integrin subunits showed qualitative and quantitative changes in the expression of beta 1 integrins by the different cell lines. The polyvalent alpha 3 beta 1 integrin was expressed by all analyzed cell lines, although the levels detected in undifferentiated spindle CarC cells were lower than those present in the rest of keratinocyte cell lines. In contrast, spindle cells expressed high levels of the specific fibronectin receptor alpha 5 beta 1, whereas this integrin was absent or expressed at very reduced levels in the other epithelial cell lines. Expression of alpha 5 beta 1 integrin in spindle cells appeared organized in cell-substratum contact areas on spread cells. In addition, high and homogenous expression of alpha 5 beta 1 was detected in fully undifferentiated tumors induced in nude mice by three independent spindle cell lines. These results suggest that the expression of alpha 5 beta 1 integrin is upregulated during the development of spindle cell carcinomas that occur in the last stages of mouse skin carcinogenesis and can be associated with the acquisition of the fibroblastoid phenotype of spindle cells. On the other hand, expression of the collagen receptor alpha 2 beta 1 was demonstrated in a transformed cell line (PDV), and it was apparently also expressed in two other malignant keratinocyte cell lines (PDVC57 and HaCa4). The expression of alpha 2 beta 1 was correlated with the increased adhesion to collagen type I and collagen type IV exhibited by the tumorigenic cell lines.
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PMID:Expression of beta 1 integrin receptors in transformed mouse epidermal keratinocytes: upregulation of alpha 5 beta 1 in spindle carcinoma cells. 753 61

Hyperplastic nodular cirrhosis was induced in rats by long-term (6 month) i.p. administration of thioacetamide at doses of 2.66 mmol/kg body wt, three times per week. The survival rate of animals at the end of the treatment was 90%. To follow the temporal changes samples at 0, 7, 15, 30, 45, 60, 90, 150 and 180 days from rats during thioacetamide intoxication and from chronological controls were obtained. The cirrhogenic ability of this treatment was assessed on the basis of morphological changes: the development of macronodular cirrhosis and the appearance of fibrous septa of collagen through portal spaces. Parameters of liver injury and cholestasis were obtained by assaying the serum activities of isocitrate dehydrogenase and gamma-glutamyltransferase. Enzymes and metabolites related to glutathione redox systems, as well as other antioxidant enzymes, were tested. Catalase and glutathione peroxidase, the two enzymes involved in the elimination of peroxides, and glutathione reductase decreased significantly at the end of the 6 months of intoxication, while Cu-Zn and Mn superoxide dismutases increased progressively during the long-term thioacetamide treatment. Protein thiol levels profile showed a biphasic change increasing from the 7th day and were insensitive to the 30% depletion of intracellular glutathione (GSH). To study the relationship of the intracellular thiols on the mechanisms of cell proliferation and differentiation during the cirrhogenic process, DNA content was assayed by flow cytometry in isolated hepatocytes, and DNA ploidy and distribution between G0-G1, S and G2 + M phases were determined. Remarkable changes in relation to a sharp increase in diploid population from 7 to 180 days (24.5%-->85.5%), a pronounced decrease in polyploid populations (tetraploid+octoploid) in the same period (73.7%-->12.3%), and elevations in the populations in S phase (S1 + S2) were observed in thioacetamide-treated rats. The results obtained indicate that hepatocytes isolated from thioacetamide-treated rats showed a marked tendency to diploidy, an enhancement in DNA replication parallel to the hepatic content of protein sulphydryl groups and a significant decline in antioxidant enzyme activities. The increase in protein thiols was independent of GSH level and of the thiol redox state.
Carcinogenesis 1995 Jul
PMID:Relationship between antioxidant systems, intracellular thiols and DNA ploidy in liver of rats during experimental cirrhogenesis. 761 93

Receptors of the integrin family regulate adhesion and terminal differentiation of keratinocytes. In order to investigate the significance of changes in integrin expression associated with malignant transformation we have examined normal human oral keratinocytes and seven oral squamous cell carcinoma (SCC) lines. Cell surface levels of the alpha 2, alpha 3, alpha 5, alpha 6, alpha v, beta 1 and beta 4 integrin subunits were determined by flow cytometry and the distribution of the beta 1 subunit was examined by immunohistochemistry. In normal keratinocytes and one SCC line the beta 1 subunit was most abundant in the basal cell layer, but in other lines anti-beta 1 antibodies stained basal and suprabasal layers uniformly. All lines had reduced surface levels of at least one integrin subunit and in some cell lines distinct subpopulations could be distinguished on the basis of differences in integrin expression. Reduced integrin expression was not, however, generally reflected in reduced adhesion to laminin, fibronectin, type IV collagen or vitronectin in three cell lines examined. Those cell lines with the lowest capacity for terminal differentiation, as measured by involucrin expression, had the lowest levels of the alpha 6 and beta 4 subunits or were completely lacking alpha v. Oral SCC show considerable variation in integrin expression, but focal or extensive loss of the alpha 6 and beta 4 subunits is a common feature of poorly differentiated tumours. The cell lines we have examined therefore provide a relevant experimental model with which to explore the relationship between aberrant integrin expression and impaired terminal differentiation capacity.
Carcinogenesis 1993 Oct
PMID:Comparison of integrin expression and terminal differentiation capacity in cell lines derived from oral squamous cell carcinomas. 769 59

Morphologically atypical cells were first detected on the 98th day after subcutaneous implantation to rats of a paraffin pellet containing 2 mg of 7,12-dimethylbenz(a)anthracene (DMBA). These cells subsequently formed groups and finally gave rise to malignant fibrous histiocytomas. Early atypical cells were located between proliferating fibroblasts and histiocytes in the center of a fibrous capsule surrounding the DMBA-pill. They exhibited a smooth cell surface, dilated rough endoplasmic reticulum, multiple Golgi complexes, and were often associated with newly formed collagen. These cells incorporated 3H-thymidine and 3H-proline intensively, and showed weak acid phosphatase activity, but no features typical for macrophages (microvilli, numerous lysosomes, high activity of acid phosphatase, nonspecific esterases, antigens recognized by monoclonal antibodies ED1 and OX-42, vital staining with trypan blue). Atypical cells also did not differentiate into muscle cells (no expression of desmin and the alpha-sarcomeric form of actin), nor into Schwann cells (no expression of S-100 protein). No point mutation of the neu gene at nucleotide 2007, which is specific for N-ethyl-N-nitrosourea and DMBA-induced malignant rat schwannoma cells, was detected by polymerase chain reaction-restriction fragment length polymorphism analyses of microscopically selected regions of individual 7 micron cryostat sections. These results support the view that malignant fibrous histiocytoma is derived from immature fibroblasts exhibiting pronounced phenotypic diversity during later stages of carcinogenesis.
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PMID:[The early stages of the morphogenesis and tissue lineage of an experimental malignant fibrous histiocytoma]. 769 95

The early cellular events in liver carcinogenesis were studied in Fischer-344 male rats that either were fed 200 ppm 2-acetylaminofluorene (AAF) for up to 10 wk or were fed the carcinogen for 8 wk followed by maintenance for an additional 24 wk. By 1 wk of exposure, AAF caused a reduction in the number of glutamine synthetase (GS)-positive centrilobular hepatocytes, an increase in DNA synthesizing hepatocytes in the central areas of the hepatic lobules, and a shift from multinucleated to mononucleated hepatocytes, although overt hepatocellular necrosis was not evident. By 3 wk, altered hepatocellular foci characterized by deficiencies in iron storage (IS-) and collagen production and by expression of gamma-glutamyl transferase (GGT+) and placental-type glutathione transferase (PGT+) activity appeared. Single PGT+ cells were also found. During continued exposure, foci increased in number, size, and total area with the increases escalating between 8 and 10 wk of exposure. Cessation of AAF exposure at 8 wk resulted in a slight decrease in the number of foci after a further 6 wk of maintenance, but with continued maintenance for another 6 and 12 wk, the number again increased. IS- characterized the majority of foci during carcinogen administration, whereas after cessation of exposure, GGT+ and PGT+ foci predominated. None of the foci were positive for GS. After AAF exposure for 10 wk, a few neoplasms developed and greater numbers occurred after maintenance for a further 24 wk of rats exposed for 8 wk. We conclude the following: (a) the low dose of AAF caused subtle alterations in function and proliferation of normal hepatocytes and converted hepatocytes into focus cells; (b) reduction of the GS+ area is a sensitive indicator of cytotoxicity of AAF; (c) the development of some foci at an early stage depends on a promoting action of AAF, which ceased when the carcinogen was withdrawn, allowing some foci to undergo reversion; (d) a strong linkage exists in expression of IS-, GGT+, and PGT+ in foci; (e) the carcinogenic process accelerates in the absence of any indication of increased cytotoxicity by AAF; and (f) under the conditions of this study, no GS+ foci, adenomas, and carcinomas were found, indicating that no carcinogen-induced expression of GS occurred in these lesions and that GS expression is not linked to other phenotypic abnormalities.
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PMID:Sequential functional and morphological alterations during hepatocarcinogenesis induced in rats by feeding of a low dose of 2-acetylaminofluorene. 773 79

Immortalized non-malignant cells do not grow in soft agarose. We found, however, that HPV-16-DNA-immortalized human uterine exocervical epithelial cells (HCE16/3 cell line) formed colonies when co-cultured with human embryonic skin fibroblasts. This appeared to be mediated by diffusible growth factors, and direct cell-cell contacts were not required. HCE16/3 cells from colonies remained unable to grow alone in soft agarose like the parental HCE16/3 cells, indicating that only transient phenotypic changes without genetic alterations had occurred in the co-cultures. In a modified soft-agarose assay, HCE16/3 cells grown as an underlying monolayer did not produce enough (transforming) growth factors which could confer an anchorage-independent phenotype to non-transformed fibroblasts. Lethally irradiated fibroblasts were able to stimulate DNA synthesis and proliferation of HCE16/3 cells. Northern-blot analysis showed that HPV-16-DNA expression of the immortalized cells was not altered in the presence of fibroblasts. The expression of the IL-I gene in the immortalized cells, however, was augmented by the co-cultured fibroblasts compared with immortalized cells alone. In organotypic collagen raft co-cultures, in which epithelial cells were grown on top of a collagen gel containing fibroblasts, HCE16/3 cells appeared to be chemotactic to fibroblasts and fibroblasts stimulated the growth of the immortalized epithelial cells. Our results suggest that fibroblasts may contribute to human epithelial carcinogenesis in vivo.
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PMID:Human skin fibroblasts induce anchorage-independent growth of HPV-16-DNA-immortalized cervical epithelial cells. 776 39

This study examined the cytogenetic characteristics of keratinocyte cell lines derived from rat oral tissues treated in vivo with the carcinogen 4-nitroquinoline-N-oxide. A parent tumour with a spectrum of differentiation was used to establish clonal subpopulations that formed differentiated (squamous cell carcinomas; SCCs) and undifferentiated (spindle cell phenotype) tumours following transplantation to athymic mice. By contrast to spindle cell tumours, SCCs elaborated basement membrane proteins (laminin and collagen IV). Both diploid and tetraploid subpopulations formed either SCCs or spindle cell tumours. An unbalanced 10q+ translocation was common to all cell lines. Anomalies of chromosomes 3 and 12 (gain, loss, deletions, translocations) were present only in cell lines that formed spindle cell tumours and were absent in keratinocytes forming SCCs. The results suggest that proto-oncogenes and/or tumour suppression genes located to rat chromosomes 3 and 12 may control tumour cell differentiation.
Carcinogenesis 1995 Jan
PMID:Loss of expression of basement membrane proteins reflects anomalies of chromosomes 3 and 12 in the rat 4-nitroquinoline-N-oxide model of oral carcinogenesis. 783 1

Epidemiologic studies have linked diets high in animal fat with colon carcinogenesis. A number of animal tumor models have shown that diets rich in omega-3 fatty acids inhibit colon carcinogenesis while diets rich in omega-6 fatty acids promote tumor growth. This study examines whether modification of the membrane fatty acid composition of both moderately (CX-1) and poorly differentiated (MIP-101 and Clone A) human colorectal carcinoma cells alters their interaction with Kupffer cells and extracellular matrix proteins (collagen type IV, fibronectin and laminin). The cells were treated with 15-16 micrograms/ml of docosahexanoic acid (22:6, omega 3) or linoleic acid (18:2,omega 6). Gas chromatography showed significant alterations in the membrane fatty acid composition of the human colorectal cancer cell lines. Binding assays were performed by measuring adherence of 51Cr-labelled tumor cells to Kupffer cell monolayers or to immobilized proteins. Omega-3 treatment significantly decreased the Kupffer cell binding of only the CX-1 line while omega-6 treatment decreased binding of all three cell lines. In contrast both omega-3 and omega-6 treatment of MIP-101 cells decreased binding to the extracellular matrix proteins with the omega-6 effect being more pronounced. These results indicate that the binding characteristics of the colon cancer cells to both Kupffer cells and extracellular matrix proteins may be determined in part by the membrane fatty acid composition. Decreased adherence to extracellular matrix proteins may lead to increased cell motility and invasiveness. Since Kupffer cell binding precedes tumor cell phagocytosis and killing, decreased binding may improve tumor cell survival.
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PMID:Effect of membrane free fatty acid alterations on the adhesion of human colorectal carcinoma cells to liver macrophages and extracellular matrix proteins. 788 22

Morphologically atypical cells were first detected in the adjacent connective tissue 98 days after implanting a paraffin pill containing 2 mg of 7,12-dimethylbenz[a]anthracene (DMBA) into the subcutaneous tissues of rats. These cells subsequently formed groups and finally produced gross malignant fibrous histiocytomas (MFH). Early atypical cells were located between proliferating fibroblasts and histiocytes in the center of a fibrous capsule surrounding the DMBA pill. They exhibited a smooth cell surface, dilated rough endoplasmic reticulum, multiple Golgi complexes, and were often associated with newly formed collagen. These cells incorporated [3H]thymidine and [3H]proline intensively, and showed weak acid phosphatase activity but no features diagnostic of macrophages (microvilli, numerous lysosomes, high acid phosphatase and non-specific esterase activities, antigens recognized by monoclonal antibodies ED1 and OX-42 and vital staining with trypan blue). There was no evidence that atypical cells differentiated into muscle cells (no expression of desmin or the alpha-sarcomeric form of actin) or Schwann cells (no expression of S-100 protein). No point mutation in the neu gene at nucleotide 2007, specific for N-ethyl-N-nitrosourea- and DMBA-induced malignant rat schwannomas, was detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analyses. These results support the view that malignant fibrous histiocytoma is derived from immature fibroblasts exhibiting pronounced phenotypic diversity during the later stages of carcinogenesis.
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PMID:Development of malignant fibrous histiocytoma induced by 7,12-dimethylbenz[a]anthracene in the rat: characterization of early atypical cells. 790 72

Rat liver responds to carcinogen treatment with growth of glutathione S-transferase P (GST-P)-positive enzyme-altered foci. In this paper a method is described where GST-P-positive hepatocytes are isolated from carcinogen-treated rats. The method utilizes ethacrynic acid, which is a good substrate for GST-P, and which induces toxicity mainly in GST-P-negative cells. The toxicity results in a loss of attachment to collagen. The method gives a 70% pure population of GST-P-positive cells attached to collagen-coated plates. Use of additional markers supports the conclusion that the GST-P-positive cells were derived from foci. Isolated GST-P-positive hepatocytes spread out and formed primary cultures of normal appearance. It was also shown that they synthesized DNA and did not respond to transforming growth factor beta 1. It is concluded that isolated GST-P-positive hepatocytes can be used for studies on alterations in enzyme-altered foci that cannot be done with in situ immunohistochemistry or in situ hybridization.
Carcinogenesis 1994 Aug
PMID:Isolation of glutathione S-transferase P-positive hepatocytes from carcinogen treated rats by use of ethacrynic acid as selecting agent. 791 75


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