A TGFß hatásmechanizmusai, TGFß rezisztencia háttere a daganat növekedésében és terápiás válaszában = The mechanism of TGFß effect, the background of TGFß resistance in tumor growth and in therapeutic response

Daganatok es lymphomak eseteben is jol ismert, hogy elveszithetik erzekenyseguket negativ szabalyozoikkal, peldaul a TGFb-val szemben. A TGFb hatasaban fontos jelatviteli halozatok szerepet, a TGFb hatasait vizsgaltuk. Kimutattuk, hogy lymphomakban a TGFb erzeketlenseg hattereben nem a jelatviteli elemek expresszio valtozasa, hianya all. Vizsgaltuk a TGFb es a Notch jelatviteli ut kolcsonhatasat. Smad4 siRNS kiserleteink segitsegevel jellemeztuk a TGFb Smad4 fuggetlen, PP2A fuggő alternativ jelatviteli mechanizmusait, amelyekkel lymphoma sejtekben aktivalhatoak a TGFb fuggő apoptotikus folyamatok. Kimutattuk, hogy a rapamycin kepes helyreallitani, fokozni a lymphomasejtek TGFb erzekenyseget in vitro, igy segitheti a kulonboző kemoterapias szerek hatekonysagat in vivo. Jellemeztuk a rapamycin es egy masik immunszuppressziv szer a mycophenolsav lymphoma ellenes hatasait in vitro es in vivo. Kimutattuk, hogy a rapamycin kepes fokozni a Rituximab hatasat NHL xenograftokban. Vizsgaltuk a kulonboző lymphomasejtek mTOR aktivitasat. Eredmenyeink alapjan bizonyos lymphomak eseteben az mTOR aktivitas terapias celpont lehet, gatlasa segitheti a lymphomasejtekben gatolt negativ szabalyozok felszabaditasat, az alkalmazott terapiak hatasanak fokozasat. Parhuzamosan jellemeztuk lymphoproliferativ betegsegek TGFb erzekenyseg valtozasat. Kimutattuk, hogy SLEs betegek lymphocytaiban a lymphomasejtekkel ellentetben a jelatviteli elemeinek expresszio valtozasa all a TGFb rezisztencia hattereben. | Tumors of a variety of origin - including lymphomas - often lose their sensitivity to negative regulators such as TGFb. We studied the effects of TGFb and the role of relevant signaling networks. We showed that resistance to TGFb is not due to the loss or expression change of signaling elements in lymphomas. We analyzed cross-talk between the TGFb and Notch pathway. Using Smad4 siRNA we characterized alternative, Smad4-independent, PP2A-dependent signaling pathways, which can activate TGFb-dependent apoptotic mechanisms in lymphoma cells. We showed that rapamycin is able to restore or augment TGFb-sensitivity in lymphoma cells in vitro, and thus, it might enhance the efficiency of chemotherapeutical agents in vivo. We characterized the anti-lymphoma effects of rapamycin and mycophenolic acid - another immunosuppressive drug - in vitro and in vivo. We showed that rapamycin is able to enhance the effect of rituximab in NHL xenografts. We also studied the activity of mTOR in different human lymphomas. Our results suggest that the mTOR pathway may be a potential therapeutical target in certain lymphomas - its inhibition may help restore the function of negative regulators, and thus augment the efficiency of already existing therapies. In addition, we characterized the changes of TGFb sensitivity in other lymphoproliferative diseases; in contrary to lymphoma cells, the lymphoytes of SLE patients lose their TGFb-sensitivity due to the expression changes of signaling elements.