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

Furan cholangiocarcinogenesis in rat liver is proving to be a unique and useful animal model for investigating important aspects of the cellular and molecular pathogenesis of cholangiocarcinoma potentially relevant to the human disease. We now describe the first culture model of rat cholangiocarcinoma cells derived from a transplantable cholangiocarcinoma originally induced in the liver of a furan-treated rat. An epithelial cell isolate highly enriched in viable cholangiocarcinoma cells was consistently obtained from transplantable cholangiocarcinoma tissue utilizing a similar procedure to that recently developed by us to establish a new rat hyperplastic bile ductular epithelial cell culture model characterized by the appearance of polarized bile ducts in vitro. Primary cholangiocarcinoma cell cultures could be readily established with these isolated cells and, in addition, we established from one such culture a novel rat cholangiocarcinoma cell line designated C611B. Cultured C611B cholangiocarcinoma cells retained a number of important characteristic features of the carcinoma cells of the parent tumor, including marked expression of the tyrosine kinase growth factor receptor proteins c-Met and c-Neu. Under basal culture conditions, the C611B cell line exhibited a cell doubling time of approximately 24 h and was aneuploid, with a predominant chromosomal count of 43. Moreover, C611B cells on collagen gels were 100% tumorigenic when transplanted into inguinal fat pads of syngeneic rats. All tumors formed at the transplantation site were cytokeratin 19-positive, mucin-producing tubular adenocarcinomas whose histological and phenotypic features closely resembled those of the furan-induced parent transplantable rat cholangiocarcinoma. Based on our findings, we believe that this novel rat cholangiocarcinoma cell culture model can serve as a valuable resource for investigating aberrant growth properties and tumor progression in biliary cancer.
Carcinogenesis 1999 Dec
PMID:Establishment of a novel rat cholangiocarcinoma cell culture model. 1059 Feb 29

A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Sprague-Dawley strain in Japan, and named the rising "Nihon" rat. In this strain, RCs develop from early preneoplastic lesions, which begin to appear at 4 weeks of age, forming adenomas by the age of 16 weeks. The RCs are predominantly of clear cell type. Southern blot, northern blot and SSCP analyses revealed no change in the Tsc1, Tsc2, VHL, and c-Met genes. Thus, the Nihon rat should be a valuable experimental model for understanding renal carcinogenesis, especially clear cell type, which is common among human RCs.
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PMID:A novel "Nihon" rat model of a Mendelian dominantly inherited renal cell carcinoma. 1109 72

Hepatocyte growth factor (HGF) is a multifunctional cytokine which acts as a mitogen, motogen, morphogen and angiogenic factor of epithelial cells. HGF receptor is encoded by a proto-oncogene, c-met, which is overexpressed in various cancers. The role of HGF and c-Met in prostate carcinogenesis, especially in the early stages, is undefined. In this study, prostatic dysplasia and carcinomas were induced by testosterone propionate and 17 beta-estradiol in Noble rats. The expression of HGF and c-Met was assessed at a protein level by immunohistochemistry and western blot analysis. Intense immunostaining for HGF alpha and c-Met beta-chain was co-localized in dysplastic lesions and in primary and metastatic cancer cells. The levels of HGF alpha expression were similar among normal control, dysplastic and cancerous prostate tissues, as determined by western blot analysis. Immunoblot study for c-Met under reducing conditions identified two bands at 145 kDa (beta-subunit of c-Met) and 170 kDa (precursor form of c-Met) in rat liver extracts. However, two bands at approximately 220 and 245 kDa were detected in hormone-treated dysplastic prostate tissues and primary tumors. Overexpression of the 220 kDa band was observed in long-term (10-12 months) hormone-treated prostate and primary tumor extracts. Metastatic tumors consistently exhibited up-regulation of a single 245 kDa band. Under non-reducing conditions, however, protein bands of 220, 280 or 300 kDa were seen in the blots. The hormone-treated prostate tissues and metastatic tumors expressed the 220 and 300 kDa proteins, respectively. The majority of primary tumors expressed the 280 kDa protein. In summary, HGF and its receptor, c-Met, were co-expressed in dysplastic and tumor cells, suggesting that an autocrine mode of action may be involved in prostate carcinogenesis. The close correlation of expression of the high-molecular-weight isoforms of c-Met with different stages of carcinogenesis implicates that they might play differential roles in the onset, progression, growth and metastasis in prostate cancer.
Carcinogenesis 2000 Dec
PMID:Aberrant expression of hepatocyte growth factor and its receptor, c-Met, during sex hormone-induced prostatic carcinogenesis in the Noble rat. 1113 7

Tumour progression to the metastatic phenotype is mainly dependent on tumour cell invasiveness. Cell migration is a crucial step in this process. Here we investigate the effect of hepatocyte growth factor (HGF) on the induction of in vitro invasiveness of poorly aggressive Caco-2 colonic cancer epithelial cells. Invasion assays through a Matrigel barrier were performed. Proteases were assessed by zymography, reverse transcription-polymerase chain reaction and immunoblotting. Caco-2 cells were found to express HGF receptor but not HGF and to secrete several proteases, namely matrix metalloproteinase-1 (MMP-1), MMP-2, possibly MMP-9 and urokinase plasminogen activator (uPA). Exogenous HGF promoted invasiveness of Caco-2 cells through an artificial basement membrane matrix and enhanced their production of proteases. In addition, analyses of media at the end of invasion assays indicated that anti-HGF antibody inhibited protease production in parallel with cell invasion. The involvement of proteases in the HGF-induced invasion process was further investigated using either a synthetic general MMP inhibitor or neutralizing antibodies against MMPs or uPA. All components significantly inhibited HGF-promoted cell invasion. Moreover, specific inhibitors of PKCalpha/beta1 and PI3 kinase also decreased both HGF-promoted cell invasion and protease expression in invasion assay media. Thus, our findings provide evidence that the process of HGF-activated invasiveness of Caco-2 cells involves PI3 kinase and PKC and results from close association of two events, stimulation of cell motile activity and concomitant overproduction of proteases, which permits cell migration through a degraded extracellular matrix.
Carcinogenesis 2001 Jul
PMID:Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. 1140 46

Growth factor receptor tyrosine kinase signaling plays key roles in regulating growth of normal hepatocytes, however, which receptor-type tyrosine kinase (RTK) is involved in hepatocarcinogenesis remains undetermined. The aim of this study was to characterize the expression of these receptors in different stages of rat liver carcinogenesis. We compared the expression profile of RTK genes in rat normal liver and diethylnitrosamine-induced hepatoma tissues using a homology cloning method with degenerated primers. In situ hybridization, immunohistochemical staining, and RT-PCR were performed to analyze the cell type-specific expression of target RTKs during the chemically-induced hepatocarcinogenesis. Sequence analysis of 459 clones identified 23 different RTK genes. The Tie-2, c-Met, and Flk-1 genes were the most abundant RTK genes cloned in rat hepatoma compared to normal liver. In situ hybridization and immunohistochemical studies showed overexpression of c-Met and Flk-1 in GST-P positive preneoplastic lesions as well as neoplastic lesions. Tie-2 was expressed not only in endothelial cells but also in so-called oval cells, which are thought to be liver stem cells. Tie-2 ligand, angiopointin-1, mRNA was detected in both normal livers and hepatoma cells/tissues. In contrast, angiopoietin-2 mRNA was detected only in hepatoma tissues. These results indicate that c-Met, Tie-2 and Flk-1 signals play important roles in different stages of chemically-induced hepatocarcinogenesis. Distinctive gene expression of RTK may contribute to epigenic implication of hepatoma formation.
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PMID:Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis. 1195 51

Hepatocyte growth factor (HGF) was discovered as a potent mitogen for adult hepatocytes from the plasma of patients with fulminant hepatic failure. It is now known to be a broad-spectrum, multi-functional mitogen, motogen and morphogen. The activities of HGF are mediated through the signalling pathway of its receptor, c-Met. During tooth development, HGF is expressed in the dental papilla and c-Met is expressed in the inner enamel epithelium. The expression of HGF and c-Met indicates that HGF is involved in morphogenesis of the tooth by mediating epithelial-mesenchymal interactions. In the mature tooth, HGF expression by fibroblasts is enhanced in pulpitis and mediated through the induction of prostaglandin (PG) E(2); it is induced not only by inflammatory cytokines, but also by components of oral bacteria. Consequently, concentrations of HGF in gingival crevicular fluid (GCF) increase in periodontitis. The mitogenic and other biological activities, such as angiogenesis, of HGF contribute towards wound healing. Both HGF and c-Met are expressed in the developing tongue, and the signalling pathway of the latter is shown to be essential for myogenesis. Dysregulation of c-Met signalling is observed in carcinogenesis, but HGF also has cytotoxic activity to certain tumour cells. The reason for the discrepancy between these observations is not clear at present.
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PMID:Hepatocyte growth factor/scatter factor in development, inflammation and carcinogenesis: its expression and role in oral tissues. 1459 69

Interactions between hepatocyte growth factor (HGF) and its receptor, c-Met, have been associated with invasion, metastasis and carcinogenesis in in vitro experiments. We investigated the relationship between HGF/c-Met immunoreactivity and the clinical features of 33 patients with high grade salivary gland carcinomas. c-Met and stromal HGF (expression of HGF in fibroblasts adjacent to tumor nests) were found to significantly correlate with regional lymph node and distant metastasis (p<0.05), but not with HGF expression, in tumor cells. Stromal HGF was also found to correlate with tumor size (p<0.05). In addition, a significant correlation between c-Met and stromal HGF expression (p<0.0001) was observed. Overall survival in patients with c-Met and stromal HGF immunoreactivity was significantly worse than in patients without c-Met and stromal HGF immunoreactivity (p=0.0002). The present findings suggest that HGF may bind to c-Met in a paracrine fashion, thereby enabling metastasis of high grade salivary gland carcinomas. Thus, HGF/c-Met immunoreactivity might be associated with a poor prognosis in patients with high grade salivary gland carcinomas.
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PMID:Hepatocyte growth factor and c-Met immunoreactivity are associated with metastasis in high grade salivary gland carcinoma. 1549 87

Neuroblastoma is the most frequent extracranial solid malignancy of childhood with a high mortality in advanced tumour stages. The hallmark of neuroblastoma is its clinical and biological heterogeneity. The molecular mechanisms leading to favourable or unfavourable tumour behaviour are still speculative. However, amplification of the oncogene MYCN and expression of the neurotrophin receptor TrkB are known to contribute to a highly malignant phenotype. To define the mechanisms through which TrkB may mediate neuroblastoma progression, we stably expressed this receptor in the neuroblastoma cell lines SH-SY5Y and SK-N-AS. The transfectants, but not the controls, had an increased invasive potency both, in vitro and in vivo, as demonstrated by Matrigel-invasion and chorioallantoic membrane assays, respectively. The retinoic acid-induced TrkB expression in parental SH-SY5Y cells was also associated with enhanced cell invasiveness. The TrkB mediated invasiveness involved the upregulation of the hepatocyte growth factor (HGF) and its receptor c-Met, resulting in an autocrine loop. Inhibition of HGF activity by anti-HGF neutralizing antibodies or disabling the function of c-Met by small interfering RNA suppressed the TrkB-induced invasiveness. The enhanced TrkB expression was associated with a significant increase in the secretion of various matrix-degrading proteases. Immunostaining and real-time RT-PCR analysis of tumour specimens demonstrated coordinated expression of TrkB and HGF/c-Met in experimental and primary neuroblastomas. We conclude that TrkB expression in neuroblastoma cells results in an increase in their invasive capability via upregulated expression of HGF/c-Met and enhanced activity of proteolytic networks.
Carcinogenesis 2005 Dec
PMID:The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness. 1605 41

Several studies have suggested a possible role of the hepatocyte growth factor (HGF)/c-Met system in lung tumor development and progression. Extent of expression of both HGF and c-Met have been shown to be negative prognostic indicators of survival and recurrence in non-small-cell lung cancer, especially adenocarcinoma. To further define a role for HGF in lung cancer development and growth, we have generated transgenic mice that overexpress HGF in the airway epithelium. HGF transgenic and wild-type mice were exposed to the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or saline control and killed 10-38 weeks after exposure. Lungs were formalin inflated, paraffin embedded and sectioned. It was verified that the HGF transgene was expressed only in the lungs of transgenic mice. The transgenic mouse lung histology exhibited congestion in the alveolar spaces, excess production of blood vessels and a convoluted pattern of airways with wide bifurcations. The number of lung tumors from NNK-treated transgenic animals versus the number of lung tumors from NNK-treated wild-type animals was significantly higher (P = 0.0001, Poisson regression). The percentage of animals with tumors was 75% in the transgenic group compared with 48.8% in the wild-type group. The main effect was an increase in tumor multiplicity; average size of tumors was not different between the groups. Additionally, the tumors that arose in the transgenic mice contained increased HGF protein compared with tumors from the wild-type mice. These results indicate that lung carcinogenesis induced by a tobacco carcinogen is enhanced by expression of the HGF transgene. This model recapitulates the phenotype of aggressive lung adenocarcinoma that overexpresses HGF and will be useful in evaluating antitumor agents that target either the HGF/c-Met pathway or downstream effects such as angiogenesis or invasion.
Carcinogenesis 2006 Aug
PMID:Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer. 1651 78

Helicobacter pylori interacts with gastric epithelial cells, activating signaling pathways important for carcinogenesis. In this study we examined the role of H. pylori on cell invasion and the molecular mechanisms underlying this process. The relevance of H. pylori cag pathogenicity island-encoded type IV secretion system (T4SS), CagA, and VacA for cell invasion was also investigated. We found that H. pylori induces AGS cell invasion in collagen type I and in Matrigel invasion assays. H. pylori-induced cell invasion requires the direct contact between bacteria and cancer cells. H. pylori-mediated cell invasion was dependent on the activation of the c-Met receptor and on increased MMP-2 and MMP-9 activity. The abrogation of the c-Met receptor using the specific NK4 inhibitor or the silencing of c-Met expression with small interference RNA suppressed both cell invasion and MMP activity. Studies with different H. pylori strains revealed that cell invasion, c-Met tyrosine phosphorylation, and increased MMP-2 and MMP-9 activity were all dependent on the presence of a functional bacterial T4SS, but not on VacA cytotoxicity. Our findings demonstrate that H. pylori strains with a functional T4SS stimulate gastric epithelial cell invasion through a c-Met-dependent signaling pathway that comprises an increase in MMP-2 and MMP-9 activity.
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PMID:Helicobacter pylori induces gastric epithelial cell invasion in a c-Met and type IV secretion system-dependent manner. 1699 Feb 73


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