Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas

Abstract

We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL. (Blood. 2005; 105:2916-2923)

Prognostic Significance of Survivin and Caspase-3 Immunohistochemical Expression in Patients with Diffuse Large B-cell Lymphoma Treated with Rituximab and CHOP

“…Nevertheless, more likely explanation is that caspase-3 cannot be evaluated properly because all tumor cells, as well as non-tumor cells, express this form of caspase-3. To avoid this problem, more recent studies tested the expression of the active form of caspase-3 [16,17]. However, it was demonstrated that prognostic value of active caspase-3 is closely related to expression levels of other apoptosis-related proteins.…”

“…demonstrated that immunohistochemical localization of caspase-3 can be correlated with clinical outcome in DLBCL [15]. More recent studies evaluated expression of active (cleaved) caspase-3 [16,17]. However, the expression of active caspase-3 is generally very low and it may be difficult to determine if active caspase-3 positive cells are indeed neoplastic.…”

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib

“…23,24 The BCL2-IGH translocation is present in LY10 cells (CY and YLW, data not shown). Downregulation of BCL2 may, therefore, account for the cell death induced by dasatinib in LY10 cells.…”

Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis

“…Very few reports on a prognostic influence of CASP9 expression in cancer have been published until now, with conflicting results. In large B-cell lymphomas, inhibition of CASP9 was strongly associated with a poor response to chemotherapy (19). However, as described here, other studies have Results are presented in log10 scale and are expressed as fold-change.…”