The prevention of spontaneous apoptosis of follicular lymphoma B cells by a follicular dendritic cell line: involvement of caspase-3, caspase-8 and c-FLIP.
BACKGROUND
Follicular lymphoma, the neoplastic counterpart of germinal center B cells, typically recapitulates a follicular architecture. Several observations point to the crucial role of the cellular microenvironment in the development and/or progression of follicular lymphoma cells in vivo. The aim of our study was to characterize the spontaneous apoptosis of follicular lymphoma cells in vitro, and the modulation of this apoptosis by follicular dendritic cells.


METHODS
We used a cell line derived from follicular dendritic cells to model the functional interactions of these cells and lymphoma cells in co-culture. Follicular lymphoma cells were isolated from tissue biopsies. Apoptosis was quantified by flow cytometry and apoptotic pathways were investigated by western blotting.


RESULTS
The spontaneous apoptosis of follicular lymphoma cells in vitro involves the activation of caspases-3 and -8 but not of caspase-9, occurs despite persistent high levels of BCL-2 and MCL-1, and is associated with down-regulation of c-FLIP(L). Spontaneous apoptosis of follicular lymphoma cells is partially prevented by co-culture with the follicular dendritic cells, which prevents activation of caspase-8, caspase-3 and induces an upregulation of c-FLIP(L). Using neutralizing antibodies, we demonstrated that interactions involving CD54 (ICAM-1), CD106 (VCAM-1) and CD40 are implicated in this biological process.


CONCLUSIONS
Follicular dendritic cells constitute a useful tool to study the functional interactions between follicular lymphoma cells and follicular dendritic cells in vitro. Understanding the molecular mechanisms involved in these protective interactions may lead to the identification of therapeutic agents that might suppress the survival and growth of follicular lymphoma cells.
Department of Pathology, CHU Sart Tilman, Liège, Belgium.
Jean-Jacques
JJ
Goval
Caroline
C
Thielen
Caroline
C
Bourguignon
Roland
R
Greimers
Emmanuel
E
Dejardin
Yong Sung
YS
Choi
Jacques
J
Boniver
Laurence
L
de Leval
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001402:B-Lymphocytes / Q000201:enzymology / Q000473:pathology*; D001706:Biopsy; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D020566:Dendritic Cells, Follicular / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008224:Lymphoma, Follicular / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014481:United States / Q000453:epidemiology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D053148:Caspase 3; D053181:Caspase 8