Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

Abstract

Multiple Myeloma (MM) induces bone destruction, decreases bone formation, and increases marrow angiogenesis in patients. We reported that osteocytes (Ocys) directly interact with MM cells to increase tumor growth and expression of Ocy-derived factors that promote bone resorption and suppress bone formation. However, the contribution of Ocys to enhanced marrow vascularization in MM is unclear. Since the MM microenvironment is hypoxic, we assessed if hypoxia and/or interactions with MM cells increases pro-angiogenic signaling in Ocys. Hypoxia and/or co-culture with MM cells significantly increased Vegf-a expression in MLOA5-Ocys, and conditioned media (CM) from MLOA5s or MM-MLOA5 co-cultured in hypoxia, significantly increased endothelial tube length compared to normoxic CM. Further, Vegf-a knockdown in MLOA5s or primary Ocys co-cultured with MM cells or neutralizing Vegf-a in MM-Ocy co-culture CM completely blocked the increased endothelial activity. Importantly, Vegf-a-expressing Ocy numbers were significantly increased in MM-injected mouse bones, positively correlating with tumor vessel area. Finally, we demonstrate that direct contact with MM cells increases Ocy Fgf23, which enhanced Vegf-a expression in Ocys. Fgf23 deletion in Ocys blocked these changes. These results suggest hypoxia and MM cells induce a pro-angiogenic phenotype in Ocys via Fgf23 and Vegf-a signaling, which can promote MM-induced marrow vascularization.

The multifunctional role of Notch signaling in multiple myeloma

“…Recent evidence suggests that Notch signals between MM cells, marrow cells, and endothelial cells can contribute to angiogenesis in MM. Endothelial cells from MM patients exhibit higher expression of Jagged 1 and 2, Notch receptors 1 and 2, and Notch target genes than endothelial cells from MGUS patients [78,79] . In vitro work has shown that Jagged-mediated signals from MM cells can increase angiogenesis by activating Notch and stimulating the release of Vegf in both endothelial cells and marrow stromal cells [77] .…”

“…In vitro, genetic knockdown of Notch receptor 1/2 or blockade of Notch signaling with GSI decreased angiogenesis induced by MM cells. Further, GSI treatment reduced the secretion of pro-angiogenic cytokines in conditioned media and decreased angiogenesis in animal models of MM [48,78,79] . Until recently, MM cells or stromal cells have been considered the main source of angiogenic factors in the MM niche.…”

Myeloma–Bone Interaction: A Vicious Cycle via TAK1–PIM2 Signaling

“…Osteocytes were recently reported to produce VEGF-A [42]. Its expression is enhanced by fibroblast growth factor (FGF23) from osteocytes under a hypoxic setting or cocultures with MM cells, suggesting promotion of angiogenesis and thereby MM progression by osteocytes.…”

Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma

“…Ostecytes play a key role in the progression of MM by promoting neoangiogenesis through the expression of molecules, including VEGF [115]. It is now shown that VEGF by stimulating its type 2 receptor (VEGFR2) induces neoangiogenesis, favoring the progression of MM [116]. Single nucleotide polymorphisms (SNPs) of VEGF and VEGFR2 genes have been demonstrated to play a key role in MM progression.…”

“…Single nucleotide polymorphisms (SNPs) of VEGF and VEGFR2 genes have been demonstrated to play a key role in MM progression. For example, the presence of the VEGFR2-604TT genotype is associated with stage II or III tumours but not with stage I tumours [116]. Furthermore, endothelial dysfunction that accompanies neoangiogenesis in turn favors the passage of immune cells into the tumour environment through the expression of direct chemokines and cell adhesion molecules on the surface of endothelial cells as also occurs in chronic immune-mediated diseases [117,118].…”