Vascular endothelial growth factor (VEGF) is expressed by neoplastic Hodgkin–Reed–Sternberg cells in Hodgkin's disease

Abstract

Vascular endothelial growth factor (VEGF) is involved in tumour angiogenesis, an important process for the growth and metastatic potential of solid tumours. Numerous studies have demonstrated up-regulation of VEGF at both mRNA and protein level in various tumours and a correlation with advanced stage and prognosis has been demonstrated in some cases. Limited information exists about its role in lymphoid malignancies and in particular, Hodgkin's disease. The present study examined the immunohistochemical expression of VEGF using the monoclonal antibody VG1 in a series of 61 cases of Hodgkin's disease, including both classical Hodgkin's disease and the nodular lymphocyte predominance variant, and correlated these results with microvessel density, using an anti-CD31 monoclonal antibody. In 41 cases (70.6%) of classical Hodgkin's disease and one of the three cases of nodular lymphocyte predominance Hodgkin's disease, the neoplastic Reed-Sternberg and Hodgkin cells expressed VEGF. The staining observed was cytoplasmic, either diffuse or with a focal paranuclear distribution. Macrophages were always positive, while reactive lymphocytes showed occasional positivity. A variable amount of strong extracellular staining was also observed in the tissue stroma and intravascular plasma staining was prominent. There was no statistically significant relationship between VEGF expression and the subtype of Hodgkin's disease or microvessel density. In vitro studies using the Reed-Sternberg cell lines L428 and KM-H2 were also performed in both normoxia and hypoxia and VEGF protein production was assessed by flow cytometry (FACS), immunoassay of cell culture supernatant, and RT-PCR. Analysis by FACS demonstrated a subset of cells in both cell lines reacting with VG1 and analysis of secreted VEGF (pg/ml per 1x10(6) cells) in cell culture supernatant confirmed the normoxic production in both cell lines and significant hypoxic induction (p<0.005). Additionally, both cell lines expressed VEGF mRNA, as demonstrated using the RT-PCR method. In conclusion, neoplastic cells express VEGF in Hodgkin's disease, as is the case in solid tumours, and this expression may be induced by hypoxia. The presence of VEGF in reactive macrophages and in the extracellular matrix might facilitate tumour progression.

Angiogenesis in Hodgkin's lymphoma: a morphometric approach in 286 patients with prognostic implications

“…A recent report has shed light upon this issue demonstrating that both neoplastic cells and macrophages are capable of expressing VEGF in HL. 22 The absence of a significant relationship, however, between VEGF expression and MVD in the same study 22,36 implies that VEGF might not be the only factor regulating angiogenesis in HL, other inhibitory and stimulatory molecules being probably important in this regard, as for example thymidine phosphorylase, thrombospondin or TGF-beta produced by the neoplastic or reactive cells. 37 Several features have been proposed to predict an inferior FFS and overall survival in HL, including both conventional clinical and laboratory characteristics and biological factors.…”

“…20 Published information regarding angiogenesis in HL is limited to two recent reports focusing on the expression of VEGF by Reed-Sternberg cells. 21,22 In the present study, we evaluated for the first time multiple morphometric microvascular characteristics, in addition to microvessel density (MVD), in a large series of homogeneously treated patients with HL, relating them to several clinical, laboratory and pathologic parameters as well as to clinical outcome.…”

Chronic idiopathic myelofibrosis: independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining

“…4 In addition to the well-established role of angiogenesis in solid tumors, 4 the increase in tumor vascularity has been previously investigated in a variety of hematological neoplasms, including acute lymphatic 15 and myeloid 16,17 leukemias, myelodysplastic syndromes, 14,18 Hodgkin's disease, 19 myeloma, 20-25 lymphoproliferative disorders, 26-31 systemic mastocytosis 32 and chronic myeloproliferative disorders, 5,14 including CIMF. 8 The number of small vessels in a tumor, or MVD, is considered a surrogate indicator of angiogenesis.…”

Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b+/F4/80+ myeloid cell recruitment

“…Lymphoma patients show abnormal plasma levels of cytokines produced primarily by lymphoma cells or secondarily by stromal cells. 23 Myeloid cells can provide proangiogenic factors such as VEGF-A and MMP-9. 24 VEGF-A can be liberated from extracellular matrix stores after Plg or MMP activation.…”