Histology and histopathology Vol.25, nº3 (2010)
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- PublicationOpen AccessSurvivin overexpression in HCC and liver cirrhosis differentially correlates with p-STAT3 and E-cadherin(Murcia : F. Hernández, 2010) Peroukides, Stavros; Bravou, Vasiliki; Alexopoulos, Alexandros; Varakis, John; Kalofonos, Haralabos; Papadaki, HelenSurvivin, a member of the family of inhibitorof apoptosis proteins, functions as a key regulator ofapoptosis and cell proliferation. Overexpression ofsurvivin has been implicated in several human cancers,including human hepatocellular carcinoma (HCC).Although several factors have been shown in vitrotoupregulate survivin expression in cancer cells, the invivoregulators of survivin in human hepato-carcinogenesis are largely unknown. We studied byimmunohistochemistry the protein expression ofsurvivin in relation to cyclin D1, phosphorylated signaltransducer and activator of transcription 3 (p-STAT3), ß-catenin, E-cadherin and phosphorylated-Akt (p-Akt) in69 cases of HCC and adjacent liver cirrhosis. Survivinwas expressed in 63/69 (91.3%) cases of HCC and in40/47 (85.1%) cases of liver cirrhosis. Survivinlocalization in HCC was exclusively nuclear, whileintense cytoplasmic and low nuclear expression ofsurvivin was observed in cases of cirrhosis. Survivinexpression in HCC correlated significantly with lowgrade tumors, expression of cyclin D1 and p-STAT3.Expression of survivin in liver cirrhosis correlated withdownregulation of E-cadherin expression. There was nosignificant correlation of survivin with ß-catenin or p-Akt in HCC or liver cirrhosis. In conclusion, we showedan association of nuclear survivin with welldifferentiated HCC, as well as with the expression of thecell cycle regulator cyclin D1. Activation of STAT3 andloss of E-cadherin but not ß-catenin or Akt pathwaysseem to be implicated in survivin upregulation in HCCand liver cirrhosis.
- PublicationOpen AccessMCM proteins as diagnostic and prognostic tumor markers in the clinical setting(Murcia : F. Hernández, 2010) Giaginis, constantinos; Vgenopoulou, Stephanie; Vielh, Philippe; Theocharis, StamatiosMinichromosome maintenance (MCM)proteins are essential for the process of DNA replication,functioning as license components for the S-phase ofcell-cycle initiation and further exerting weak helicaseactivity to unwind DNA from its supercoiled state atreplication forks. The requirement for MCM proteins incycling cells and their absence in quiescent onessupports evidence for their potential clinical applicationas cell proliferation markers. In the last few years, asidefrom their utility as cell proliferation markers, theassessment of MCM expression levels in diverse humanmalignancies has been the focus of extensive research inan aim to facilitate tumor diagnosis and prognosis inclinical settings. The present article aims to review theavailable data so far concerning the clinical significanceof MCM protein expression in human neoplasia incomparison to conventional proliferative markers. Areview of the literature revealed that MCM expression isassociated with important clinicopathological parametersfor patient management and also exhibits significantdiagnostic and prognostic value in several malignancies.MCMs are characterized by higher specificity andsensitivity than the conventional proliferative markers,such as Ki-67 and PCNA, and are thus considered asdiagnostic and prognostic tools of greater clinicalsignificance in several types of human malignancy.
- PublicationOpen AccessClinicopathological variables, immunophenotype, chromosome 1p36 loss and tumour recurrence of 247 meningiomas grade I and II(Murcia : F. Hernández, 2010) Ruiz, Juan; Martínez, Armando; Hernández, Susana; Zimman, Horacio; Ferrer, Milagros; Fernández, Cristina; Sáez, Mamen; López-Asenjo, José A.; Sanz Ortega, JuliánThe WHO grading scheme distinguishesbenign (grade I), atypical (grade II) and anaplastic(grade III) meningiomas. Both atypical and anaplasticmeningiomas exhibited an overall increased rate ofrecurrence, but between 15-20% benign meningiomaswill also exhibit an unfavourable clinical course withrecurrence before 10 years despite aggressive surgery.We investigated 247 cases of meningiomas grade I andII. The immunohistochemical expression of 30 differentmolecular biomarkers of cell adhesion molecules, cell-cycle and apoptosis regulators and checkpoints wasanalyzed. We also determined apoptosis by in-situhybridization (APOPDETEK™) and loss ofchromosome 1p36 by FISH. The study revealed astatistically significant co-variation (p<0.05) betweenmeningiomas grade II associated with severalclinicopathological features (Simpson grade of clinicalresection, necrosis, nuclear atypia, macronucleoli,transition to small cell, sheet-like growth, highcellularity), increased expression of several biomarkersof tumour proliferation (Cyclin A, Cyclin E, MIB-1 orMDM2), proteases (Cathepsin D) or cell-adhesion(CD44) and lower expression of progesterone receptorsthan meningiomas grade I. The presence of Psammomabodies or the location at convexity were protectiveprognostic factors for tumour recurrence while highcellularity and early age of onset (<57 year-old) wereindicators of increased recurrence risk. The expressionof COX-2, γ-catenin, Topoisomerase IIa, VEGF andMIB-1 was significantly higher in the cohort of recurrentmeningiomas. Meningiomas with chromosome 1p36 lossshowed a higher recurrence rate (33.3%) than meningiomas with normal chromosome 1p36 (18%).Increased COX-2 expression in recurrent meningiomamay also suggest a putative role of COX-2 inhibitors asa chemopreventive treatment for recurrence.
- PublicationOpen AccessExpression of p53 family members and CD44 in oral squamous cell carcinoma (OSCC) in relation to tumorigenesis(Murcia : F. Hernández, 2010) Bidaud, Pauline; Chasle, Jacques; Sichel, François; Rousseau, Stéphane; Petit, Pascal; Pottier, Didier; Picquenot, Jean Michel; Louis, Marie-Yolande; Lechevrel, MathildeOral squamous cell carcinomas (OSCCs) aredescribed as the result of a multistep tumorigenesisprocess. In order to develop useful diagnosis of pre-malignant lesions, expression of p53 family membersand the cancer stem cell (CSCs) marker, CD44v6, werestudied in histologically normal oral epithelium,precancerous lesions and succeeding invasive OSCCs.p53 was expressed focally in normal epithelium adjacentto tumors, while expression was high in intra-epithelialneoplasia and moderate in OSCC. p63 nuclear stainingwas important in basal and suprabasal layers ofhistologically normal oral mucosa and in immaturecompartments of premalignant lesions and cancer. Inepithelium without neoplasia, intense p73 staining wasobserved in the basal layer, while focal expression waspresent in suprabasal layers. Most immature dysplasticareas showed either high or moderate staining, whereasthose in OSCCs expressed low and moderate p73 levelexpression. CD44v6 was only expressed in poorlydifferentiated areas of epithelium, altered or not. p53,p63 and p73 positive stainings were statistically relatedin intra-epithelial neoplasia to tumours. Analysis ofTP53 mutations in 17% of tumours principally revealedG>A and A>G transitions. No relation was observedbetween this mutational profile and differentimmunostainings. In conclusion, our results support thatimmunostaining of p53 family members might behelpful in diagnosis and monitoring of high-risk pre-malignant lesions of oral epithelium. The combination ofstaining patterns of p63, p73αand CD44v6 enabled us to isolate phenotypic undifferentiated or transientamplifying areas, reflecting the immaturity of the tumourcell lineage. While CD44v6 expression is an interestingmarker of such epithelial cells, it is not specific enoughto be useful alone and other phenotypic markers areneeded.
- PublicationOpen AccessHistological scoring of articular cartilage alone provides an incomplete picture of osteoarthritic disease progression(Murcia : F. Hernández, 2010) Barley, R.D.C.; Bagnal, K.M.; Jomha, N.M.Purpose: To ascertain whether molecularsubcategories of disease progression exist withinestablished histological grades of articular cartilage(AC). Methods: Based on H&E and safranin-O stainingof AC sections obtained from 18 knee arthroplastysurgeries, 30 samples ranging from Mankin ScoringSystem grade 1 through 5 were identified. Immuno-histochemical (IHC) analysis for collagen type II andaggrecan was performed on serial sections of theparaffin-embedded AC samples. Six AC samples fromeach of the five Mankin Scoring System grades wereexamined. Results: Significant IHC differences incollagen type II and aggrecan deposition were seenwithin AC samples from all five histological grades. Therange of IHC differences in collagen type II andaggrecan increased with increasing histological grade. Achange in the pattern of collagen type II deposition wasobserved in MG-3 AC that was consistent with a switchin collagen type II metabolism. Conclusions: IHCstaining of collagen type II and aggrecan can identifydifferences within histological grades of AC that areconsistent with the existence of molecular subcategories.These differences were detectable even within the lowesthistological grades; therefore the use of IHC staining canfurther enhance and refine the scoring of ACdeterioration in early osteoarthritis (OA). Furthermore,the changes seen in the deposition pattern for bothaggrecan and collagen type II suggest that they could beused to monitor key molecular events in OAprogression. These findings also underscore the need forthe development of IHC scoring criteria.
- PublicationOpen AccessAngiopoietin-1Tie2 receptor signaling in vascular quiescence and angiogenesis(Murcia : F. Hernández, 2010) Fukuhara, Shigetomo; Sako, Keisuke; Noda, Kazuomi; Zhang, Jianghui; Minami, Masayoshi; Mochizuki , NaokiAngiopoietin (Ang) 1 is a ligand forendothelium-specific receptor tyrosine kinase Tie-2. Inadult vasculature, Ang1/Tie2 signaling is thought toregulate both maintenance of vascular quiescence andpromotion of angiogenesis. However, it has beenunknown how Tie2 signal regulates these distinctbiological functions. Recently, we and Alitalo’s grouphave clarified that Ang1 assembles distinct Tie2signaling complexes in either presence or absence ofendothelial cell-cell adhesions. Ang1 induces trans-association of Tie2 at cell-cell contacts, whereas Tie2 isanchored to the extracellular matrix (ECM) by Ang1 atthe cell-substratum interface. Trans-associated Tie2 andECM-anchored Tie2 activate distinct signalingpathways. In this review, we discuss how Ang1/Tie2signal regulates both maintenance of vascular quiescenceand promotion of angiogenesis, especially focusing onthe roles of trans-associated Tie2 and ECM-anchoredTie2
- PublicationOpen AccessP21, p27, bax, cathepsin and survivin pathways in macular dystrophy corneas(Murcia : F. Hernández, 2010) Szentmáry, Nora; Stündl, Adrienn; Szende, Béla; Süveges, IldikoThe purpose of our study was to elucidatepathways of genetically programmed cell death(apoptosis) in corneas with macular dystrophy.10 corneal buttons (10 patients) with maculardystrophy and 8 buttons (8 patients) from enucleatedeyes with chorioideal melanoma (controls) wereanalysed histologically. Immunohistochemical analysiswas performed to investigate the presence of p21, p27,bax, cathepsin and survivin proteins. The number ofpositive cells was determined by analysis of 100 cellsand given in percentages.The bax protein was present in 25.6% of epithelialcells in macular dystrophy corneas but was absent incontrols. P21 and p27 were found in 35.7 and 87.5% ofepithelial cells of macular dystrophy corneas,respectively, but again not in control tissue. In contrast, alower percentage of cathepsin-positive (30.7% vs58.8%) and survivin-positive cells (37.6% vs 52.1%)were present in epithelial cells of macular dystrophycorneas than in control epithelial cells. The differencereached statistical significance in the expression of p21and p27 genes (p<0.05 in both).P21 was positive in 3% of keratocytes, p27 in 1% ofendothelial cells of macular dystrophy corneas butnegative in controls (0%). Bax, cathepsin and survivinimmunopositivity was not detected in keratocytes orendothelial cells of either group. We conclude that the down-regulation of p21, p27and cathepsin in epithelial cells of macular dystrophycorneas may be related to defense mechanisms againstapoptotic cell death.
- PublicationOpen AccessChronic morpho-functional damage as a consequence of transient ischemia-reperfusion injury of the small bowel(Murcia : F. Hernández, 2010) Morini, Sergio; Elias, Georg; Brown, Melisa; Subbotin, Vladimir; Rastellini, Cristiana; Cicalese, LucaIntroduction: The prevailing notion is thatischemia reperfusion injury of the small bowel inducestransient changes that resolve within a few days post-occurrence. However, chronic injury has been describedfollowing a single ischemia reperfusion in the kidney.We proceeded to ascertain if a similar outcome is alsowitnessed in the small bowel. Materials and methods:ACI rats (n=32) underwent 1, 2 or 3 episodes ofischemia reperfusion by clamping the superiormesenteric artery for 45 minutes at 7-day intervals.Control groups included sham-operated (n=6) or non-operated (n=5) rats. Morphology was examined at dayninety post-ischemia reperfusion and immunostainingwas used to evaluate macrophage infiltration,microvascular distribution, and apoptosis. RT-PCR wasused to evaluate expression of Inter-Cellular AdhesionMolecule-1 (ICAM-1), transforming growth factor-ß(TGF-ß), Insulin Growth Factor-I (IGF-1), and InsulinGrowth Factor-I Receptor (IGF-R). Intestinal functionwas evaluated by D-xylose performed 24 hours and 4, 8,and 12 weeks after reperfusion. Results: Chronicmorphologic changes were observed with degenerationof crypts, endothelial damage, matrix degeneration, andheightened lymphocyte degeneration within the Payer’spatches. Major structural changes were characterized byvillous atrophy from partial to total. The grade ofhistological injuries was significantly increased(P<0.001) after multiple ischemia reperfusion episodes.A higher number of apoptotic cells (P<0.001) and aprominent macrophage infiltration (P<0.05) was alsowitnessed. Altered expression of ICAM-1, TGF-ß, andIGF-1 was observed. At 24 hours after ischemiareperfusion D-xylose absorption was diminished,returning to baseline values within 4 weeks and becoming abnormal again at 8 and 12 weeks (P<0.05).CONCLUSIONS: Unlike the prevailing conviction,these data demonstrate that transient ischemiareperfusion repeated injuries of the small bowel result inchronic intestinal damage.
- PublicationOpen AccessStem cells in human breast cancer(Murcia : F. Hernández, 2010) Roberto Oliveira, Lucinei; Jeffrey, Stefanie S.; Ribeiro Silva, AlfredoIncreasing data support cancer as a stem cell-based disease. Cancer stem cells (CSCs) have beenfound in different human cancers, and recent evidenceindicates that breast cancer originates from and ismaintained by its own CSCs, as well as the normalmammary gland. Mammary stem cells and breast CSCshave been identified and purified in in vitroculturesystems, transplantation assays and/or by cell surfaceantigen identification. Cell surface markers enable thefunctional isolation of stem cells that can initiate andpropagate tumorigenesis in mammary gland. Theseobservations have dramatic biological and clinicalsignificance due to increasing evidence suggesting thatthe recurrence of human cancer and treatment failuremay reflect the intrinsic quiescence and drug resistanceof CSCs. Thus, the CSC hypothesis providesfundamental implications for understanding breastcarcinogenesis and for developing new strategies forbreast cancer prevention and therapy for advanceddisease. Further strategies to isolate breast CSCs, to findadditional trustworthy surface markers, and to comparegene expression pathways profiles with their normalstem cells counterparts are necessary to more accuratelydefine putative breast cell-lineage markers for thedifferent cell types present in the mature mammarygland and to identify potential therapeutical targets inbreast cancer. This review discusses the currentknowledge about stem cells and CSCs, focusing onmammary stem cells and breast CSCs, and theirconsequences for breast tumorigenesis and implicationsfor breast cancer susceptibility, prognosis, and treatment.
- PublicationOpen AccessCarbonic anhydrase II is secreted from bovine parotid glands(Murcia : F. Hernández, 2010) Mau, M.; Kaiser, T.M.; Südekum, K.-H.Besides carbonic anhydrase VI (CA-VI),CA-II is suggested to be a second secreted isoenzyme inruminant saliva. Therefore, the aim of the present studywas to investigate the expression of salivary CA-II inbovine parotid glands at the protein level. Moreover, weintended to identify the cells which secrete the enzymeinto the saliva. Two commercially available CA-IIspecific antibodies were tested for use inimmunohistochemistry on frozen sections of bovineparotid tissue. Intense positive staining for CA-II wasfound in luminal duct cells and for the first time alsoinside the duct lumen, clearly demonstrating theexpression and secretion of salivary CA-II in bovineparotid glands. The presence of CA-II protein wasverified for parotid tissue and whole saliva usingimmunoblot analysis. Both salivary CA-II and CA-VIare highly active in supplying the alimentary tract withbicarbonate. It is suggested that a decrease in theexpression of either one of these enzymes might severelydisturb digestion and/or increase susceptibility toacidosis in ruminants.
- PublicationOpen AccessThe dynamic stem cell microenvironment is orchestrated by microvesicle-mediated transfer of genetic information(Murcia : F. Hernández, 2010) Deregibus, Maria Chiara; Tetta, Ciro; Camussi, GiovanniIt has been commonly supposed that adultstem cells co-localize with supporting cells withinspecific regions or specialized microenvironment in eachtissue/organ, called stem cell niche. This concept wasbased on the assumption that stem cells are intrinsicallyhierarchical in nature. However, recent data indicate thatstem cells may represent a continuum with reversiblealterations in phenotype taking place during the transitthrough cell cycle. Based on this dynamic interpretationit has been suggested that the so-called niche isrepresented by a single or only few cell types continuallyadjusting their phenotype and function to individualcircumstances. A critical component in the regulation ofthe continuum of stem cell phenotypes is themicroenvironment. In this context, microvesicles (MVs)account for the transfer of genetic information betweencells. Originally considered inert cellular debris, MVsare increasingly recognized to be important mediators ofcell-to-cell communication. MVs may transfer receptors,proteins, mRNA and microRNA to target cells viaspecific receptor-mediated interaction. In stem cellbiology the exchange of genetic information may bebidirectional from stromal to stem cells. In the context oftissue injury the MV-mediated transfer of geneticinformation may reprogram the phenotype of stem cellsto acquire features of the injured tissue cells. In addition,MVs derived from stem cells may induce de-differentiation of cells which have survived injury with acell cycle re-entry that may allow tissue regeneration. Inthe present review we discuss the possibility of acontinuous genetic modulation of stem cells by a MV-mediated transfer of information between cells.
- PublicationOpen AccessTranscriptional regulation of the Oct4 gene, a master gene for pluripotency(Murcia : F. Hernández, 2010) Kellner, Steven; Kikyo, NobuakiOct4 is one of the most importanttranscription factors required to maintain anundifferentiated state (self-renewal) and pluripotency ofhuman and mouse embryonic stem (ES) cells as well asearly embryonic cells. In addition, Oct4 is the onlyknown transcription factor that has to be exogenouslyintroduced into differentiated cells to make inducedpluripotent stem (iPS) cells. Therefore, it is of greatimportance to understand howOct4transcription isregulated in ES cells and embryos and how it becomesactivated during iPS cell formation. In this article, wewill review the regulation of the mouse Oct4gene fromthe viewpoint of DNA methylation, binding of orphannuclear receptors, histone modifications and synergisticeffects with other pluripotency factors. We will also raiseseveral key questions that need to be addressed in futurework to improve our understanding of Oct4generegulation and its essential role in self-renewal andpluripotency.
- PublicationOpen AccessComparison of the tumorigenic potential of liver and kidney tumors induced by N-nitrosodimethylamine(Murcia : F. Hernández, 2010) Trencsenyi, Gyorgy; Juhasz, Tamas; Bako, Fruzsina; Marian, Terez; Pocsi, Itsvan; Kertai, Pal; Hunyadi, Janos; Banfalvi, GasparThe aim of the study was to determine thetumorigenic potential of two cell lines established fromN-nitrosodimethylamine induced rat hepatocarcinoma(HeDe) and mesenchymal renal tumors (NeDe). Thebasis of the distinction is that human cancers are knownto overexpress facilitative GLUT transporters and TGF-ß1 protein. These proteins are linked to the increasedmetabolic energy consumption indicating uncontrolledgrowth and proliferation. We have assayed not only theexpression of GLUT-1, GLUT-3 and TGF-ß1 proteins,but also the uptake of 2-fluoro-[18F]-2-deoxi-D-glucose(18FDG), a tracer for cancer diagnosis. Western blotanalysis and whole body autoradiography were used tomeasure the 18FDG uptake of tumor cells. Elevated18FDG uptake was measured in both tumor cell lines.Whole body autoradiography provided evidence that theuptake of 18FDG was lower in the necrotic inner partthan in the more vascularized outer parts of primaryhepatocarcinoma and mesenchymal renal tumors.GLUT-1 overexpression in hepatocarcinoma tumor, andhigh levels of GLUT-3 were found in the NeDe cell lineand in the mesenchymal renal tumor. TGF-ß-1 wasoverexpressed in hepatocarcinoma and mesenchymalrenal tumors. In vitroand in vivo parameters support theview that the tumorigenic potential of cancer cellscannot be determined by the expression of a singleparameter such as the expression of either GLUT-1,GLUT-3 or 18FDG uptake. Besides the tumorigenicpotential of the hepatocarcinoma, the high metabolicactivity of the renal tumor indicated by its 18FDGuptake, GLUT-3 and TGF-ß1 expression, themesenchymal renal tumor induced by N-nitroso-dimethylamine is not a benign, but an an aggressiverenal carcinoma.