Angiogenesis and Multiple Myeloma

Abstract

The bone marrow microenvironment in multiple myeloma is characterized by an increased microvessel density. The production of pro-angiogenic molecules is increased and the production of angiogenic inhibitors is suppressed, leading to an "angiogenic switch". Here we present an overview of the role of angiogenesis in multiple myeloma, the pro-angiogenic factors produced by myeloma cells and the microenvironment, and the mechanisms involved in the myeloma-induced angiogenic switch. Current data suggest that the increased bone marrow angiogenesis in multiple myeloma is due to the aberrant expression of angiogenic factors by myeloma cells, the subsequent increase in pro-angiogenic activity of normal plasma cells as a result of myeloma cell angiogenic activity, and the increased number of plasma cells overall. Hypoxia also contributes to the angiogenic properties of the myeloma marrow microenvironment. The transcription factor hypoxia-inducible factor-1α is overexpressed by myeloma cells and affects their transcriptional and angiogenic profiles. In addition, potential roles of the tumor suppressor gene inhibitor of growth family member 4 and homeobox B7 have also been recently highlighted as repressors of angiogenesis and pro-angiogenic related genes, respectively. This complex pathogenetic model of myeloma-induced angiogenesis suggests that several proangiogenic molecules and related genes in myeloma cells and the microenvironment are potential therapeutic targets.

Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1

“…[8][9][10] Aberrant angiogenesis has been reported in MM-infiltrated BM, [11][12][13] and increased angiogenic activity is associated with endothelial activation, increased capillary permeability, and hyperperfusion. [14][15][16] Evidence suggests that MM cells promote angiogenic activity via hypoxia-inducible factor (HIF)-1a, a key transcription factor of hypoxia, leading to the overproduction of angiogenic cytokines such as vascular endothelial growth factor (VEGF), 17 angiopoietin-1, 18 and osteopontin. 19 In addition to conventional signaling pathways responding to hypoxia (ie, direct cell-cell contact or VEGF signaling), 10 our group and others have shown that exosomes, small endosome-derived vesicles containing a wide range of functional proteins, mRNA, and miRNA, from hypoxic cancer cells help to modulate the microenvironment without contacting the surrounding noncancer cells.…”

The functional significance of the bone marrow microenvironment in multiple myeloma development and progression

“…The activation of these cells leads to secretion of factors that are of particular importance for the proliferation and survival of myeloma cells, especially IL-6, VEGF, and IGF-1, to the environment and intensification of chemotherapy resistance 8,9 . It has also been confirmed that factors such as basic fibroblast growth factor (bFGF), angiopoietin-1 (Ang-1), transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and interleukin 1 (IL-1), secreted by stromal cells of patients with MM, affect the growth of myeloma cells 10 . Recently, it has been reported that there is a novel mechanism of intercellular transfer of genetic information which involves stromal cell-derived exosomes, which, after entering myeloma cells, modulate their growth mediated by specific miRNAs 11 .…”

Potential Therapeutic Effects of Natural Extracts in Multiple Myeloma

“…Angiogenesis, supporting the growth, survival, progression, and drug resistance acquisition of the MM cells, plays a critical role in the pathophysiology and progression of MM [54] . Hypoxia, a key feature of the most MM microenvironment, is a leading cause of angiogenesis [55] .…”