Bcl‐2 expression correlates positively with serum basic fibroblast growth factor (bFGF) and negatively with cellular vascular endothelial growth factor (VEGF) in patients with chronic lymphocytic leukaemia

Abstract

Summary.A large proportion of B-chronic lymphocytic leukaemia (B-CLL) cells express the anti-apoptotic protein Bcl-2. Basic fibroblast growth factor (bFGF) has been shown to upregulate the expression of Bcl-2 in B-CLL cell lines. Vascular endothelial growth factor (VEGF) has been shown to enhance the survival of endothelial cells by upregulating the expression of Bcl-2. In the present study, we measured serum and cellular levels of bFGF and VEGF in 85 patients with CLL using a commercial quantitative sandwich enzyme immunoassay technique. Levels of Bcl-2 were also assayed concomitantly using Western blot analysis.The mean serum level of bFGF was 53´4 pg/ml (range 0±589) and that of VEGF 459´2 pg/ml (range 33±1793). The mean cellular level of bFGF was 158´3 pg/2 Â 10 5 cells (range 0´8±841) and VEGF, 42´4 pg/2 Â 10 5 cells (range 0±244). A high correlation was found between serum and cellular bFGF levels (P , 0´001), but not between the corresponding VEGF levels. Twenty-nine of 69 patients (42%) evaluated for Bcl-2 level, expressed it. The Bcl-2 level was positively correlated with the serum bFGF level (P 0´007). However, surprisingly there was a negative correlation between Bcl-2 expression and intracellular VEGF level (P 0´003). A positive correlation was also found between serum bFGF and disease follow-up time and log white blood cell count. These findings indicate that in CLL there is a correlation between angiogenesis-related factors and apoptosis-related protein expression, and elevated bFGF levels may account for the elevated Bcl-2 levels.

Role of angiogenesis in chronic lymphocytic leukemia

“…53 Similarly, production of the bcl-2 protein was found to positively correlate with serum bFGF and negatively with cellular VEGF levels. 39 Contrary to what was seen in an in vitro study, CLL cells did not bind strongly to exogenous bFGF, and application of bFGF did not increase phosphorylation (i.e., activation) of well-established proliferation kinases and did not have any effect on the viability of B-CLL cells in 5-day cultures. 35 Several researchers have reported on the ability of CLL cells to produce bFGF.…”

“…33,34 The second subset, malignant CLL cells, produces strong angiogenic factors such as VEGF and bFGF, 35 which have an antiapoptotic effect on the CLL cells 36,37 and correlate positively with expression of bcl-2, a well-established antiapoptotic gene. 38,39 This interplay of cytokines and their functions is further expanded by the active role of nearby stromal cells (the third subset) that produce hematopoietic growth factors under the influence of angiogenic factors. 40 The possible interactions of various cytokines and cell types found in the bone marrow microenvironment and the possible interference of antiangiogenic agents are shown in Figure 2.…”

CD38 expression on B-cell chronic lymphocytic leukemic cells is strongly correlated with vascular endothelial growth factor expression

“…7 We could not find any correlation between the expression of either CD38 or VEGF on the CLL cells and serum VEGF and bFGF. Others have reported a lack of correlation between bone marrow angiogenesis and serum VEGF 3 and between serum and intracellular VEGF levels 8 in CLL, perhaps due to contributions to serum VEGF levels from other sources. Also, serum levels of bFGF may not accurately reflect any possible contribution to angiogenesis by bFGF because of low cellular release of bFGF.…”

“…Also, serum levels of bFGF may not accurately reflect any possible contribution to angiogenesis by bFGF because of low cellular release of bFGF. 8 We are currently investigating the relationship between CD38 expression in CLL and other measures of angiogenesis, in particular bone marrow microvessel density and VEGF expression. The demonstration of more conclusive evidence of increased angiogenesis associated with increased surface expression of VEGF could provide a rationale for the use of antiangiogenic agents in CD38 þ CLL.…”

Prognostic relevance of angiopoietin-2, fibroblast growth factor-2 and endoglin mRNA expressions in chronic lymphocytic leukemia

“…Elevated circulating levels of FGF-2 in CLL have also been reported [24,25], but their prognostic relevance remains controversial [25,26] and knowledge regarding possible association of FGF-2 mRNA with prognosis of CLL is scanty [27,28]. Moreover, FGF-2 expression may be post-transcriptionally regulated by antisense molecule (nucleoside diphosphate-linked moiety X motif 6 gene [NUDT6]) responsible for altered FGF-2 mRNA stability [29].…”