Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas

The suppression of apoptosis is one mechanism by which tumours become drug resitant. Extracellular signals from the germinal centre (GC) of secondary lymphoid tissue can rescue B cells from physiological- and chemotherapy-ind uced apoptosis. Such survival signals include CD40 receptor ligation, inter leukin-4 (IL-4) receptor stimulation and the interaction of the integrin li gand VCAM-1 with its receptor. The GC environment was modelled in vitro by providing B lymphoma cells with these survival signals. JLP119B lymphoma ce lls underwent apoptosis after exposure to the topisomerase II inhibitor eto poside and this was dramatically reduced when the cells were cultured in th e GC system. CD40 receptor ligation resulted in increased levels of Bcl-X-L . Etoposide diminished the binding between Bar and Bcl-X-L but this was res tored by IL-4 and VCAM-1 triggered signals. These data demonstrate combined effects of three microenvironmental signals on the Bcl-2 family and illust rate the potential importance of such signalling pathways in drug resistanc e of tumour cells.