Relevance of both individual risk factors and occupational exposure in cancer survival studies: the example of intestinal type sinonasal adenocarcinoma.

Objectives/hypothesis: Wood dust is a well-established risk factor for intestinal type sinonasal adenocarcinoma. The 5-year overall survival has varied from 20% to 80% according T1-T4 stages; 5-year survival according to histologic subtype has varied from 20% to 50%. To date, no study has evaluated whether environmental, occupational, and personal risk factors have any impact on both overall and cancer-specific survival.

Dietary prevention of malignant glioma aggressiveness, implications in oxidant stress and apoptosis.

Our study explored the influence of diet on gliomagenesis and associated systemic effects (SE) in rats. The experimental diet contained various ingredients supposed to interfere with carcinogenesis, mainly phytochemicals (PtcD for phytochemical diet) and its effects were compared to those of the same diet without the phytochemicals (BD for basal diet). Glioma was induced by ethylnitrosourea to pregnant females fed the diets from the start of gestation until the moment of sacrifice of the offpsrings.

[Translational research and Cancer Plan].

The French Cancer Plan 2003-2007 has made translational research central to its research programme, to ensure the care-research continuum and the quickest application possible for the most recent discoveries, for the patients' benefit. This is a new field of research, still little-known or ill-understood. A working group, composed of physicians and researchers from academic research and industrial research, sought to define translational research in cancerology and define the issues at stake in it.

Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients' survival in glioblastoma multiforme.

Prostaglandin E(2) plays multiple roles both in the physiology and the physiopathology of human brain, which are not completely understood. We have identified in a subset of human glioblastoma multiforme (GBM) tumors, the most common form of adult brain cancer, an increased expression of mPGES-1, the enzyme which catalyses the isomerization of PGH(2) into PGE(2) downstream of cyclooxygenase 2 (COX-2). The sensitivity of primary cultures of GBM to apoptosis was augmented by the overexpression of mPGES-1, whereas the knockdown of its expression by shRNA decreased the apoptotic threshold in vitro and stimulated tumor growth in vivo.

Changes in liver mitochondrial plasticity induced by brain tumor.

Background: Accumulating data suggest that liver is a major target organ of systemic effects observed in the presence of a cancer. In this study, we investigated the consequences of the presence of chemically induced brain tumors in rats on biophysical parameters accounting for the dynamics of water in liver mitochondria.

Methods: Tumors of the central nervous system were induced by intraveinous administration of ethylnitrosourea (ENU) to pregnant females on the 19th day of gestation.

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study.

To analyze the involvement of structured water (bound to macromolecules) in apoptosis-induced mitochondrial outer-membrane permeability, we compared the dynamics of water protons from nuclear magnetic resonance (NMR) data in apoptotic liver mitochondria with that of control mitochondria incubated in vitro with free Ca(2+) (opening of the permeability transition pore, PTP) or with Bax alpha. Our results demonstrate that water molecules in apoptotic mitochondria exhibit an accelerated translational motion of structured water common with that induced by the opening of the PTP, but limited in amplitude. On the other hand, no significant quantitative change in structured water was observed in apoptotic mitochondria, a phenomenon also observed with Bax alpha-induced permeability.

Profiling dendritic cell maturation with dedicated microarrays.

Dendritic cell (DC) maturation is the process by which immature DC in the periphery differentiate into fully competent antigen-presenting cells that initiate the T cell response. However, DC respond to many distinct maturation stimuli, and different types of mature DC induce qualitatively different T cell responses. As DC maturation involves the coordinated regulation of hundreds of genes, comprehensive assessment of DC maturation status would ideally involve monitoring the expression of all of these transcripts.

Caspase-3 can be pseudo-activated by a Ca2+-dependent proteolysis at a non-canonical site.

We have shown previously that calcium could trigger nuclear fragmentation, which was associated with a caspase 3 (C3)-like activity [Juin, P., Pelletier, M., Oliver, L.

Constitutive presence of cytochrome c in the cytosol of a chemoresistant leukemic cell line.

The release of holocytochrome c (cyt c) from mitochondria into the cytosol is reportedly a landmark of the execution phase of apoptosis. As shown here, the P-glycoprotein- (P-gp) expressing K562/ADR cell line (but not the parental K562 cell line) exhibits both cytosolic and mitochondrial cyt c in the absence of any signs of apoptosis. K562/ADR cells were found to be relatively resistant to a variety of different inducers of apoptosis, and blocking the P-gp did not reverse this resistance.

Large intestine intraepithelial lymphocytes from Apc+/+ and Apc+/Min mice and their modulation by indigestible carbohydrates: the IL-15/IL-15R alpha complex and CD4+ CD25+ T cells are the main targets.

We have shown recently that some indigestible carbohydrate (short-chain fructo-oligosaccharides [sc-FOS]) reduced colon tumor incidence in Apc+/Min mice, and that this effect depended on a functional local immune system. In addition, IL-15 mRNA was concomitantly modulated in the mucosa. Since intraepithelial lymphocytes (IELs) are in close contact with intestinal epithelial cells, these cells are the candidates most likely to be involved in early cancer immunosurveillance.

Distinct domains control the addressing and the insertion of Bax into mitochondria.

The translocation of Bax from the cytosol into the mitochondrial outer membrane is a central event during apoptosis. We report that beyond the addressing step, which involves its first alpha-helix (halpha1), the helices alpha5 and alpha6 (halpha5alpha6) are responsible for the insertion of Bax into mitochondrial outer membrane bilayer. The translocation of Bax to mitochondria is associated with specific changes in the conformation of the protein that are under the control of two prolines: Pro-13, which controls the unfolding of halpha1, and Pro-168, a proline located immediately before the hydrophobic carboxyl-terminal end (i.

Impact of pH on Bax alpha conformation, oligomerisation and mitochondrial integration.

The change in the conformation of Bax at the onset of apoptosis is a determinant for the execution of this cell death programme. However, very few models can account for this modification and the factors involved in this process remain elusive. We have analysed the modifications in the conformation induced by a variation in pH using a cell-free assay.

The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA.

The mechanism by which some BH3-only proteins of the Bcl-2 family directly activate the "multidomain" proapoptotic member Bax is poorly characterized. We report that the first alpha helix (Halpha1) of Bax specifically interacts with the BH3 domains of Bid and PUMA but not with that of Bad. Inhibition of this interaction, by a peptide comprising Halpha1 or by a mutation in this helix, prevents ligand-induced activation of Bax by Bid, PUMA, or their BH3 peptides.

Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system.

Background: The relative role of anti apoptotic (i.e. Bcl-2) or pro-apoptotic (e.

The mitochondrial apoptosis-induced channel (MAC) corresponds to a late apoptotic event.

We have investigated the mechanism responsible for mitochondria permeabilization occurring during cell apoptosis. We have developed an in vivo model of apoptotic rat liver. Mitochondria appeared as an homogenous population in control liver.

Increased expression of inducible HSP70 in apoptotic cells is correlated with their efficacy for antitumor vaccine therapy.

Apoptosis is a physiologic process in normal development, tissue remodeling and cell turnover. This cell death is noninflammatory and nonimmunogenic, but when associated with a danger signal, it can activate the immune system. However, the capacity of apoptotic cells to activate the immune system is not clearly established, although dead tumor cells have been largely exploited as a source of TAA in cellular therapy against cancer.

Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit.

We report that the induction and completion of the apoptotic program is delayed in a doxorubicin-resistant cell line (HL60/ADR). This hindrance to cell death occurred downstream of the multidrug-resistant protein (mrp), a transmembrane transporter. In vitro studies showed that these cells were incapable of correctly activating procaspase 3 (pC3), the main executioner of apoptosis.

The p18 truncated form of Bax behaves like a Bcl-2 homology domain 3-only protein.

p21(Bax) is a pro-apoptotic member of the Bcl-2 family and is converted by calpain into a truncated form called p18(Bax). This proteolysis enhanced the apoptogenic properties of Bax by a mechanism not yet elucidated. We have shown recently that the first alpha helix (Halpha1) of p21(Bax) contained a mitochondrial addressing sequence, which appeared to be necessary for p21(Bax)-induced apoptosis (Cartron, P.

Impact of proapoptotic proteins Bax and Bak in tumor progression and response to treatment.

The cell death program, apoptosis, is currently viewed as the ultimate obstacle in cancer therapy. Inhibition of apoptosis is thought to be involved in both tumorigenesis and resistance to chemo- and radiotherapy. Considerable efforts are underway to design new tools capable of overcoming this inhibition.

Apc+/Min colonic epithelial cells express TNF receptors and ICAM-1 when they are co-cultured with large intestine intra-epithelial lymphocytes.

Adenomatous polyposis coli (APC) functions are involved in the heterotypic interactions occurring between intestinal epithelial cells (IECs) and intra-epithelial lymphocytes (IELs). These interactions may be of interest in cancer prevention, since recent data provide evidence for lymphocyte mediated immunosurveillance of epithelial cancers. The present study attempts to determine if APC inactivation induces changes in the cross-talk between IEC and large intestine IEL (LI-IEL) through intercellular adhesion molecule (ICAM-1)/leukocyte function-associated (LFA-1) interactions.

Nonredundant role of Bax and Bak in Bid-mediated apoptosis.

Animal models suggest that Bax and Bak play an essential role in the implementation of apoptosis and as a result can hinder tumorigenesis. We analyzed the expression of these proteins in 50 human glioblastoma multiforme (GBM) tumors. We found that all the tumors expressed Bak, while three did not express Bax.

Butyrate restores motile function and actin cytoskeletal network integrity in apc mutated mouse colon epithelial cells.

Loss of function of the Apc gene product is an early and frequent event in colorectal carcinogenesis. Altered migration of intestinal epithelial cells has been described in vivo in the Min mouse Apc+/Min model. Using cell lines established from this model we show in vitro that Apc+/Min cells are less motile than Apc+/+ cells and exhibit a disordered actin cytoskeletal network.

Difference in antigenic determinant profiles between human and rat myeloperoxidase.

We tested whether rat and human MPO have similar antigenic determinants using 36 human MPO-ANCA positive sera, one mouse anti-rat MPO and four mouse anti-human MPO monoclonal reagents. Purified rat and human MPO were used in ELISA, with or without crossinhibition by preincubation with human MPO or irrelevant antigen in the liquid phase. Only one human MPO ANCA positive serum exhibited significant binding in rat MPO ELISA.

Transient exposure of dendritic cells to maturation stimuli is sufficient to induce complete phenotypic maturation while preserving their capacity to respond to subsequent restimulation.

Dendritic cells (DC) are activated by pathogens, cytokines and activated T cells. We investigated the impact of a transient initial DC stimulation on the kinetics of maturation using a combination of double-stranded RNA and TNFalpha and subsequent restimulation by T cell-derived stimuli. Transient stimulation of DC was sufficient to start an irreversible program of phenotypic maturation which proceeded in the absence of the initial stimulus.

Minimal BH3 peptides promote cell death by antagonizing anti-apoptotic proteins.

The pro-apoptotic "BH3 domain-only" proteins of the Bcl-2 family (e.g. Bid and Bad) transduce multiple death signals to the mitochondrion.