Repozitorij Medicinskog fakulteta Sveučilišta u Zagrebu

Imunohistokemijska koekspresija 4-hidroksinonenala i prominina-1 u glijalnim tumorima mozga [The coexpression of 4-hydroxynonenal and prominin-1 in glial tumors of the brain]

Kolenc, Danijela (2010) Imunohistokemijska koekspresija 4-hidroksinonenala i prominina-1 u glijalnim tumorima mozga [The coexpression of 4-hydroxynonenal and prominin-1 in glial tumors of the brain]. PhD thesis, Sveučilište u Zagrebu.

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    Croatian abstract

    Oksidacijski stres je stanje u kojem oksidacijski procesi nadvladaju antioksidacijske sposobnosti stanica i tkiva. Oštećenje stanice izazvano je slobodnim radikalima koji se stvaraju tijekom aerobne respiracije stanice u OS. U ravnotežnim uvjetima slobodni radikali se razgrađuju enzimatskim i neenzimatskim proteinima. Lipidna peroksidacija je autokatalitički proces potaknut OS pri čemu se oštećuju lipidi i posljedično dolazi do stvaranja visoko reaktivnih spojeva poput HNE-a. HNE se smatra sekundarnim toksičnim glasnikom jer oštećuje stanice i dovodi do njihove smrti. Tijekom OS nastali HNE smatraju se važnim čimbenikom inicijacije i promocije karcinogeneze. U brojnim tumorima pa tako i gliomima mozga, opisana je nazočnost HNE i drugih reaktivnih aldehida nastalih lipidnom peroksidacijom. Hipoteza tumorskih matičnih stanica temelji se na pretpostavci da sve stanice unutar tumora ne mogu proliferirati i doseći pravu tumorsku masu, već je za to odgovoran mali broj stanica koji zovemo tumorske matične stanice. Prominin-1 (CD133) identificiran je u ljudi i miševa i prepoznat je kao biljeg primitivnih hematopoetskih i neuralnih matičnih stanica. Različita tkivna oštećenja SŽS-a (trauma, virusi, ishemija) povećavaju količinu produkata OS što dovodi i do oštećenja endotela krvnih žila koji pokreću endotelne progenitorske stanice iz koštane srži (EPCs), te stanice pokazuju ekspresiju CD133 i CD34 te imaju bitnu ulogu u angiogenezi. Cilj ovog rada bio je utvrditi imunohistokemijski istovremenu pojavnost 4-HNE, kao pokazatelja lipidne peroksidacije, i prominina-1 (CD133) kao biljega tumorskih matičnih stanica u pojedinim vrstama glijalnih tumora mozga. Monoklonskim protutijelom na HNE–histidinske konjugate i poliklonskim protutijelom na prominin-1 analiziran je HNE i CD133 imunopozitivitet u astrocitnim (30 PA, 30 DA, 30 AA i 30 GBM), oligodendroglijalnim (30 O i 30 AO) i ependimskim tumorima (20 E, 20 AE i 10 S) različitog stupnja zloćudnosti. HNE imunopozitivitet zamijećen je u svim tumorskim skupinama u različitom intenzitetu u tumorskim stanicama, krvnim žilama i stromi, dok je CD133 zamijećen u svim tumorskim skupinama, ali ne i svim uzorcima. Razina HNE imunopozitiviteta raste s malignošću astrocitoma, ependimoma i oligodendroglioma, ali je zamijećena i visoka HNE imunoreaktivnost u PA što ukazuje da konačni produkt lipidne peroksidacije, HNE, ne mora uvijek korelirati s malignošću astrocitoma, već je odraz regresivnih promjena u dobroćudnim spororastućim tumorima. Zamijećen je porast kvantitativne i kvalitativne HNE i CD133 koekspresije u tumorskim stanicama, stromi i krvnim žilama u astrocitomima s porastom njihove malignosti što ukazuje da bi oba biljega mogla biti dobri prognostički pokazatelji malignosti astrocitoma. Nadalje, porast HNE-a u tumorskim stanicama, krvnim žilama i stromi ependimoma porastom njihove malignosti ukazuje da bi HNE mogao biti dobar prognostički pokazatelj malignosti ependimoma, dok sporadična nazočnost i pad CD133 imunopozitiviteta u tumorskim stanicama i stromi s porastom malignosti ependimoma ukazuje da matične tumorske stanice nemaju značajniji utjecaj na ovu tumorsku skupinu.

    English abstract

    Oxidative stress is the condition that occurs when antioxidative capacity of tissue and cells is overcome. The oxidative damage of cells is caused by free radicals which are products of OS. In equilibrium, free radicals are disintegrated by enzymatic and nonenzymatic proteins. Lipid peroxidation is an autocatalitic process caused by OS which damages lipids and causes production of highly reactive species as HNE. HNE is thought to be second toxic messenger that damages cells causing their death. ROS and RNS are products of OS and they play an important role in both initiation and promotion of carcinogenesis. The brain is very vulnerable to damage mediated by ROS since cells in central nervous system (CNS) have low levels of antioxidant defenses, high iron content and high level of poly-unsaturated fatty acids. The cancer stem cell hypothesis suggests that not all the cells in the tumor have the same ability to proliferate and maintain the growth of the tumor. Only a relatively small fraction of cells in the tumor, termed cancer stem cells, posseses the ability to proliferate and self-renew extensively. Prominin-1 (CD133) has been identified in both human and mice and was originally classified as a marker of primitive haematopoietic and neural stem cells. Different tissue damages of CNS such as trauma viruses and ishaemia, increase the amount of OS product which damages the endothelial cells which consequently excess production from bone marrow-derived endothelial progenitor cells (EPCs). EPCs are immunoreactive for CD133 and CD34 and thus important in the process of angiogenesis. The aim of this study was to determine the coexpression of HNE-histidine conjugates and CD133 in glial tumors of the brain. The expression of HNE in astrocytic (30 pilocytic astrocytomas, 30 diffuse astrocytomas, 30 anaplastic astrocytomas and 30 glioblastomas), oligodendroglial (30 oligodendrogliomas and 30 anaplastic oligodendrogliomas) and ependymal tumors (10 subepenymomas, 20 ependymomas and 20 anaplastic ependymomas) was analyzed using monoclonal antibody on HNE-histidine conjugates and polyclonal antibody on prominin-1 (CD133). HNE immunopositivity was found in all tumor groups in different intensity in tumor cells, blood vessels and stroma while a CD133 was found in all tumor groups, but not all samples. The level of HNE immunopositivity increased with malignancy of astrocytomas, ependymomas and oligodendrogliomas but high level of HNE expression was found in PA which indicates that final product of lipid peroxidation, HNE, does not correlate with malignancy of astrocytomas but is a reflection of regressive changes in the benign slow growing tumors. An increase in quantitative and qualitative coexpression of HNE and CD133 in tumors cells, stroma and blood vessels in astrocytomas was found with the increase of their malignancy, indicating that both markers could be good prognostic indicators malignancy of astrocytoma. Furthermore, the increase in HNE in the tumor cells, blood vessels and stroma ependymoma with an increase in their malignancy suggests that HNE may be a good prognostic indicator of ependymoma malignancy, while sporadic presence and reduction of CD133 in the tumor cells and stroma with an increase of ependymoma malignancy suggests that tumor stem cells have no significant effect on this tumor group.

    Item Type: Thesis (PhD)
    Mentor: Žarković, Kamelija
    Divisions: Katedra za patologiju
    Depositing User: Marijan Šember
    University: Sveučilište u Zagrebu
    Institution: Medicinski fakultet
    Number of Pages: 143
    Status: Unpublished
    Creators:
    CreatorsEmail
    Kolenc, Danijela
    Date: 22 July 2010
    Date Deposited: 25 Oct 2010
    Last Modified: 23 Sep 2011 18:11
    Subjects: /
    Related URLs:
      URI: http://medlib.mef.hr/id/eprint/866

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