Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors

Abstract

Antiangiogenic drugs are currently tested in haematological malignancies. As these drugs target different angiogenic regulators, and as cancers are inherently heterogeneous, a detailed characterization of angiogenesis in individual cancers is needed. Hence, we measured bone marrow microvessel density (MVD), plasma concentrations of eight angiogenesis-related parameters and the expression in blood mononuclear cells of 40 angiogenesis-related mRNAs in 93 patients with haematological neoplasias (acute myeloid leukaemia; chronic lymphatic leukaemia; multiple myeloma (MM); or non-Hodgkin's lymphoma (NHL)) before start and after completion of cancer therapy. Compared with healthy individuals, the patients had significantly increased bone marrow MVD, especially patients with advanced stage disease. A novel finding was that patients with NHL also had increased bone marrow MVD. The plasma levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6 and IL-8 were significantly increased. VEGF levels were highest in those who did not achieve complete remission after cancer therapy. The mRNA expression of IL-8 was upregulated 15-fold. Our data show that patients with haematological malignancies have increased bone marrow MVD; hence, supporting the notion that bone marrow angiogenesis plays a role in the pathogenesis and progression of these cancers. VEGF, IL-6 and IL-8 seem to contribute to the malignant phenotype.

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

“…The capacity of HIF-1a to regulate VEGFA and IL8 gene expression by MM cells confirmed our previous data, 27,39 and supports HIF-1a as a key regulator of angiogenesis also in MM cells because VEGF 9,10 and at least in part of IL-8 39,40 are well-known factors involved in MM-induced angiogenesis. CCL2 and MMP9 could be also involved in the pro-angiogenic role of HIF-1a, because both cytokines are produced by MM cells and contribute to angiogenesis and BM spreading.…”

Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition

“…A total of 1.6×10 4 HUVECs dispersed evenly in medium containing 1% FBS were placed onto the Matrigel layer in each well. The cells were treated with DMSO (0.1%) or various concentrations of QSN-10c (25, 50, 100, and 200 μmol/L).…”

“…The growth of a tumor mass beyond 2 to 3 mm 3 is often preceded by increased formation of new blood vessels essential for the delivery of nutrients and oxygen as well as the removal of metabolic waste from the tumor microenvironment [1,2] . Moreover, many recent studies have demonstrated the important role of angiogenesis in hematologic neoplasms [3][4][5] . Therefore, anti-angiogenic and angio-prevention therapies represent promising approaches to control tumor growth and metastasis [6,7] .…”

Interleukin-8: A potent promoter of angiogenesis in gastric cancer

“…Due to its pro-angiogenic characteristics, IL-8 may be a key mediator in the angiogenesis and progression of various tumors. IL-8 has been revealed to be involved in seminal plasma-induced regulation of vascular function in cervical cancer (20), transition between liver cirrhosis and highly vascularized hepatocellular carcinoma (18), the malignant phenotype of hematological malignancies (38), Epstein-Barr virus latent membrane protein-1-induced angiogenesis in nasopharyngeal carcinoma through the NF-κB-binding site (22) and tumor growth and angiogenesis in melanoma via the secretion of tumor necrosis factor α and IL-1α (21). A previous study has identified that gastric cancer cells secret various levels of IL-8 protein and, more notably, the level of IL-8 mRNA in the neoplasms is markedly associated with vascularization in vivo, suggesting that IL-8 may regulate neovascularization and the growth and spread of gastric cancer (39).…”