Survivin i VEGF-C u papilarnom i anaplastičnom karcinomu štitaste žlezde: ekspresioni profili, uloga u biologiji tumora i kliničko-patološki značaj

Abstract

Progresija malignih tumora štitaste žlezde od dobro diferenciranih (papilarni karcinom) u nediferencirane, agresivne forme (anaplastični karcinom) praćena je različitim promenama na molekularnom nivou, koje omogućavaju malignoj ćeliji kontinuiranu aberantnu stimulaciju rasta i izbegavanje apoptotske smrti, što uz neoangiogenezu (formiranje novih krvnih i limfnih sudova) predstavlja preduslove tumorskog rasta i širenja. Predmet ovog rada je izučavanje molekularnih promena koje prate dediferencijaciju papilarnog u anaplastični karcinom štitaste žlezde, tj. ispitivanje promena ekspresionih profila apoptotskih molekula (Bcl-2, Bax, survivin) i limfangiogenog faktora (VEGF-C) u korelaciji sa kliničkim parametrima tokom progresije maligniteta tumora štitaste žlezde. Imunohistohemijskom analizom ekspresionih profila članova Bcl-2 familije konstatovano je da tokom progresije dolazi do smanjenja ekspresije Bcl-2 (antiapoptotski molekul), ali da je in situ apoptotska smrt detektovana TUNEL metodom na niskom nivou, uprkos visokih ekspresionih nivoa Bax (pro-apoptotskog) molekula. U isto vreme sa smanjenjem ekspresije Bcl-2 tokom progresije maligniteta dolazi do postepenog povećanja drugog antiapoptotskog molekula, survivina, koji je operativan nizvodno od Bax-a. Visoka ekspresija survivina je bila u korelaciji sa sniženim stepenom in situ detektovane apoptotske smrti, što sugeriše da survivin, a ne odnos Bcl-2/Bax ima ulogu u inhibiciji finalizacije programirane ćelijske smrti. Poređenjem imunohistohemijske ekspresije survivina sa kliničko-patološkim parametrima pacijenata utvrđena je značajna korelacija između visoke ekspresije survivina i prisustva metastaza u limfnim čvorovima. Ekspresioni profili VEGF-C proteina (angiogeni faktor koji promoviše formiranje tumorske vaskulature, a time i rast i širenje tumora) pokazali su porast tokom tumorske progresije i značajnu korelaciju sa prisustvom limfnih metastaza, ekstratiroidnom invazijom i uznapredovalim stadijumom tumorske bolesti...

Progression of malignancy of thyroid gland tumors from well differentiated (papillary carcinoma) to undifferentiated, aggressive form (anaplastic carcinoma) is accompanied by molecular changes. These enable continuous stimulation of aberrant growth and escape from apoptotic death, together with neoangenesis (formation of new blood and lymphatic vessels) which are prerequisites for tumor growth and spread. The objective of this work was examination of some molecular changes accompaning dedifferentiation of papillary to anaplastic carcinoma of the thyroid gland, i.e. an investigation of alterations in expression profiles associated with apoptosis (Bcl-2, Bax, survivin) and lympfhangiogenic factor, VEGF-C, in correlation with clinicopathological parameters during the progression of malignancy of thyroid gland tumors. Immunohistochemical analysis of expression profiles of Bcl-2 family members revealed decrease of Bcl-2 expression (anti-apoptotic molecule) during this progression, but a low level of in situ apoptotic cell death detected by the TUNEL method, despite high levels of Bax (pro-apoptotic molecule). The decrease of Bcl-2 expression was followed by increase of another anti-apoptotic molecule, survivin, which acts downstream from Bax. High survivin expression was found to correlate with the lower rate of in situ apoptotic cell death, suggesting that survivin, but not the Bcl-2/Bax ratio, has a role in finalization of programmed cell death. By comparing survivin immunohistochemical expression with clinico-pathological parameters of patients we found a significant positive correlation between high survivin expression and the presence of lymph node metastases. Expression profiles of VEGF-C protein (an angiogenic factor which promotes the formation of tumor vasculature, and thereby tumor growth and spread) revealed increased levels during tumor progression and a significant correlation with the presence of lymph node metastases, extrathyroid invasion and advanced stages of disease. Significant correlation between the expressions of two molecules, survivin and VEGF-C, in tumors with the presence of lymph metastases and in their metastatic tissues, suggests their coordinated roles in the metastatic process...