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

P44 Ro (Mel) is a human malignant melanoma cell line derived from a testicular metastasis in a DNA repair deficient, xeroderma pigmentosum patient. This line harbors a N-ras gene mutated in codon 61. To investigate other cellular genes possibly contributing to the expression of its transformed phenotype, four XP44 revertant cell lines were isolated by different selection procedures and the association of the level of expression of various oncogenes (including N-ras) and tumor suppressor genes with the selection for the revertant phenotype was determined. The revertants exhibited a significant but variable degree of phenotypic reversion, according to the selective pressure to which they were submitted, and a phenotypic stability dependent on their constant maintenance in selective medium. Back-revertant lines were isolated by culturing revertant lines in control medium for several weeks. The comparison between parental, revertant and back-revertant cells has revealed that, beyond the mutation in codon 61 of N-ras, two groups of genes appear to be also implicated in the transformation process of XP44 RO (Mel) cells: one group, comprising pim A, trk, Rb and p53, whose expression is independent of the cell selection conditions; the other group, comprising Ha-ras, N-ras, neu 1, fos and met H, whose expression is more or less dependent upon such conditions. The myc gene is apparently not involved in this phenomenon. These results, besides strengthening the concept that carcinogenesis is a multigenic process, suggest that diverse mechanisms can lead to the transformed phenotype, but that these mechanisms might have some pathway(s) in common.
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PMID:Cellular genes possibly involved in the transformation process of the human melanoma cell line XP44 RO (Mel). 765

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

We examined whether the inhibition of neoplastically transformed cell growth by co-cultured non-transformed cells involved gap junctional intercellular communication (GJIC). The growth of poorly communicating (approximately 25-35% dye-coupled cells), Ha-ras and neu oncogene-transformed WB-F344 rat liver epithelial cells was inhibited by co-culture with highly communicating (90-95% dye-coupling), non-transformed WB-F344 cells. Inhibition was dependent upon heterologous cell-cell contact and required that the non-transformed cells were GJIC competent. GJIC-deficient mutant WB-F344 cells did not suppress transformed cell growth. Restoration of mutant cell GJIC by transfection with rat connexin43 cDNA restored growth-inhibiting activity. These results clearly demonstrate a role for GJIC in the inhibition of transformed cell growth by non-transformed cells.
Carcinogenesis 1995 Apr
PMID:In vitro growth inhibition of neoplastically transformed cells by non-transformed cells: requirement for gap junctional intercellular communication. 772 74

The human c-erbB-2 oncogene is homologous to the rat neu oncogene, both encoding transmembrane growth factor receptors. Overexpression and point mutations in the transmembrane domain of the encoded proteins in both cases have been implicated in cell transformation and carcinogenesis. In the case of the neu protein, it has been proposed that these effects are mediated by conformational preferences for an alpha-helix in the transmembrane domain, which facilitates receptor dimerization, an important step in the signal transduction process. To examine whether this is the case for c-erbB-2 as well, we have used conformational energy analysis to determine the preferred three-dimensional structures for the transmembrane domain of the c-erbB-2 protein from residues 650 to 668 with Val (nontransforming) and Glu (transforming) at position 659. The global minimum energy conformation for the Val-659 peptide from the normal, nontransforming protein was found to contain several bends, whereas the global minimum energy conformation for Glu-659 peptide from the mutant, transforming protein was found to be alpha-helical. Thus, the difference in conformational preferences for these transmembrane domains may explain the difference in transforming ability of these proteins. The presence of higher-energy alpha-helical conformations for the transmembrane domain from the normal Val-659 protein may provide an explanation for the presence of a transforming effect from overexpression of c-erbB-2. In addition, docking of the oncogenic sequences in their alpha-helical and bend conformations shows that the all-alpha-helical dimer is clearly favored energetically over the bend dimer.
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PMID:Conformation of the transmembrane domain of the c-erbB-2 oncogene-encoded protein in its monomeric and dimeric states. 777 61

A retrovirus containing a neu oncogene was introduced into a Fischer F344 rat liver epithelial cell line (WB-F344) to study the effect of the expression of neu oncoprotein on gap junctional intercellular communication (GJIC), the ability to form colonies in soft agar and the ability to form tumors in rat liver by these cells. After viral infection, five different neu-transduced epithelial clones were randomly selected for further analysis. Southern blot analysis of HindIII-digested genomic DNA hybridized with a neu-specific probe indicated that the neu oncogene carried by the retrovirus was integrated into different chromosomal locations in the five different neu-transduced WB cell lines. Using the fluorescence recovery after photobleaching (FRAP) assay, we found that GJIC was significantly reduced in neu-transduced WB clones, compared with control virus-infected and parental WB cells. Western blot analysis of connexin 43 in the neu-transduced cell lines showed altered phosphorylation patterns compared with the normal WB-rat liver cell line. Confocal image analysis of the neu-transduced cells showed that the connexin 43 protein, as detected by fluorescent immunostaining, was localized in the cell nucleus. The neu-transduced WB cell lines also acquired the ability to grow in soft agar. Furthermore, cells from three of the five neu-transduced cell lines, when injected into the liver of Fischer F344 rats through the portal vein, were highly tumorigenic (multiple focal hepatic tumors developed within 2 weeks). Cells derived from the tumor were shown to be G-418 resistant, demonstrating that the tumor was derived from the injected WB-neu cells. The results of this study demonstrate that the expression of the neu oncogene is able to block GJIC and to induce tumorigenicity in the rat liver WB-F344 cell line.
Carcinogenesis 1995 Feb
PMID:Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene. 785 63

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

Point mutations of the transmembrane domain coding region of the neu proto-oncogene in N-nitroso-N-ethylurea-induced hamster neurofibromas were found at high frequency (93%; 14 of 15). They involved codons 659 as well as 658, the latter not having been reported previously in rat tumors. The mutational change was seen even in the early stage neurofibroma. On the other hand, no mutations were detected in melanomas or Wilms' tumors induced in the same N-nitroso-N-ethylurea-treated animals, even when the melanomas demonstrated extensive schwannian differentiation. Moreover, any human Schwann cell tumors including neurofibroma, schwannoma, and malignant schwannoma did not show the mutation of c-erbB-2 gene (0 of 34), which is homologous to the hamster neu. Since high expression of neu mRNA is evident in the hamster Schwann cell at the late gestational and neonatal stages, transplacental administration of N-nitroso-N-ethylurea is considered to interact directly to carcinogenesis of the hamster Schwann cell through neu gene mutation.
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PMID:neu proto-oncogene mutation is specific for the neurofibromas in a N-nitroso-N-ethylurea-induced hamster neurofibromatosis model but not for hamster melanomas and human Schwann cell tumors. 790 99

Over-expression of the c-erbB-2 oncogene-encoded p185 protein product has been implicated in the pathogenesis of a wide variety of human malignancies, including lung cancer. Over-expression of p185 can be detected immunologically by quantification of the extracellular domain of p185 (c-erbB-2 oncopeptide) in extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the c-erbB-2 oncopeptide was used to examine banked serum samples of 11 pneumoconiosis patients who subsequently developed lung cancer and serum samples from 11 hospital controls matched for age, sex, ethnic group and smoking as well as 55 unmatched general population controls. The mean serum level for the c-erbB-2 oncopeptide in human neu units/ml in the lung cancer cases (1,756 +/- 549 HNU/ml) was statistically significantly elevated (p < 0.001) in comparison to the mean level in the matched controls (976 +/- 488 HNU/ml) or the general population controls (888 +/- 655 HNU/ml). Defining a positive elevation of the serum c-erbB-2 oncopeptide as any value more than 2 standard deviations above the mean of the matched controls, 64% (7 of 11) of the lung cancer cases were positive compared to 0% (0 of 11) matched controls and 5% (3 of 55) of the unmatched controls. In addition, 4 of the 7 c-erbB-2 oncopeptide-positive cancer cases had positive serum samples prior to the time of disease diagnosis (average = 35 months). These results suggest that serum c-erbB-2 oncopeptide may be elevated at an early stage of pulmonary carcinogenesis and that further prospective study of the utility of this biomarker is warranted.
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PMID:Detection of increased amounts of the extracellular domain of the c-erbB-2 oncoprotein in serum during pulmonary carcinogenesis in humans. 790 54

In 58 gastric carcinomas the expression of the Her2/neu gene product p185 was immunohistochemically analyzed. Fresh tumor tissue for molecular studies was available in 25 cases. The results were correlated with various pathohistological and prognostic factors. A 16-32fold Her2/neu amplification was found in 20% of the tumors (n = 5). The oncogene product p185 was detected at the basement membrane in 38% of the tumors (n = 22). Amplification and p185 overexpression occurred in intestinal, but not diffuse type carcinomas (p < 0.001). p185 expression was independent from tumor site and tumor stage, but correlated with pT-stage (p < 0.001). Overall prognosis was influenced by tumor stage and R-classification, but not by p185 expression. Multivariate analysis, however, defined patients with stage IIIA/B and IV and R0-resection who had a poorer survival in case of p185 expression (p < 0.05). Her2/neu amplification and p185 overexpression appear to be characteristic molecular events in intestinal type gastric carcinogenesis and may help in identifying a subgroup of patients at increased risk for shorter survival.
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PMID:[Molecular biology and immunohistochemical studies of Her2/neu oncogene in stomach cancer]. 791 66

Three transgenic mouse lines carrying v-Ha-ras (TG-SH), c-myc (TG-M) or c-neu (TG-NK) oncogenes under regulatory control of mouse mammary tumor virus (MMTV) long terminal repeat (LTR) sequences were evaluated for responses to two chemical carcinogens. p-Cresidine, a mutagenic urinary bladder carcinogen, increased the incidence of urinary bladder carcinomas in males and females in all three lines, and these tumors occurred at comparable incidences and grade in transgenic and non-transgenic mice. p-Cresidine did not affect the rates of mammary or salivary gland neoplasms in transgenic mice; these tumors did not occur in non-transgenic littermates. No other tumor types were observed in exposed or control animals. Reserpine, a non-mutagenic mammary gland carcinogen, was administered under the same protocol, but the high control rates of mammary gland adenocarcinomas in the TG-M and TG-NK strains made it difficult to detect any tumor-enhancing effect of reserpine. However, the incidences of multiple mammary gland tumors were significantly increased in dosed females from both lines. The incidence of mammary gland adenocarcinomas was significantly increased in TG-SH females receiving 5 p.p.m. reserpine. Reserpine did not induce any carcinogenic effects in non-transgenic mice. These results indicate that the transcriptional regulation of these three transgenes is a major determinant in the response to p-cresidine and reserpine. The use of transgenic models for the general detection of carcinogens may require lines in which appropriate genes are targeted for expression in many tissues, or lines in which critical genes have been inactivated.
Carcinogenesis 1993 Jan
PMID:Chemical effects in transgenic mice bearing oncogenes expressed in mammary tissue. 809 62


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