Histology and histopathology Vol.17, nº 3 (2002)

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Open Access
Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats somatotroph response in vitro
(Murcia : F. Hernández, 2002) Jiménez Reina, L.; Cañete, R.; De la Torre, M.J.; Bernal, G.
Growth hormone (GH) is secreted in the anterior pituitary gland by the somatotroph cells. Secretion is regulated by growth hormone releasing hormone (GHRH) and somatostatin. Morever, GH secretagogues (GHS) can exert a considerable effect on GH secretion. In order to determine the effects of chronic treatment with the GHS Ipamorelin on the composition of the somatotroph cell population and on somatotroph GH content, an in vitro analysis was performed of the percentage of somatotroph cells (% of total), the ratio of different GH cell types (strongly/weakly-staining) and individual GH content, in pituitary cell cultures obtained from young female rats receiving Ipamorelin over 21 days (Ipamorelin group) and the effects were compared with those of GHRH (GHRH group) or saline (saline group). The ultrastructure of somatotroph cells did not change, but the volume density of secretion granules was increased (P<0.05) by previous in vivo Ipamorelin or GHRH treatment. In 3-day basal pituitary cell monolayer cultures, the percentage of somatotroph cells showed no modifications between groups, nor was there any change in the ratio of strongly/weakly immunostaining GH cells. In the Ipamorelin group alone, in vitro treatment with Ipamorelin (10-8 M), or GHRP 6 (10-8 M), or GHRH (10-8 M) for 4 hours, increased the percentage of somatotroph cells, without modifying the ratio of strongly/weakly immunostained GH cells. Basal intracellular GH content in somatotroph cells over 4 hours was lower in the Ipamorelin group and the GHRH group than in the saline group. Only in the Ipamorelin group did Ipamorelin (10-8 M), GHRP 6 (10-8 M) and GHRH (10-8 M) prompt increased intracellular GH content. These data suggest that, at least in the young female rat, the GHS Ipamorelin is able to exert a dynamic control effect on the somatotroph population and on GH hormone content.
Open Access
Biliary papillary neoplasm of the liver
(Murcia : F. Hernández, 2002) Nakanuma, Y.; Sasaki, M.; Ishikawa, A.; Tsui, W.; Chen, T.C.; Huang, S.F.
Biliary papillary neoplasia of the liver characterized by intraductal papillary growth of neoplastic biliary epithelia with a fine fibrovascular stalk has been sporadically reported, and includes intraductal growing cholangiocarcinoma and biliary papillomatosis. In addition, biliary papillary dysplasia and in situ and microinvasive carcinoma with papillary configuration reported in hepatolithiasis and in other chronic biliary diseases, could be included in this category. Usually, they arise in the intrahepatic large bile ducts, and the neoplastic and non-neoplastic parts of the intrahepatic biliary tree show saccular and segmental dilatation with mucin hypersecretion. This neoplasia frequently shows intraductal spreading and peribiliary glandular involvement. Acute repeated episodes of cholangitis or obstructive jaundice are a frequent clinical manifestation. Gastroenteric metaplasia with aberrant expression of cytokeratin 20, MUC2, MUC5AC, and/or MUC6, is frequent in the neoplastic parts, and biliary epithelial dysplasia with such metaplasia may give rise to in situ and then invasive carcinoma in hepatolithiasis. Interestingly, this type tends to contain foci of mucinous carcinoma elements, and this element may be predominant (mucinous carcinoma). Some may progress to “mucinous biliary cystadenocarcinoma” without ovarian mesenchymal stroma and with intraluminal continuous growth into the neighboring bile duct lumens. Interestingly, the biliary papillary neoplasm resembles histologically, phenotypically and clinically intraductal papillary mucinous neoplasm of the pancreas which is now being established as an infrequent, slowgrowing pancreatic neoplasm. Recognition of such biliary papillary neoplasm with respect to the pancreatic equivalent may lead to a better understanding and further studies of the intrahepatic biliary neoplasm.
Open Access
Rab3D a regulator of exocytosis in non-neuronal cells
(Murcia : F. Hernández, 2002) Millar, A.L.; Pavlos, N.J.; Xu, J.; Zheng, M.H.
Rab3D, a small Ras-like GTPase, is a key regulator of intracellular vesicle transport during exocytosis. It has been shown that Rab3 GTPases are abundant in cells with regulated secretory pathways and are thought to confer the specificity of docking and fusion during regulated exocytosis. Unlike other Rab3 isoforms, Rab3D is enriched in a number of nonneuronal tissues and is localised to secretory granules in the cytoplasm of these cells. The structure of Rab3D exhibits all of the conserved domains from the Rab family and also contains hypervariable N- and Cterminal regions. Rab3D undergoes post-translational isoprenylation and cycles between GDP- and GTPbound forms. Apart from the factors involved in the Rab activation cycle, few Rab3D effector proteins have been identified to date. Nevertheless, it has long been suggested that Rab3D plays a role in regulated exocytotic processes as well as apically directed transcytosis. This review summarises the recent work on the biological function, structural integrity and molecular interactions of Rab3D in non-neuronal cells.
Open Access
Circulating nucleic acids as a tumor marker
(Murcia : F. Hernández, 2002) Chan, K.C.A.; Lo, Y.M.D.
Patients suffering from malignant diseases have been shown to have increased amounts of cell free nucleic acids in their circulation. As genetic and epigenetic alterations are increasingly characterized in different types of tumors, such changes can be used to detect tumor-derived nucleic acids in the circulation. To date, nearly all tumor-associated nucleic acids have been detected in the plasma or serum of cancer patients. Moreover, increased levels of circulating viral nucleic acids have also been demonstrated in patients with certain cancers associated with viral infections. The concentration of these tumor-associated nucleic acid species is generally related to the tumor load and the extent of the disease. Serial monitoring of plasma nucleic acids thus provides a good way to follow disease progress and to predict the outcome of such patients. In this review, different approaches of detecting tumorrelated nucleic acids in the circulation and their potential as tumor markers in the screening, monitoring and prognostication of malignant diseases are discussed.
Open Access
The Rho small GTPase Functions in health and disease
(Murcia : F. Hernández, 2002) Toksoz, D.; Merdek, K.D.
Cell shape changes, contractility, adhesion, migration, gene transcription, cytokinesis, membrane trafficking, and growth, require Rho small GTPase function. The basis for this is that Rho regulates actin filament assembly, and serum response factor (SRF)- mediated gene transcription. Upon activation by serum or cell adhesion, Rho stimulates a distinct signal transduction pathway that induces cytoskeletal and transcriptional responses through diverse effectors. Rho activity is tightly controlled by guanine nucleotide exchange factors, GTPase activating proteins, and guanine dissociation inhibitors. Dysregulation of the Rho pathway is implicated in multiple pathological conditions including cancer and metastasis, cardiovascular disease, bacterial and viral pathogenesis, hepatic disease, and developmental disorders.
Open Access
Alterations induced by cyclosporine A in myocardial fibers and extracellular matrix in rat
(Murcia : F. Hernández, 2002) Rezzani, R.; Angoscini, P.; Rodella, L.F.; Bianchi, R.
Cyclosporine A (CsA) is the first choice immunosuppressant universally used in allotransplantation. However, it has been demonstrated that this drug produces unwanted side effects in several organs and in particular in the kidney and in the heart. While the cardiac toxicity, due to alteration of myocardial prostanoid has been reported, no data are available about the effects of CsA on myocardial cytoarchitecture. We studied the CsA induced alterations of the myocardial structure and of the extracellular matrix components (ECM). To test the ECM enzymatic changes we studied a family of enzymes (matrix metalloproteinase-MMP), responsible for the degradation of extracellular matrix components. In particular we investigated MMP1, MMP2 and MMP9. The study was carried out on two groups of Wistar rats. The group I animals served as a control and were injected subcutaneously daily with castor oil for 21 days. Group II: animals were subcutaneously injected daily with CsA (dose: 15 mg/Kg in castor oil) for 21 days. The group I animals (control) had normal heart architecture and low levels of MMP1, MMP2 and MMP9. The group II animals showed degenerative changes with myocardial fibrosis, low levels of MMP1 and MMP9 but a clear increase in MMP2. We suggest that the myocardial fibrosis was a consequence of the cardiotoxic effect of CsA determining the alteration of the balance between synthesis and degradation of ECM. The increase in MMP2 suggests that this enzyme could play a protective role during myocardial damage and represent a compensatory mechanism for the excessive accumulation of collagen.
Open Access
GADD153 is an independent prognostic factor in melanoma immunohistochemical and molecular genetic analysis
(Murcia : F. Hernández, 2002) Korabiowska, M.; Cordon-Cardo, C.; Betke, H.; Schlott, T.; Kotthaus, M.; Stachura, J.; Brinck, U.
The main role of growth arrest and DNA damage-inducible (GADD) genes is to block proliferation at G1 and G2 checkpoints in response to DNA damage. The goal of this study was to examine the expression of GADD genes in primary melanomas with respect to prognosis. GADD34 was found in 73% of the primary melanomas investigated. GADD45 and GADD153 were positive in 60% and 80% of primary melanomas, respectively. Cox regression demonstrated that only GADD153 had any independent prognostic impact. We therefore decided to establish a PCR assay for detection of GADD153 in paraffin-embedded tissue. GADD153 deletion was found in 3/26 melanomas. None of the 3 cases with GADD153 deletion showed any expression of GADD153. Sequencing analysis detected polymorphism T-C at amino acid position 10 in 6/23 melanomas. In 6 cases with GADD153 polymorphism, GADD153 expression was found in 2 melanomas with a maximum GADD153 index of 10%. We postulate that the GADD gene family plays an important role in melanoma progression.
Open Access
Promotion of metastasis in nasopharyngeal carcinoma by Epstein-Barr virus latent membrane protein-1
(Murcia : F. Hernández, 2002) Yoshizaki, T.
Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV). Latent membrane protein-1 (LMP-1) is an EBVencoded oncoprotein and is detected in approximately 50-70% of patients with NPC. LMP-1 is thought to play an essential role in tumorigenesis of NPC. In addition to its transforming properties, LMP-1 has been suggested to be associated with promotion of metastasis. Metastasis is a phenomenon composed of multiple sequential cascades. Reduction of tumor cell adhesion, degradation of extracellular matrix, basement membrane, enhancement of cell motility, and promotion of neovascularization are thought to be essential steps. LMP-1 down-regulates expression of E-cadherin, induces matrix metalloproteinase-9 and urokinase typeplasminogen activator through activation of NF-?B and AP-1, and enhances cell motility via ets-1 activation. LMP-1 also induces vascular endothelial growth factor through cyclooxygenase-2 activation and interleukin-8 through NF-?B activation. Clinical studies suggested the association of these factors with metastatic status of patients with NPC. In this review, the role of LMP-1 in the metastasis of NPC is discussed.
Open Access
Autophagy in neurons a review
(Murcia : F. Hernández, 2002) Larsen, K.E.; Sulzer, D.
Macroautophagy is a process of regulated turnover of cellular constituents that occurs during development and under conditions of stress such as starvation. Defects in autophagy have serious consequences, as they have been linked to neurodegenerative disease, cancer, and cardiomyopathy. This process, which exists in all eukaryotic cells, is tightly controlled, but in extreme cases results in the death of the cell. While major insights into the molecular and biochemical pathways involved have come from genetic studies in yeast, little is known about autophagic pathways in mammalian cells, particularly in neurons. Recently, research in neuronal culture models has begun to identify some characteristics of neuronal macroautophagy. The results suggest that macroautophagy in neurons may provide a neuroprotective mechanism. Here, we review the defining characteristics of autophagy with special attention to its role in neurodegenerative disorders, and recent efforts to delineate the pathway of autophagic protein degradation in neurons.
Open Access
Molecular pathology of head and neck cancer
(Murcia : F. Hernández, 2002) Crowe, D.L.; Hacia, J.G.; Hsieh, C.L.; Sinha, U.K.; Rice, D.H.
Squamous cell carcinoma of the head and neck region (HNSCC) is the sixth most frequent cancer worldwide, comprising almost 50% of all malignancies in some developing nations. In the United States, 30,000 new cases and 8,000 deaths are reported each year. Survival rates vary depending on tobacco and alcohol consumption, age, gender, ethnic background, and geographic area. This variability reflects the multifactorial pathogenesis of the disease. Early detection and diagnosis has increased survival but the overall 5 year rate of 50% is among the lowest of the major cancers. Differences between normal epithelium and cancer cells of the upper aerodigestive tract arise from specific alterations in genes controlling DNA repair, proliferation, immortalization, apoptosis, invasion, and angiogenesis. These proteins include both tumor suppressors and activating oncogenes which regulate a wide variety of intracellular signaling pathways. Included in these pathways are growth factor receptors, signal transducers, and transcription factors which regulate DNA damage response, cell cycle arrest, and programmed cell death. In head and neck cancer, alterations of three signaling pathways occur with sufficient frequency and produce such dramatic phenotypic changes as to be considered the critical transforming events of the disease. These changes include mutation of the p53 tumor suppressor, inactivation of the cyclin dependent kinase inhibitor p16, and overexpression of epidermal growth factor receptor (EGFR). This review will focus on the molecular changes which occur in these pathways and how they contribute to the pathogenesis of HNSCC.
Open Access
Expression of ribosomal protein L4 (rpL4) during neurogenesis and 5-azacytidine, (5AzC)-induced apoptotic process in the rat
(Murcia : F. Hernández, 2002) Ueno, M.; Nakayama, Hiroyuki; Kajikawa, S.; Katayama, K.; Suzuki, K.; Doi, K.
5-Azacytidine (5AzC) induces neuronal apoptosis in rat and mouse fetuses. 5AzC also induces apoptosis in undifferentiated PC12 cells, and ribosomal protein L4 (rpL4) mRNA expression increases prior to apoptosis. To clarify the roles of rpL4 during neurogenesis, we first examined the distribution of rpL4 mRNA in the developing rat brain by in situ hybridization and RT-PCR, and compared the results to the distribution of TUNEL- or PCNA-positive cells. rpL4 mRNA expression was strong in the ventricular zone (VZ), subventricular zone (SVZ), cortical plate (CP), cerebral cortex, granule cell layer (GCL), pyramidal cell layer (Py) and external granular layer (EGL) during embryonic and early postnatal days, and it was remarkably weakened thereafter. A lot of PCNApositive cells were observed in VZ, SVZ, and EGL during embryonic and early postnatal days, and such distribution of PCNA-positive cells was almost identical to rpL4 mRNA distribution. Only few TUNEL-positive cells were observed in VZ, SVZ, cerebral cortex, EGL, and hippocampus during embryonic and early postnatal days, and the regions with TUNEL-positive cells were not identical to rpL4 mRNA distribution. Next, the changes of rpL4 mRNA expression in the brain of 5AzC-treated rat fetuses were examined by in situ hybridization and RT-PCR. Apoptotic cells appeared at 9 to 24 hours after treatment (HAT). However, the rpL4 mRNA expression was unchanged during the apoptotic process. From the results, it is suggested that rpL4 would have certain roles in cell proliferation and differentiation during neurogenesis, but have no roles in 5AzC-induced apoptosis in the fetal brain.
Open Access
Trypanosoma cruzi infection patterns in intact and athymic mice of susceptible and resistant genotypes
(Murcia : F. Hernández, 2002) Gonçalves da Costa, S.C.; Calabrese, K.S.; Zaverucha do Valle, T.; Lagrange, P.H.
Inbred strains of mice inoculated with the T. cruzi Y strain behaved as susceptible (A/J, C3H/HeN), intermediate (BALB/c) or relatively resistant (C57BL/6) with respect to the magnitude of parasitaemia and mortality rate. C57BL/10 mice were susceptible in relation to parasitaemia but resistant when mortality was analyzed. Infection with T. cruzi CL strain presented the same results, except for C57BL/6 which behaved as susceptible mice. Athymic mice of various backgrounds revealed no differences in susceptibility, presenting the same dramatic parasitaemia, tissue colonization pattern and no inflammatory reaction in any of the tissues studied. Infection of euthymic and athymic BALB/c mice elicited the production of parasite-specific antibodies, which reached similar levels on the first 9 days but differed after day 13. Serum transfer experiments in BALB/c mice did not show great differences in parasitaemia but altered T. cruzi polymorphism reducing the slender forms in athymic mice. Histopathology of athymic BALB/c mice showed the same tissue tropism when infected either with T. cruzi Y or CL strain.
Open Access
Computer-aided morphometric analysis of the developing concentric structure of the human fetal intestinal tube
(Murcia : F. Hernández, 2002) Bagyánszki, M.; Kovács, É.G.; Resch, B.A.; Román, V.; Resch, B.E.; Fekete, Eva
The Image-Pro Plus 3.0 morphometric program was used to study the region-specific organization of the human fetal intestine across the radial axis of the gut at weeks 12 and 18 of gestation. The thicknesses of the epithelium, the submucosa, the muscular layers and the myenteric ganglia were measured in resin-embedded semithin sections. Statistical analysis of the collected data was performed by using the two-way ANOVA, the SNK test and the Pearson correlation. The structural changes relating to the gut morphogenesis within this developmental period were followed both light and electron microscopically. The various tissues forming the radial axis of the intestinal tube exhibited different trends concerning their individual development. The thickness of the epithelium did not change in the fetal period investigated, although the epithelial surface displayed characteristic ultrastructural changes. The thickness of the submucosal layer increased significantly, but with different dynamics along the longitudinal axis, whereas the increases in size of the muscular layers and the myenteric ganglia did not differ significantly along the longitudinal axis of the embryonic intestine. The Pearson correlation revealed a significant correlation between the development of the circular muscle layer and that of the myenteric plexus along the whole length of the intestinal tube. The epithelium, the submucosa and the longitudinal muscle layers developed independently between weeks 12 and 18 of gestation.
Open Access
Interocular effect of intravitreal injection of 6-hydroxydopamine and dopamine on spinule formation in teleost retina
(Murcia : F. Hernández, 2002) García, M.; Grzywacz, N.M.; De Juan, J.
Terminal dendrites of cone horizontal cells (HCs) in teleost retinas show numerous spine-like protrusions named spinules, which are invaginated into the cone pedicles during light-adaptation, but retracted during dark-adaptation. Somata of HC show nematosomes whose size decreases as the number of spinules increases. Mechanisms regulating these changes in nematosomes and spinules are only partially understood, being an area of controversy in retinal cell biology. It has been suggested that efferent fibres from the brain to the retina might be involved in the control of spinule formation. Moreover, we have reported that actin depolymerization has an interocular effect on spinule formation, which could be mediated by these fibres. In the present report, we show an interocular effect on spinule dynamics: the monocular intravitreal injection of dopamine (DA) and 6-hydroxydopamine (6-OHDA), two drugs that affect the spinule formation, produces the same effects in the contralateral, untreated eye as in the injected eye. Our results reinforce the idea of an interocular central control of this phenomenon of synaptic plasticity. Dopamine-dependent events in the retina appear to be necessary to forge the afferent signals eliciting this interocular effect.
Open Access
Classification of lymphoproliferative disorders by spectral imaging of the nucleus
(Murcia : F. Hernández, 2002) Greenspan, H.; Rothmann, C.; Cycowitz, T.; Nissan, Y.; Cohen, A.M.; Malik, Z.
Spectral nuclear morphometry was used for the classification of lymphocytes in lymphoproliferative disorders. May-Grunwald-Giemsa-stained blood specimens were taken from thirty patients with infectious mononucleosis, non-Hodgkin lymphoma or chronic lymphocytic leukemia, and from ten healthy individuals. Blood specimens were analyzed by spectral imaging. Seventeen distinct spectra were collected into a spectral library and a distinct pseudo color was assigned to each one of them. The library was used to scan all the cells in the database and to create a spectrally classified image of each cell. The spectral map, per cell, reveals distinct spectral-response regions in each cellular compartment, via the distinct region colors. Computational analysis of the spectral maps allows for the objective quantification of a set of parameters, or features, representing the cell. The features used in this work include the area and perimeter of the nucleus, circularity, edginess and the spectral pattern. The analysis pursued showed that each class of cells is associated with a set of unique parameters. We conclude that spectral analysis combined with feature analysis provides significant information in the analysis of lymphoproliferative disorders and may serve as an additional tool for the histopathological evaluation of disease.
Open Access
Regulation of human endometrial transforming growth factor ß1 and ß3 isoforms through menstrual cycle and medroxyprogesterone acetate treatment
(Murcia : F. Hernández, 2002) Reis, F.M.; Ribeiro, M.F.M.; Maia, A.L.; Spritzer, P.M.
The progesterone-induced differentiation of endometrial tissue from proliferative into secretory and decidua seems to be modulated by locally produced hormones and cytokines. Transforming growth factor beta (TGFß), a cytokine produced by endometrial cells, has been shown to modulate endometrial cell proliferation in vitro. Our aim was to evaluate the effects of medroxyprogesterone acetate (MPA) and the influence of menstrual cycle on the expression of TGFß1 and TGFß3 in human endometrium in vivo. In a doubleblind, placebo-controlled trial, 46 healthy women with regular menstrual cycles received either MPA (10 mg/day) or placebo during 10 days. Endometrial and blood samples were collected 8-12 hours after the last MPA or placebo administration. Patients were classified into three groups according to biopsy dating and treatment: proliferative [tissue]/placebo, secretory [tissue]/placebo and secretory [tissue]/MPA. The immunohistochemical distribution of TGFß1 and TGFß1 mRNA was similar in all groups. Immunoreactive TGFß3 was present in the epithelium in 9.1% of proliferative samples, in 41.2% of secretory/placebo samples and in 87.5% of secretory/MPA samples (p=0.001). In the stroma, the frequency of TGFß3 staining was markedly increased after treatment with MPA (62.5%) compared to placebo (proliferative: 9.1%; secretory: 5.9%; p=0.005). The levels of TGFß3 mRNA increased during the secretory phase and were higher in the MPA-treated group, being directly correlated with morphological endometrial differentiation. It is concluded that MPA administration to healthy women increased TGFß3 but did not change TGFß1 gene and protein expression in the endometrium. This finding suggests that TGFß3 may be a local factor mediating progesterone- and progestogen-induced endometrial differentiation.
Open Access
The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis
(Murcia : F. Hernández, 2002) Afuwape, A.O.; Kiriakidis, S.; Paleolog, E.M.
The expansion of the synovial lining of joints in rheumatoid arthritis (RA), and the subsequent invasion by the pannus of underlying cartilage and bone, necessitates an increase in the vascular supply to the synovium, to cope with the increased requirement for oxygen and nutrients. New blood vessel formation - ‘angiogenesis’ - is now recognised as a key event in the formation and maintenance of the pannus in RA. Although many pro-angiogenic factors have been demonstrated to be expressed in RA synovium, the potent pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been demonstrated to have a central involvement in the angiogenic process in RA. The additional activity of VEGF as a vascular permeability factor may also increase oedema and hence joint swelling in RA. Several studies, including those from the Kennedy Institute of Rheumatology Division, have shown that targeting angiogenesis in animal models of arthritis ameliorates disease. Inhibition of angiogenesis, as an adjunct to existing therapy of RA, or even as a stand-alone treatment, would not only prevent delivery of nutrients to the synovium, but could also lead to vessel regression and possibly reversal of disease.
Open Access
STAT and SMAD signaling in cancer
(Murcia : F. Hernández, 2002) Iwamoto, T.; Oshima, K.; Senga, T.; Feng, X.; Oo, M.L.; Hamaguchi, M.; Matsuda, S.
STAT and SMAD often exert opposite biological effects on diverse cellular functions. Recent studies have shown that STAT can interface with SMAD at molecular level and that some novel molecules, such as SOCS (also called CIS) and APRO6 (also called TOB), modulate this signaling. A cofactor p300/CBP might act as a bridging molecule to mediate the interface. Thus, STAT and SMAD signaling pathways may crosstalk each other with interweaved regulatory mechanisms. Interestingly, the importance of all the proteins’ function has been shown by the increasing evidence of their involvement in cancer. These recent progresses have been made in attributing novel exciting functions. Accordingly, we would like to review the latest advances of those pathways on a cross-section in cancer signaling.
Open Access
CD44: functional relevance to inflammation and malignancy
(Murcia : F. Hernández, 2002) Yasuda, M.; Nakano, K.; Yasumoto, K.; Tanaka, Y.
CD44 is a principal cell surface receptor for hyaluronan, a major component of extracellular matrices. Cells are surrounded by and encounter matrix in vivo, which in turn serves a variety of cell functions through the direct adhesion via their receptors. CD44 communicates cell-matrix interactions into the cell via “outside-in signaling” and has an important role in biological activities. The interaction of CD44 with fragmented hyaluronan on rheumatoid synovial cells induces expression of VCAM-1 and Fas on the cells, which leads to Fas-mediated apoptosis of synovial cells by the interaction of T cells bearing FasL. On the other hand, engagement of CD44 on tumor cells derived from lung cancer reduces Fas expression and Fas-mediated apoptosis, resulting in less susceptibility of the cells to CTL-mediated cytotoxicity through Fas-FasL pathway. Thus, although the CD44-mediated signaling differs among cells and circumstances, we here propose the functional role of CD44 in inflammatory processes and tumor susceptibility and the rational design of future therapeutic strategies including the exploitation of CD44-mediated pathway in vivo.
Open Access
Antiproliferative effect of topic hyaluronic acid gel. Study in gingival biopsies of patients with periodontal disease
(Murcia : F. Hernández, 2002) Mesa, F.L.; Aneiros, J.; Cabrera, A.; Bravo, M.; Caballero, T.; Revelles, F.; Del Moral, R.G.; O’Valle, F.
Hyaluronic acid (HA) is the most abundant glycosaminoglycan of high molecular weight in the extracellular matrix of soft periodontal tissues. Our group recently demonstrated an HA-induced reduction in lymphoplasmocyte inflammatory infiltrate in periodontal disease. The objective of this study was to determine the effect of an HA gel of high molecular weight on cell proliferation, inflammation, and different periodontal lesion parameters. A double-blind clinical trial was conducted on the effect of an HA gel on cell proliferation in gingival biopsies from 28 patients with periodontal disease. A split-mouth design was used, randomly applying the gel to one quadrant and a placebo to the contralateral one. A gingival biopsy was taken for histopathological and immunohistochemical study, in order to determine the expression of cell proliferation antigen Ki-67 and to evaluate the inflammatory infiltrate. HA gel treatment induced a significant reduction in the proliferation index of the gingival epithelium, with 276 (range 234-317) Ki-67-positive cells per mm2 in treated samples versus 514 (range 158-876) per mm2 in controls (Mann-Whitney U test, p<0.003). In 13 patients, the number of Ki-67-positive fibroblastic cells was reduced by the treatment, whereas in 6 patients no differences were found (global difference, p=0.12). In 10 patients, Ki-67-positive cells were decreased in chronic inflammatory infiltrate present in the lamina propria, whereas in 6 patients no differences were found (global difference, p=0.054). We conclude that high molecular-weight HA gel reduces cell proliferation in epithelial cells such as fibroblasts and lymphocytes, abates the inflammatory process, and improves the periodontal lesion in patients with chronic periodontitis.