Régénération de l’épithélium des voies aériennes

RésuméIntroductionLa régénération de l’épithélium respiratoire est un phénomène complexe qui peut, en conditions pathologiques (asthme, BPCO, mucoviscidose), aboutir à un remodelage chronique, altérant la fonctionnalité de l’épithélium.État des connaissancesLe développement de modèles d’étude in vivo et in vitro a permis d’étudier les mécanismes du remodelage bronchique. Les principaux acteurs de ce remodelage ont ainsi été mis en évidence : composants de la matrice extracellulaire, protéases, facteurs de croissance, cytokines. Les cellules progénitrices/souches de l’épithélium des voies aériennes ont également été étudiées dans ces modèles, leur identification restant toutefois difficile.ConclusionL’identification et la caractérisation des cellules souches/progénitrices de l’épithélium des voies aériennes ainsi que la compréhension complète des mécanismes de la régénération devraient permettre l’élaboration de nouvelles stratégies thérapeutiques favorisant la reconstitution épithéliale.SummaryIntroductionEpithelial regeneration is a complex process. It can lead to the remodeling of the airway epithelium as in asthma, COPD or cystic fibrosis.BackgroundThe development of in vivo and in vitro models has allowed the analysis of remodeling mechanisms and showed the role of components of extracellular matrix, proteases, cytokines and growth factors. Airway epithelial progenitors and stems cells have been studied in these models. However, their identification remains difficult.ConclusionIdentification and characterization of airway epithelial progenitor/stem-cells, and a better knowledge of the regeneration process may allow the development of new therapeutic strategies for airway epithelial reconstitution

Human papillomaviruses and DNA ploidy in anal condylomata acuminata

Previous studies have emphasized the usefulness of DNA ploidy measurement and Human Papillomavirus (HPV) detection as pronostic markers in low grade cervical lesions. We addressed the eventual relationship between HPV type, DNA profile, and p53 tumor suppressor protein expression in anal condylomata acuminata to eventually determine parameters which may be considered as predictive risk factors for the development of cancer. DNA ploidy was assessed by image cytometry after Feulgen staining of contiguous serial sections of 45 anal condylomata acuminata without atypia containing HPV detected by in situ hybridization and Polymerase Chain Reaction (PCR). p53 expression was detected by immunohistochemistry. DNA aneuploidy was found in 53.3% of these lesions, 48.9% containing non oncogenic HPV types 6 andtor 11 and 4.4% harbouring HPV types 11 and 18. The DNA diploid lesions were all associated with non oncogenic HPV types 6 andtor 11 and one case also contained HPV type 33. There was no significant correlation between the detection of DNA aneuploidy and the presence of immunodetected p53. DNA aneuploidy was not related to the presence of oncogenic HPV in anal condylomata acuminata. The DNA aneuploid profile frequently observed, especially in lesions associated with non oncogenic HPV types, is not yet well explained and cannot be considered as a prognostic factor. In contrast, a more intensive clinical follow-up should be proposed in patients with oncogenic HPV associated to DNA aneuploidy

Distribution of laminin in tumor pathology, Immunofluorescence study

peer reviewe

Regulation of membrane-type 1 matrix metalloproteinase expression by zonula occludens-2 in human lung cancer cells.

During tumor invasion, tumor epithelial cells acquire migratory and invasive properties involving important phenotypic alterations. Among these changes, one can observe reorganization or a loss of cell-cell adhesion complexes such as tight junctions (TJs). TJs are composed of transmembrane proteins (occludin, claudins) linked to the actin cytoskeleton through cytoplasmic adaptor molecules including those of the zonula occludens family (ZO-1, -2, -3). We here evaluated the potential role of ZO-2 in the acquisition of invasive properties by tumor cells. In vivo, we showed a decrease of ZO-2 expression in bronchopulmonary cancers, with a preferential localization in the cytoplasm. In addition, in vitro, the localization of ZO-2 varied according to invasive properties of tumor cells, with a cytoplasmic localization correlating with invasion. In addition, we demonstrated that ZO-2 inhibition increases invasive and migrative capacities of invasive tumor cells. This was associated with an increase of MT1-MMP. These results suggest that ZO-2, besides its structural role in tight junction assembly, can act also as a repressor of tumor progression through its ability to reduce the expression of tumor-promoting genes in invasive tumor cells

Membrane-type 1 matrix metalloproteinase expression is regulated by zonula occludens-1 in human breast cancer cells

The acquisition of a migratory/invasive phenotype by tumor cells is characterized by the loss of cell-cell adhesion contacts and the expression of degradative properties. In this study, we examined the effect of the disorganization of occludin/zomda occludens (ZO)-1 tight junction (TJ) complexes on the expression of membrane-type I matrix metalloproteinase (MT1-MMP). We first compared the expression of MT1-MMP and the localization of occludin/ZO-1 complexes in breast tumor cell lines displaying various degrees of invasiveness. We showed that the expression of MT1-MMP in invasive breast tumor cell lines correlates with the absence of occludin and with a cytoplasmic localization of ZO-1. In contrast, noninvasive cell lines displayed a membrane staining for both ZO-1 and occludin and did not express MT1-MMP. In vivo, cytoplasmic ZO-1 and MTI-MMP could be detected in invasive tumor clusters of human breast carcinomas. We then used RNA interference strategy to inhibit ZO-1 expression in invasive BT549 cells and to evaluate the effect of ZO-1 downregulation on MTI-MMP expression. We observed that ZO-1 small interfering RNA transfection down-regulates MT1-MMP mRNAs and proteins and subsequently decreases the ability of tumor cells to invade a reconstituted basement membrane in a Boyden chamber assay. Inversely, transfection of expression vectors encoding wild-type ZO-1 or the NH2-terminal fragment of ZO-1 comprising the PSD95/DLG/ZO-1 domains in BT549 activated a human MT1-MMP promoter luciferase reporter construct and increased cell invasiveness. Such transfections concomitantly activated the beta-catenin/TCF/LEF pathway. Our results therefore show that ZO-1, besides its structural role in TJ assembly, can intervene in signaling events promoting tumor cell invasion