Angiogenic Molecules in Hodgkin's Disease: Results from Sequential Serum Analysis

Fh, Passam; Mg, Alexandrakis; Moschandrea, J.; Sfiridaki, Aekaterini; Pa, Roussou; Nm, Siafakas

doi:10.1177/205873920601900116

Cited by 21 publications

(13 citation statements)

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“…High expression of VEGF in myeloma cells or increased serum VEGF levels in patients with myeloma is linked with aggressive disease and resistance to chemotherapy, suggesting that the VEGF pathway may be a critical therapeutic target [20,21]. VEGF is also expressed in Hodgkin lymphomas [22] and increased serum levels in these patients have been reported [23]. In NHL, several studies stress the prognostic importance of high serum or plasma VEGF levels [10][11][12][13], while immunohistochemical studies confirm high angiogenic activity and VEGF expression in neoplastic tissues [14][15][16][17].…”

Section: Discussionmentioning

confidence: 96%

Phosphorylated VEGFR2/KDR receptors are widely expressed in B‐cell non‐Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

Giatromanolaki

Koukourakis

Pezzella

et al. 2008

Hematological Oncology

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The expression of hypoxia inducible factors (HIF) 1alpha and 2alpha, of vascular endothelial growth factor (VEGF) and of the phosphorylated form of its receptor VEGFR2 (pVEGFR2/KDR) were investigated immunohistochemically in a series of 146 B-cell non-Hodgkin's lymphomas and 48 normal lymph nodes. These proteins were significantly up-regulated in neoplastic lymphocytes and a significantly higher expression of HIF1alpha (p = 0.05), VEGF (p = 0.02) and pVEGFR2/KDR (p = 0.007) was recorded in diffuse large B-cell lymphomas(DLBCL) compared to follicular lymphomas (FL). A strong statistical association of pVEGFR2/KDR expression with high HIF1alpha, HIF2alpha and VEGF was noted in both DLBCL and FL. HIF1alpha andHIF2alpha were linked with VEGF expression but no association between HIF1alpha and HIF2alpha was noted. Vascular density was significantly higher in the lymphoma compared to normal tissue, but there was no association with any of the examined parameters. It is concluded that the VEGF/receptor pathway is active in more than half of NHLs and particularly in DLBCL. The intimate correlation of VEGF production with the presence of phosphorylated VEGF-receptors strongly supports the concept of an autocrine pathway. The strong association of HIFalphas with the expression of VEGF and pVEGFR2/KDR found in the study provide strong evidence on the role of HIFalphas inthe activation of angiogenic and VEGF-autocrine pathways that may be critical therapeutic targets for HIF-inhibitors or other anti-angiogenic agents.

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Section: Discussionmentioning

confidence: 96%

Phosphorylated VEGFR2/KDR receptors are widely expressed in B‐cell non‐Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

Giatromanolaki

Koukourakis

Pezzella

et al. 2008

Hematological Oncology

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“…56 Inflammatory cytokines and angiogenic factors, such as vascular endothelial growth factor, basic fibroblast growth factor, and interferon-␥, resulted in increased expression levels of cathepsin S and secretion in human microvascular endothelial cells, supporting its putative role in angiogenesis. 57 Cathepsin S secretion by the HRS cells might be closely related to angiogenic activity 58 and basic fibroblast growth factor expression 59 observed in HL.…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes

Yue¹,

Visser²,

Roelofsen³

et al. 2008

Blood

117

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IntroductionHodgkin lymphoma (HL) is characterized by a minority of neoplastic cells, the Hodgkin and Reed-Sternberg cells (HRS cells), and an extensive inflammatory background. Many studies have documented that HL is associated with disturbed cytokine production. 1 Cytokine and chemokine production may not only promote growth of HRS cells and help to evade immune surveillance, but also cause the characteristic histology and the clinical symptoms of HL. 2 Cross-talk between HRS cells and surrounding lymphocytes has been studied for many years, and this interaction is regarded to be important for the pathogenesis of HL.The application of proteomics techniques has been proven to be a powerful tool for the identification of new biomarkers involved in pathogenesis of many diseases (reviewed by Hanash 3 ). Some studies on hematologic malignancies using proteomics approaches have been reported, 4,5 but application of proteomics technology to HL is still limited. Fujii et al compared HL cell line proteome to anaplastic large cell lymphoma (ALCL) and non-Hodgkin lymphoma (NHL) using a 2-dimensional difference gel electrophoresis approach of total cell lysates. 6,7 HL expressed higher levels of pyridoxine-5Ј-phosphate oxidase, vinculin, dihydropyrimidinase-related protein-2 and NADHubiquinone oxidoreductase compared with ALCL. In comparison to NHL cell lines, HL cell lines showed higher expression of pyridoxine-5Ј-phosphate oxidase, ␥-enolase, vinculin, vimentin, galectin-1, annexin A5, and protein kinase C substrate. 7 Carvalho et al identified changes in the spectrum using quadrupole-time-of-flight hybrid mass spectrometer in serum of HL patients compared with normal controls, but no further protein identification was performed. 8 Overall, only very limited proteomics data are available for HL.To gain more insight into the proteins secreted by HRS cells that might be involved in the cross-talk with infiltrating lymphocytes or might serve as tumor biomarkers, the secretome of HL cell lines was determined in cell culture supernatant. Protein identification was performed by nanoscale reversed-phase liquid chromatography tandem mass spectrometry (LC-MS/MS) after 1D-SDS-PAGE fractionation. Proteins related to immune response were validated in cell culture supernatant and patient plasma by enzyme-linked immunosorbent assay (ELISA) and in tumor tissues by immunohistochemistry. Methods Cell lines and cultureThe HL cell lines L1236 and KMH2 were established from HL patients with mixed cellularity subtype, L428 from nodular sclerosis subtype and DEV from nodular lymphocyte predominant HL (NLPHL) subtype. They were cultured in RPMI 1640 medium (Lonza Walkersville, Walkersville, MD) supplemented with fetal calf serum (Lonza Walkersville). For analysis of secreted proteins, to avoid the masking effects of high-abundance serum proteins in the culture medium, the cells were washed 3 times with RPMI 1640 medium to deplete all serum proteins, and cultured in RPMI 1640 medium without serum for 24 hours. Under these conditions, cell via...

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“…Passam et al . found VEGF levels to be elevated in 60 Hodgkin patients and to decrease significantly after standard treatment. VEGF is highly expressed by Reed–Sternberg (RS) cells and is secreted by HL cell lines under hypoxic conditions .…”

Section: Hodgkin's Lymphomamentioning

confidence: 96%

Targeting the vascular endothelial growth factor in hematologic malignancies

Paesler

Gehrke

Poll-Wolbeck

et al. 2012

European J of Haematology

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There exists increasing evidence that apart from solid tumors, angiogenic growth factors also play important roles in the development and/or maintenance of hematolymphoid malignancies. Thus, in these cancers, angiogenesis and bone marrow microvessel density often correlate with prognosis and disease burden. Several reports speculated on the role of angiogenesis and the resulting possible therapeutic options in hematologic malignancies. The most prominent angiogenic factor, vascular endothelial growth factor (VEGF), is expressed in a number of established leukemic cell lines as well as in freshly isolated human leukemias and lymphomas, and several human leukemias express VEGF receptor 1 and/or VEGF receptor 2. VEGF/VEGF-receptor interactions are also involved in proliferation, migration, and survival of leukemic cells by autocrine and paracrine mechanisms. As a consequence, a possible drugable effect by inhibiting VEGF signaling in different hematologic malignancies has been discussed. This review focuses on angiogenesis-independent effects of VEGF on survival and proliferation of leukemic or lymphoma cells and on possible therapeutic approaches using anti-VEGF/VEGF-receptor therapies to inhibit proliferation or induce apoptosis of malignant cells in hematologic diseases.

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Angiogenic Molecules in Hodgkin's Disease: Results from Sequential Serum Analysis

Abstract: Copyright(;)by BIOLlFE,s.a.s. This publication and/orarticleis for individual use only and may not be further reproduced withoutwrittenpermission fromthe copyrightholder. Unauthorized reproduction may resultsin financial and other penalties

Cited by 21 publications

References 49 publications

Phosphorylated VEGFR2/KDR receptors are widely expressed in B‐cell non‐Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

Phosphorylated VEGFR2/KDR receptors are widely expressed in B‐cell non‐Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes

Targeting the vascular endothelial growth factor in hematologic malignancies

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