The VEGF receptor, neuropilin-1, represents a promising novel target for chronic lymphocytic leukemia patients

Abstract

Angiogenesis has been shown to substantially contribute to the progression of chronic lymphocytic leukemia (CLL). Neuropilin-1 (NRP1) represents a receptor for vascular endothelial growth factor (VEGF), which has been reported to be overexpressed in several malignancies. In our study, we characterized mRNA levels of VEGF receptors including NRP1 in a large cohort of CLL patients (n = 114), additionally we performed a detailed characterization of NRP1 expression on B cells, plasmacytoid dendritic cells (PDCs) and regulatory T cells (Tregs). The expression of NRP1 was significantly higher on leukemic lymphocytes compared to control B lymphocytes on mRNA and protein levels (22.72% vs. 0.2%, p = 0.0003, respectively), Tregs (42.6% vs. 16.05%, p = 0.0003) and PDCs (100% vs. 98% p < 0.0001). In functional studies, we found higher NRP1 expression on CLL cells after stimulation with VEGF. The correlation between expression of VEGF receptors: FLT1, NRP1 and FOXP3 expression (r(2) = 0.53, p < 0.0001 and r(2) = 0.49, p < 0.0001, respectively) was observed. Earlier we described the specific Treg reduction during the therapy with thalidomide in vivo. Now we observe the reduction of the NRP1 expression on Tregs in vitro, thereby suggesting a possible target of thalidomide action. In conclusion, NRP1 might represent an interesting link between angiogenesis and tolerance mechanisms and represents interesting target for therapy.

The progress of angiogenic factors in the development of leukemias

“…For example, it was first reported by Perez-Atayde et al in 1997 that the angiogenesis phenomenon existed in the bone marrow of childhood acute lymphoblastic leukemia (ALL) (2). Much subsequent research also discovered that a number of hematological malignancies were accompanied with angiogenesis which was related to the prognosis of childhood ALL or made a contribution to the development and progression of chronic lymphocytic leukemia (CLL) (3,4). Usually, angiogenesis is regulated by a balance of angiogenic and antiangiogenic cytokines, and angiogenesis can be induced by leukemia cells in the bone marrow, and leukemia may be more likely to be angiogenesis dependent, which raises the probability for antiangiogenic drugs in the treatment of leukemia.…”

Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

“…Two co-receptors of VEGFR-1 and VEGFR-2, neuropilin-1 and -2 (NRP1/2) [20], regulate angiogenesis, tumour development, and immunological responses [7]. Recently Piechnik et al reported higher NRP1 expression on leukemic lymphocytes when compared to healthy Blymphocytes in a cohort that included 114 CLL patients [7]. Furthermore, they detected an increase in NRP1 expression upon VEGF stimulation.…”

“…In fact, recent research exploring the mechanism of action of bevacizumab on CLL cells showed the efficiency of this monoclonal antibody in inducing apoptosis of leukaemia cells [13]. Whilst many studies highlight the importance of VEGF as target of research in CLL angiogenesis [7,11,[13][14][15][16][17], we are still refining our understanding of the VEGF family in the CLL context.…”

“…The sensitivity of CLL cells to VEGF ligands is illustrated by their expression of the three VEGF receptors [14]. Two co-receptors of VEGFR-1 and VEGFR-2, neuropilin-1 and -2 (NRP1/2) [20], regulate angiogenesis, tumour development, and immunological responses [7]. Recently Piechnik et al reported higher NRP1 expression on leukemic lymphocytes when compared to healthy Blymphocytes in a cohort that included 114 CLL patients [7].…”

“…Concomitantly with a significant density increase of microvessels, they reported increased levels of basic fibroblast growth factor (bFGF) in urine samples of CLL patients, fostering the idea that angiogenesis is an active processes in CLL [6]. Today it is widely accepted that angiogenesis contributes to the development and progression of CLL [7], yet the molecular mechanisms of most angiogenic growth factors on the CLL context factors are unclear.…”