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Dominique Wendum

Publications and source records attributed to Dominique Wendum.

34 records · Page 2Linked to original sources
PubMed2005

Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma.

De-regulations in insulin and insulin-like growth factor (IGF) pathways may contribute to hepatocellular carcinoma. Although intracellular insulin receptor substrate-2 (IRS-2) is the main effector of insulin signaling in the liver, its role in hepatocarcinogenesis is unknown. Here, we show that IRS-2 was overexpressed in two murine models of hepatocarcinogenesis: administration of diethylnitrosamine and hepatic overexpression of SV40 large T antigen. In both models, IRS-2 overexpression was detected in preneoplastic lesions and at higher levels in tumoral nodules. IRS-2 overexpression associated with IGF-2 and IRS-1 overexpression and with GSK-3beta inhibition. Increased expression of IRS-2 was also detected in human hepatocellular carcinoma specimens and hepatoma cell lines. In murine and human hepatoma cells, IRS-2 protein induction associated with increased IRS-2 mRNA levels. The functionality of IRS-2 was demonstrated in Hep 3 B cells, in which IRS-2 tyrosine phosphorylation and its association with phosphatidylinositol-3 kinase were induced by IGF-2. Moreover, down-regulation of IRS-2 expression increased apoptosis in these cells. In conclusion, we demonstrate that IRS-2 is overexpressed in human and murine hepatocellular carcinoma. The emergence of IRS-2 overexpression at preneoplastic stages during experimental hepatocarcinogenesis and its protective effect against apoptosis suggest that IRS-2 contributes to liver tumor progression.

Alkylating Agents↗
PubMed2005

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer.

In colorectal cancer, cyclooxygenase-2 (COX-2) overexpression in stromal cells induces angiogenesis through EP2 prostaglandin E2 receptor signaling. Cytoplasmic phospholipase A2 (PLA2) alpha preferentially hydrolyses arachidonic acid, which is the limiting substrate for prostaglandin production, from membrane phospholipids. We therefore investigated a possible relationship between cytoplasmic PLA2 and COX-2 overexpression in stromal cells, angiogenesis and microsatellite instability in 48 human colorectal adenocarcinomas. Cytoplasmic PLA2 and COX-2 expression in stromal cells and vascular endothelial growth factor (VEGF) expression in tumor cells were evaluated by immunohistochemistry. Microvessel density was assessed in 10 x 400 fields after CD31 staining. Microsatellite instability was evaluated by PCR and immunohistochemistry. A total of 16 tumors had microsatellite instability. We found an overexpression of cytoplasmic PLA2 in superficial stromal cells. These cells corresponded to fibroblasts and myofibroblasts. There was an association between the number of cytoplasmic PLA2 and COX-2-expressing cells (P=0.006). Cytoplasmic PLA2-positive stromal cells usually also expressed COX-2. A high number of cytoplasmic PLA2-positive stromal cells was correlated with a high microvessel density (P=0.002), a strong VEGF (P=0.01) and the absence of microsatellite instability (P=0.001). The coordinate overexpression of cytoplasmic PLA2 and COX-2 in stromal cells could lead to an important prostaglandin production. These results suggest that cytoplasmic PLA2 overexpression in these cells regulates COX-induced angiogenesis probably by providing arachidonic acid, which is the limiting factor for prostaglandin production. The lower number of cytoplasmic PLA2-positive stromal cells in carcinomas with microsatellite instability could be related to their lower microvessel density and VEGF expression.

Adult↗
PubMed2004

Cyclooxygenase-2 and its role in colorectal cancer development.

Cyclooxygenase 2 (COX-2), also called prostaglandin endoperoxide synthase 2, is involved in colorectal tumor development. This review deals with particular questions raised in this field such as the mechanisms of COX-2 related tumor promotion, the role of the different types of cells (epithelial and interstitial) expressing COX-2, the factors that trigger COX-2 induction, and the clinical potential of selective COX-2 inhibitors to treat or prevent colorectal tumors. Several mechanisms of COX-2 related tumor promotion have been identified. Some are dependent on prostaglandin E(2) production (such as induction of cell proliferation, angiogenenis or local immunosuppression, inhibition of apoptosis, increase in cell motility) and others are not (such as carcinogen activation or malondialdehyde production). COX-2 expression has been demonstrated in epithelial cells of colorectal cancers and adenomas and also in interstitial cells. These cells correspond to macrophages and/or fibroblasts and endothelial cells. COX-2 expression in these interstitial cells participates in tumor development. Factors or events that trigger COX-2 expression include oncogene activation, antioncogene inactivation, cytokines, growth factors, some fatty acids, bile salts, and mucins. Finally, selective COX-2 inhibitors may be effective in preventing or treating colorectal adenomas or carcinomas. However, their real efficiency and the cost/benefit balance are currently evaluated, and no definite conclusion can be made at the moment.

Adenomatous Polyposis Coli↗
PubMed2004

Expression of inflammatory secretory phospholipase A2 and cytosolic phospholipase A2 in premalignant and malignant Barrett's oesophagus.

AIMS: To establish the prevalence of inflammatory secretory phospholipase A2 (sPLA2) and cytoplasmic phospholipase A2 (cPLA2) expression in a surgical series of Barrett's adenocarcinoma and associated preneoplastic lesions and to correlate this expression with clinicopathological data and prognosis. METHODS: sPLA2 and cPLA2 were analysed by means of immunohistochemistry in surgical specimens of 67 and 73 cases of Barrett's adenocarcinomas, respectively. Barrett's mucosa was analysed in 31 cases. RESULTS: Expression of sPLA2 was detected in 48% of Barrett's mucosa negative for intraepithelial neoplasia and 63% of Barrett's adenocarcinoma. Semi-quantitative analysis revealed a significant increase in sPLA2 expression between Barrett's mucosa negative for intraepithelial neoplasia and adenocarcinoma. cPLA2 expression was detected in 18% of Barrett's adenocarcinoma. An inverse correlation was found between cPLA2 expression and depth of tumour infiltration, neoplastic vascular invasion and neoplastic perineural invasion. Survival analysis showed no significant prognostic value for sPLA2 and cPLA2. CONCLUSION: sPLA2 is frequently expressed in Barrett's oesophagus. The increasing expression of sPLA2 that we observed from Barrett's mucosa to adenocarcinoma suggests that sPLA2 could be involved in Barrett's carcinogenesis. In contrast, cPLA2 expression is less frequently observed in Barrett's oesophagus and is inversely associated with aggressive pathological features of the tumours.

Adenocarcinoma↗
PubMed2004

Cytosolic phospholipase A2-p11 interaction controls arachidonic acid release as a function of epithelial cell confluence.

Madin-Darby canine kidney type II cells were shown to release low amounts of AA (arachidonic acid) and prostaglandin E2 in response to various stimuli when analysed after cell confluence. In contrast, non-confluent Madin-Darby canine kidney type II cells released much higher amounts of AA and prostaglandin E2. In both stationary and non-confluent cells, AA was released by type IV cPLA2 (cytosolic phospholipase A2), as shown by the use of specific inhibitors and by analysis of the profile of fatty acids released. This confluence-dependent cPLA2 activation was not due to a difference in expression, or in phosphorylation of the enzyme, or in the amount of its substrate. To find out the mechanism by which cPLA2 activation may be regulated as a function of cell confluence, immunofluorescence and co-immunoprecipitation experiments were performed using cPLA2, p11, a natural inhibitor of the enzyme, and annexin II, the natural ligand of p11. These three proteins were expressed at a constant level, regardless of the cell confluence. In contrast, whereas annexin II and cPLA2 interacted at a constant rate, p11 and cPLA2 interacted more strongly in stationary cells, thus indicating that cPLA2 activation is regulated by its accessibility to p11, independent of their expression level. Our results indicate that, in epithelial cells, the cell confluence, i.e. the establishment of cell-cell contacts, rather than cell proliferation directly controls cPLA2 activation by changing the stoichiometry of p11/cPLA2 interaction.

Animals↗
PubMed2004

[Liver involvement revealing systemic mastocytosis: report of two cases].

Systemic mastocytosis is a disease defined by an abnormal infiltration of mast cells involving several extra-cutaneous organs. Hepatic involvement is frequent, however it rarely reveals the disease. We report two cases of systemic mastocytosis revealed by hepatic symptoms: liver failure in one case and jaundice in the second case. The diagnosis is often difficult. Mast cell tissular infiltration can be identified on paraffin sections by tryptase or CD117 (c-kit) immuno-staining.

Aged↗
PubMed2004

Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis.

BACKGROUND/AIM: We have previously shown that the histological stage and severity of lymphocytic piecemeal necrosis (LPN) are independent predictive factors of cirrhosis development in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cirrhosis (PBC). Our aim during this study was to determine whether biochemical parameters classically used in PBC management and measured under UDCA could be considered as reliable surrogate markers for these histological prognostic indices in clinical practice. METHOD: The study included 153 patients with PBC who had undergone a control liver biopsy after 2 years of UDCA therapy. The relationships between histological and biological features were assessed by variance analysis and logistic regression. The diagnostic value of independent markers was assessed in terms of their sensitivity, specificity, positive predictive value (PPV) and negative value (NPV) and receiver-operating characteristic curves. RESULTS: Two variables were independently associated with extensive fibrosis (i.e. advanced histological stages): serum levels of bilirubin and hyaluronic acid (HA). A fibrosis index ([bilirubin (micromol/l)/14]+[HA (microg/l)/143]) higher than 1.5 exhibited good PPV and specificity (>74%) but rather poor NPV and sensitivity (<64%) regarding a diagnosis of extensive fibrosis. The only independent marker of LPN was aspartate aminotransferase (AST) activity. AST activity of more than twice the upper limit of normal showed acceptable PPV (>70%) but very low sensitivity (<25%) for a diagnosis of LPN. CONCLUSIONS: Serum bilirubin and HA levels measured under UDCA therapy are of acceptable diagnostic value for extensive fibrosis, but none of the biochemical tests commonly employed in the management of PBC can be considered as surrogate markers of LPN. Taken together with our previous results, these findings suggest that liver biopsy may be necessary to screen UDCA-treated patients who might require additional therapies.

Aspartate Aminotransferases↗
PubMed2003

The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis.

The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle alpha-actin-immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle alpha-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle alpha-actin, alpha1 (I) collagen mRNA, and PDGF receptor-beta subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease P100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle alpha-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct-ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle alpha-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis.

Actins↗
PubMed2003

COX-2, inflammatory secreted PLA2, and cytoplasmic PLA2 protein expression in small bowel adenocarcinomas compared with colorectal adenocarcinomas.

Cyclooxygenase-2 (COX-2), human synovial inflammatory secreted phospholipase A2 (sPLA2) and cytoplasmic phospholipase A2 (cPLA2) are involved in eicosanoid production and also seem to participate in colorectal tumorigenesis. As there are no data regarding these enzymes in human small bowel tumors, we wanted to determine whether they were involved in human small bowel tumorigenesis, and whether their expression was different in small bowel compared to colorectal adenocarcinomas, as suggested by animal studies. We studied their protein expression by immunohistochemistry in 25 small bowel adenocarcinomas and compared it to 48 colorectal adenocarcinomas. Seventy-six percent of the small bowel and 88% of the colorectal adenocarcinomas had a moderate or strong COX-2 expression. Sixty-eight percent of the small bowel and 67% of the colorectal adenocarcinomas had a moderate or strong sPLA2 expression. Forty-eight percent of the small bowel and 35% of the colorectal adenocarcinomas had a moderate or strong cPLA2 expression. In conclusion, the increased expression of COX-2, sPLA2, and sometimes cPLA2 in both small bowel and colorectal adenocarcinomas is in accordance with the likely eicosanoid involvement in tumor development. The same pattern of protein expression found in both types of adenocarcinoma contradicts experimental results in mice. Moreover, our results strengthen the similarities between these two types of human cancer.

Adenocarcinoma↗
PubMed2003

[Quality assessment of intraoperative frozen sections in a teaching hospital: an analysis of 847 consecutive cases].

We evaluated the accuracy of 847 consecutive frozen section diagnoses in order to develop a quality control. We also evaluated the time needed to perform them. Frozen sections and final diagnoses agreed in 92.6% and disagreed in 1.7% (14 cases). 5.8% of the cases were deferred. The only case of false-positive frozen sections (0.1%) was due to a pathologist's misinterpretation. False-negative frozen sections were due to sampling errors: in 5 cases, diagnostic tissue was present only in permanent sections of the frozen block and in 8 cases diagnostic tissue was present only in the portion of the specimen not sampled by the frozen section. One hundred and ninety two frozen sections concerned thyroid neoplasms. Thirteen cancers were diagnosed on frozen sections, 2 cancers were considered as benign and 9 cancers had a differed diagnosis. The mean duration to perform the frozen sections was 21 minutes. In conclusion, intra operative frozen section diagnosis is rapid and reliable. Discrepancies are more often false negatives due to sampling errors. Although a high rate of differed diagnosis was observed in thyroid neoplasms, frozen sections remain useful for these lesions. Imprint cytology of thyroid nodules is advisable.

Biopsy↗
PubMed2002

Mucinous colon carcinomas with microsatellite instability have a lower microvessel density and lower vascular endothelial growth factor expression.

We determined the association between cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and microsatellite instability (MSI) or the histological type in colon adenocarcinomas. Sixty-six cases were studied, 28 MSI+ and 38 MSI-. MSI phenotype was determined using polymerase chain reaction. MVD was assessed after CD31 staining in ten x400 fields (0.96 mm(2)) in the most vascularized areas. VEGF and COX-2 expression were studied by means of immunohistochemistry. MVD positively correlated with the levels of VEGF expression (P=10(-4)) and also with the levels of COX-2 expression (P=0.007). MVD and VEGF expression were lower in MSI+ carcinomas (P=0.002 and P=0.03 respectively). When mucinous tumors were excluded from the statistical analysis, the association between low MVD, low VEGF and MSI status disappeared (P=0.5, P=1, respectively). MSI+ mucinous carcinomas had a lower MVD and VEGF expression than other MSI+ carcinomas (P=0.008 and P=0.004, respectively) and MSI- mucinous carcinomas (P=0.01 and P=0.001, respectively). COX-2 expression was lower in medullary carcinomas (P=0.001). In conclusion, mucinous MSI+ colon carcinomas represent a special group of colon adenocarcinomas relating to angiogenesis, with a lower MVD and VEGF expression than both MSI- mucinous carcinomas and MSI+ non-mucinous carcinomas. A low COX-2 expression could be related to the medullary phenotype. However, this has to be confirmed in a larger series. Finally, the low MVD of MSI+ mucinous colon adenocarcinomas could participate in their overall better prognosis.

Adenocarcinoma, Mucinous↗
PubMed2002

Hepatocyte growth factor and c-Met inhibition by hepatic cell hypoxia: a potential mechanism for liver regeneration failure in experimental cirrhosis.

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Animals↗
PubMed2002

Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.

Cirrhosis consists of hepatocyte nodules surrounded by a highly vascularized fibrous tissue. We previously showed that the development of biliary cirrhosis in the rat is associated with the occurrence of hepatocellular hypoxia and the induction of hepatic angiogenesis. We herein examined the occurrence of hypoxia in an experimental model of diethylnitrosamine (DEN)-induced cirrhosis. We also determined whether hypoxia directly affects the expression of vascular endothelial growth factor (VEGF), of VEGF receptors (Flt-1, Flk-1), and of type I and type IV collagens in activated hepatic stellate cells (HSCs) and the expression of VEGF in hepatocytes. Our results show that in DEN-treated rats, although the progression of liver fibrosis is associated with hepatocellular hypoxia and angiogenesis, VEGF and Flt-1 expressions in the liver are increased and correlated with the density of microvessels. In vitro, hypoxia induces the expression of VEGF, Flt-1, and type I collagen in activated HSCs and that of VEGF in hepatocytes. In addition, we show that hypoxia-induced type I collagen expression in HSCs may occur independently of transforming growth factor beta1 (TGF-beta1) overexpression. In conclusion, the present study provides further evidence that hepatocellular hypoxia and angiogenesis progress together with fibrogenesis after liver injury and that hypoxia directly contributes to the progression of liver fibrosis.

Alkylating Agents↗