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-induced apoptosis. Such survival signals include CD40 receptor ligation, interleukin-4 (IL-4) receptor stimulation and the interaction of the integrin ligand VCAM-1 with its receptor. The GC environment was modelled in vitro by providing B lymphoma cells with these survival signals. JLP119 B lymphoma cells underwent apoptosis after exposure to the topisomerase II inhibitor etoposide and this was dramatically reduced when the cells were cultured in the GC system. CD40 receptor ligation resulted in increased levels of Bcl-XL. Etoposide diminished the binding between Bax and Bcl-XL but this was restored by IL-4 and VCAM-1 triggered signals. These data demonstrate combined effects of three microenvironmental signals on the Bcl-2 family and illustrate the potential importance of such signalling pathways in drug resistance of tumour cells.
Taylor
S T
ST
School of Biological Sciences, Manchester, UK.
Hickman
J A
JA
Dive
C
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D018858:Germinal Center / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000187:drug effects / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000473:pathology*; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000187:drug effects / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D016023:Integrins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019948:Receptors, Interleukin-4; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D015847:Interleukin-4; D005047:Etoposide