Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo

Abstract

Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness, we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium, TNF receptors were detectable in the range of 540 to 1,500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high- affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested, with the exception of IL-2, did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.

Tumor necrosis factor receptor signaling is a driver of chronic lymphocytic leukemia that can be therapeutically targeted by the flavonoid wogonin

“…Albeit conflicting data has been presented concerning the expression of mTNFR-1 on freshly isolated PB-derived CLL cells, 15 , 30 , 31 our results clearly demonstrate that these are negative for mTNFR-1, but upregulate their expression upon in vitro cultivation. Consistent with our data, TNFR-1 expression was reported on malignant cells in diffuse large B-cell lymphoma (DLBCL), which correlated with significantly shorter OS and progression-free survival rates compared to patients with TNFR-1 negative lymphoma cells.…”

Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

“…FAS, a member of the TNFR family, was found upregulated in human primary CLL cells exposed to clodrolip, together with other key molecules of the FAS/FASL, TNF, and TRAIL pathways of cell death. Primary CLL cells do not express TNF receptors in vivo (Digel et al, 1990), but cytokines such as IL-2 are known to influence their expression (Digel et al, 1990). It is thus conceivable that in our system macrophages undergoing rapid and massive apoptosis may release cytokines and growth factors capable of upregulating TNF receptors on leukemic cells and of restoring their sensitivity to apoptosis.…”

Multifaceted link between cancer and inflammation

“…TNFα has been reported to be produced by a wide variety of tumour cells, including those of B-cell lymphoma [17], megakaryoblastic leukaemia [18], adult T-cell leukaemia [19], breast carcinoma [20], colorectal cancer, lung cancer, SCC (squamous cell carcinoma), pancreatic cancer [21,22], ovarian carcinoma [23], the cervical epithelial cancer [24], glioblastoma [25] and neuroblastoma [26]. The pro-inflammatory potential of TNFα has also been analysed in various animal models of cancer.…”