B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules

Abstract

Initial work has shown that clonal B cells from B-chronic lymphocytic leukemia (B-CLL) are able to synthesize pro-angiogenic molecules. In this study, our goal was to study the spectrum of angiogenic factors and receptors expressed in the CLL B cell. We used ELISA assays to determine the levels of basic fibroblast growth factors (bFGF), vascular endothelial growth factor (VEGF), endostatin, interferon-␣ (IFN-␣) and thrombospondin-1 (TSP-1) secreted into culture medium by purified CLL B cells. These data demonstrated that CLL B cells spontaneously secrete a variety of pro-and anti-angiogenic factors, including bFGF (23.9 pg/ml ± 7.9; mean ± s.e.m.), VEGF (12.5 pg/ml ± 2.3) and TSP-1 (1.9 ng/ml ± 0.3). Out of these three factors, CLL B cells consistently secreted bFGF and TSP-1, while VEGF was expressed in approximately two-thirds of CLL patients. Of interest, hypoxic conditions dramatically upregulated VEGF expression at both the mRNA and protein levels. We also employed ribonuclease protection assays to assay CLL B cell expression of a variety of other angiogenesis-related molecules. These analyses revealed that CLL B cells consistently express mRNA for VEGF receptor 1 (VEGFR1), thrombin receptor, endoglin, and angiopoietin. Further analysis of VEGFR expression by RT-PCR revealed that CLL B cells expressed both VEGFR1 mRNA and VEGFR2 mRNA. In summary, these data collectively indicate that CLL B cells express both proand anti-angiogenic molecules and several vascular factor receptors. Because of the co-expression of angiogenic molecules and receptors for some of these molecules, these data suggest that the biology of the leukemic cells may also be directly impacted by angiogenic factors as a result of autocrine pathways of stimulation. Leukemia (2002) 16, 911-919.

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

“…As CLL cells themselves produce VEGF, 6 VEGFR stimulation can occur in an autocrine fashion. 8 Moreover, CLL cells expressing VEGFR-2 and higher levels of VEGF in patients' serum correlate with shortened survival. 33 Importantly, no activating mutations in VEGFRs have been described in CLL, indicating that survival effects depend on VEGF binding to the receptor rather than being ligand To induce CLL proliferation, cells were stimulated with DSP30 (100 U/ml) and interleukin (IL)-2 as described elsewhere.…”

“…It was reported that CLL cells not only are capable of producing VEGF, 6 but VEGFRs were also found to be expressed on the surface of leukemic cells. [7][8][9] These observations have led to the hypothesis that the apoptosis defect of CLL cells is partly mediated through an autocrine feedback loop involving VEGF. 8 Sorafenib (BAY43-9006; Nexavar) is an oral multikinase inhibitor approved for the treatment of patients with advanced renal cell carcinoma 10 and those with unresectable hepatocellular carcinoma.…”

“…[7][8][9] These observations have led to the hypothesis that the apoptosis defect of CLL cells is partly mediated through an autocrine feedback loop involving VEGF. 8 Sorafenib (BAY43-9006; Nexavar) is an oral multikinase inhibitor approved for the treatment of patients with advanced renal cell carcinoma 10 and those with unresectable hepatocellular carcinoma. 11 This drug was initially identified as a potent inhibitor of the Raf serine/threonine kinase.…”

Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells

“…4,29 Although a causal relationship remains to be established, it is thus possible that the observed inhibition of MMP-9 production might result from HF-elicited VEGF downregulation. Indeed, due to the fact that B-CLL cells express VEGF receptors functionally active in angiogenesis, 29,30 the hypothesis of an autocrine loop of VEGF has to be considered in B-CLL, 31 and moreover, an autocrine stimulation of VEGFR-2 has been described to induce MMP-9 expression as well as cell growth and migration in some leukaemia. 32 Furthermore, elevated MMP-9 levels are also produced in the plasma of adult T-cell leukemia (ATL) patients; they are closely related to high VEGF levels and are significantly associated with strong ATL cell infiltration, suggesting that MMP-9 and VEGF could cooperate in invasion processes.…”

Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells

“…CLL cells themselves produce VEGF, 5,6 and high levels of this growth factor in serum, 7 as well as high expression of VEGF receptor (VEGFR)-2 on the malignant cells, 8 correlate with shortened patient survival. Moreover, in a previous study, 5 we observed increased vascularisation in enlarged lymph nodes of CLL patients and proposed that this was caused by paracrine stimulation of endothelial cells by CLL-cell-derived VEGF.…”