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Jean-Frédéric Blanc

Publications and source records attributed to Jean-Frédéric Blanc.

13 recordsLinked to original sources
PubMed2006

Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity.

BACKGROUND/AIMS: Statins have beneficial effects in early pre-clinical models of hepatocellular carcinoma (HCC). Our aim was to test the efficacy of pravastatin on the progression of established HCC in rat, and to study its mechanisms. METHODS: HCC was induced with diethylnitrosamine and N-nitrosomorpholine. After 14 weeks, all rats developed HCC and then received pravastatin or its solvent for 10 weeks (10 rats/group). RESULTS: Liver tumor mass was lower in pravastatin group (PG) than control group (CG), as estimated from the number of liver tumors (p<0.004) and the liver weight/body weight ratio (p<0.04). Every CG rat surviving at 24 weeks (4/4) had lung metastasis, against only 5/8 in PG. Moreover, the percentage of lung surface occupied by metastasis was 10-fold smaller in PG than CG (p<0.016). Pravastatin decreased liver matrix metalloproteinase (MMP)-9 activity and mostly suppressed MMP-2 activation (p<0.004), likely because it decreased expression of MMP-14 and tissue inhibitor of matrix metalloproteinases-2 (p<0.01), required for MMP-2 activation. CONCLUSIONS: Pravastatin reduces progression and limits metastatic diffusion of established HCC. This could be linked to the decreased MMP activity. These results, obtained in a very aggressive HCC model, further suggest the potential benefit of statins in human HCC.

Animals↗
PubMed2006

Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition.

Halofuginone, an inhibitor of collagen synthesis, appears to be a promising antitumoral drug in preclinical studies. We used a relevant rat model of autochthonous, chemically induced, spontaneously metastasizing hepatocellular carcinoma (HCC) to test the efficacy of halofuginone on tumor progression and matrix metalloproteinase (MMP) expression. Following sequential administration of diethylnitrosamine and N-nitrosomorpholine for 14 weeks, all animals developed HCC and then received halofuginone or its solvent for 10 weeks. The final number of liver tumors was lower in the halofuginone group than in the solvent group (57.2 +/- 4.6 vs 68 +/- 5.0; P < .01). The percentage of the lung surface infiltrated by metastasis was much smaller in the halofuginone group (0.3 +/- 0.2%) than in the solvent group (13.5 +/- 10.1%; P < .02). MMP-9 activity was decreased in the halofuginone group by 89% and 63% in non-neoplastic parts of the liver and tumor, respectively. The percentage of active MMP-2 was reduced by 90% in non-neoplastic parts of the liver and by 61% in tumors. This was likely subsequent to a decreased expression of both MMP-14 and tissue inhibitor of matrix metalloproteinase-2, which are required for pro-MMP-2 activation. These results, obtained from a clinically relevant model, further suggest the potential benefit of halofuginone in HCC.

Angiogenesis Inhibitors↗
PubMed2006

Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis.

Matrix metalloproteinase (MMP)-3 is a protease involved in cancer progression and tissue remodeling. Using immunofluorescence and immunoelectron microscopy, we identified nuclear localization of MMP-3 in several cultured cell types and in human liver tissue sections. Western blot analysis of nuclear extracts revealed two immunoreactive forms of MMP-3 at 35 and 45 kd, with the 35-kd form exhibiting caseinolytic activity. By transient transfection, we expressed active MMP-3 fused to the enhanced green fluorescent protein (EGFP/aMMP-3) in Chinese hamster ovary cells. We showed that EGFP/aMMP-3 translocates into the nucleus. A functional nuclear localization signal was demonstrated by the loss of nuclear translocation after site-directed mutagenesis of a putative nuclear localization signal and by the ability of the MMP-3 nuclear localization signal to drive a heterologous protein into the nucleus. Finally, expression by Chinese hamster ovary cells of EGFP/aMMP-3 induced a twofold increase of apoptosis rate, compared with EGFP/pro-MMP-3, which does not translocate to the nucleus. Increased apoptosis was abolished by site-directed mutagenesis of the catalytic site of MMP-3 or by using the MMP inhibitor GM6001. This study elucidates for the first time the mechanisms of nuclear localization of a MMP and shows that nuclear MMP-3 can induce apoptosis via its catalytic activity.

Amino Acid Sequence↗
PubMed2005

Hypervascular nodule in a fibrotic liver overloaded with iron: identification of a premalignant area with preserved liver architecture.

BACKGROUND: The presence of a hypervascular nodule in a patient with cirrhosis is highly suggestive of a hepatocellular carcinoma. CASE PRESENTATION: A 55 year old man with idiopathic refractory anaemia was addressed for the cure of a recently appeared 3.3 cm hypervascular liver nodule. The nodule was not visible on the resected fresh specimen, but a paler zone was seen after formalin fixation. The surrounding liver was fibrotic (METAVIR score F3) and overloaded with iron. However, the paler zone, thought to be the nodule, had in fact a normal architecture, was less fibrotic, and contained some "portal tract-like structures" (but with arteries only); moreover, this paler area was devoid of iron, contained less glycogen and was characterized by foci of clear hepatocytes. CONCLUSION: In spite of the absence of architectural distortion, and a normal proliferative index, the possibility of premalignancy or malignancy should be considered in this type of hypervascular and hyposiderotic nodule, occurring in the context of an iron overloaded liver.

Journal Article↗
PubMed2005

Proteomic analysis of differentially expressed proteins in hepatocellular carcinoma developed in patients with chronic viral hepatitis C.

Hepatocellular carcinoma (HCC) is a major complication of chronic viral hepatitis C. Therapy for HCC is still disappointing. It is thus of great importance to identify novel HCC markers for early detection of the disease, and tumor-specific proteins as potential therapeutic targets. We have used a proteomic approach to identify new proteins involved in HCC development. Four cases of HCC developing from chronic viral hepatitis C were analyzed by two-dimensional electrophoresis (2-DE), and results were compared to those of paired adjacent non-tumorous liver tissues. For MS fingerprinting, protein spots with differential intensity between HCC and non-tumorous liver were directly cut out of gels and processed for MALDI-MS and nano-LC-ESI-MS/MS analysis. Approximately 850 spots were visualized in each gel. The comparative analysis of paired samples indicated that 345 protein spots showed significant differences in expression level between non-tumor and tumor tissue. Among the 345 protein spots analyzed, 238 spots corresponding to 155 different proteins were identified; 49 proteins were up-regulated, whereas 106 proteins were down-regulated. Among these 155 proteins, 91 proteins were regulated in at least three cases. Although 52 out of these 91 proteins have been already described by previous proteomic or transcriptomic studies, or are already known to be involved in hepatocarcinogenesis, this experiment revealed 39 new proteins differentially expressed in HCC developing from viral hepatitis C. Variations in protein accumulation were confirmed for two selected proteins (apolipoprotein E, chloride intracellular channel 1) by Western blotting in ten additional cases of HCC developing in patients with viral hepatitis C.

Aged↗
PubMed2005

Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver.

BACKGROUND & AIMS: Telangiectatic focal nodular hyperplasia (TFNH) of the liver is generally believed to belong to the focal nodular hyperplasia (FNH) family. The aim of this study was to use molecular markers, in addition to morphologic features, to better characterize TFNH. METHODS: Thirteen patients with TFNH were compared with 28 patients with FNH and 17 patients with hepatocellular adenoma. Full clinical and morphologic data were analyzed. Molecular markers included determination of clonality by examining the active X chromosome, genome-wide allelotyping, a search for hepatocyte nuclear factor 1alpha (HNF1alpha) mutations, and determination of ANGPT1/ANGPT2 transcript levels. RESULTS: No clinical differences were evident between patients with TFNH and adenoma; in particular, bleeding was observed in 77% and 53% of the cases, respectively. Patients with TFNH were more likely to experience nodule recurrence and the presence of multiple nodules than those with either FNH or adenoma. All TFNH and adenoma samples that were available for analysis were monoclonal, in contrast to 40% of the FNH samples. Chromosome losses confirmed monoclonality and were significantly less frequent in TFNH and FNH (22% and 26%) than in adenoma (53%). HNF1alpha mutations were found exclusively in half of the adenomas. ANGPT2 was overexpressed in TFNH and down-regulated in adenoma (P < .01) and FNH (P < .0005). CONCLUSIONS: TFNHs are monoclonal lesions frequently subject to bleeding that are similar to adenomas not carrying HNF1alpha mutations and require a similar type of treatment. However, morphologic and molecular data support the hypothesis that TFNH is a separate entity.

Adenoma, Liver Cell↗
PubMed2004

Expression of leukemia inhibitory factor (LIF) and its receptor gp190 in human liver and in cultured human liver myofibroblasts. Cloning of new isoforms of LIF mRNA.

BACKGROUND: The cytokine leukemia inhibitory factor (LIF) mediates its biological effects through binding to its high affinity receptor made of the low-affinity LIF receptor subunit gp190 (LIF-R) and the gp130 subunit. LIF exerts several important effects in the liver, however, data on liver expression of LIF are scarce. The aim of this study was to examine the expression of LIF and LIF-R in human liver. RESULTS: LIF expression, analyzed by immunohistochemistry, was barely detectable in normal liver but was strong within cirrhotic fibrous septa and was found in spindle-shaped cells compatible with myofibroblasts. Accordingly, cultured human liver myofibroblasts expressed high levels of LIF as shown by ELISA and Northern blot. Biological assay demonstrated that myofibroblast-derived LIF was fully active. RT-PCR showed expression of the LIF-D and M isoforms, and also of low levels of new variants of LIF-D and LIF-M resulting from deletion of exon 2 through alternative splicing. LIF receptor expression was detected mainly as a continuous sinusoidal staining that was enhanced in cirrhotic liver, suggestive of endothelial cell and/or hepatocyte labeling. Immunohistochemistry, flow cytometry and STAT-3 phosphorylation assays did not provide evidence for LIF receptor expression by myofibroblasts themselves. LIF secretion by cultured myofibroblasts was down regulated by the addition of interleukin-4. CONCLUSIONS: We show for the first time the expression of LIF in human liver myofibroblasts, as well as of two new isoforms of LIF mRNA. Expression of LIF by myofibroblasts and of its receptor by adjacent cells suggests a potential LIF paracrine loop in human liver that may play a role in the regulation of intra-hepatic inflammation.

Journal Article↗
PubMed2003

Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells.

The membrane type-1 matrix metalloproteinase (MT1-MMP), a protease originally identified in breast carcinoma, is characterized by its capacity to activate other MMPs (MMP-2 and MMP-13) and to degrade extracellular matrix. Our study was undertaken to localize and identify the MT1-MMP expressing cells in human breast adenocarcinomas. A textural analysis of images obtained by immunohistochemistry and in situ hybridization showed precisely the co-expression of alpha smooth muscle actin (alphaSM actin) and MT1-MMP in myofibroblasts. MT1-MMP expression is confined to myofibroblasts in close contact with tumor cells. In sharp contrast, the expression of MMP-2 was more widely distributed in both alphaSM actin positive and negative cells close to and at distance from cancer cell clusters. Our in vitro observations are consistent with the higher level of MT1-MMP expression and of MMP-2 activation observed in alphaSM actin positive fibroblasts derived from breast tumors, as compared to normal breast fibroblasts. Collectively, these results implicate myofibroblasts as major producer of MT1-MMP in breast cancer and emphasize the importance of stromal-epithelial cell interactions in their progression.

Actins↗
PubMed2002

Bi-allelic inactivation of TCF1 in hepatic adenomas.

Liver adenomas are benign tumors at risk of malignant transformation. In a genome-wide search for loss of heterozygosity (LOH) associated with liver adenomas, we found a deletion in chromosome 12q in five of ten adenomas. In most cases, LOH at 12q was the only recurrent genetic alteration observed, suggesting the presence of a tumor-suppressor gene in that region. A minimal common region of deletion was defined in 12q24 that included the gene TCF1 (transcription factor 1), encoding hepatocyte nuclear factor 1 (HNF1; refs 1,2). Heterozygous germline mutations of TCF1 have been identified in individuals affected with maturity-onset diabetes of the young type 3 (MODY3; ref. 3). Bi-allelic inactivation of TCF1 was found in 10 of 16 screened adenomas, and heterozygous germline mutation were present in three affected individuals. Furthermore, 2 well-differentiated hepatocellular carcinomas (HCCs) occurring in normal liver contained somatic bi-allelic mutations of 30 screened HCCs. These results indicate that inactivation of TCF1, whether sporadic or associated with MODY3, is an important genetic event in the occurrence of human liver adenoma, and may be an early step in the development of some HCCs.

Adenoma↗
PubMed2002

Hepatocarcinoma cell lines down-regulate matrix metalloproteinase-2 expression in human hepatic myofibroblasts.

Matrix metalloproteinases (MMPs) are a family of proteases that degrade extracellular matrix components and are involved in tumor progression and metastasis. We studied the pattern of expression of MMP-2 by human hepatoma cell lines and human hepatic myofibroblasts and its regulation in co-culture between these cell types. MMP-2 expression was studied by zymography and semi-quantitative RT-PCR. The expression of MT1-MMP (involved in MMP-2 activation) was studied by Western blot analysis and RT-PCR and the secretion of TIMP-2 by ELISA and RT-PCR. Myofibroblasts expressed high levels of MMP-2, MT1-MMP and TIMP-2. The hepatoma cell lines HepG2, HuH7 and Hep3B did not express MMP-2 and weakly expressed TIMP-2 and MT1-MMP. In co-culture, no modulation of MT1-MMP or TIMP-2 expression was observed. A strong decrease in myofibroblast MMP-2 expression was seen in the presence of hepatoma cell lines. This was partly reproduced by their conditioned media. We conclude that hepatoma cell lines down-regulate the expression of MMP-2 by myofibroblasts.

Carcinoma, Hepatocellular↗