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VEGF pathways in multiple myeloma

VEGF plays an important role in both autocrine and paracrine growth in multiple myeloma.¹ Podar and colleagues found that VEGF dysregulation affects both pathogenesis and clinical features in multiple myeloma by triggering cell growth, survival, and migration, and by stimulating angiogenesis in bone marrow.^2,3 VEGF has been found to play a key role in sustaining angiogenesis in multiple myeloma.⁴

VEGF has been shown to have a pathophysiologic effect on multiple bone marrow components, as well as an impact on a range of biological functions, including angiogenesis.³

Bone marrow components and biological functions impacted by VEGF³

Within the bone marrow microenvironment, multiple myeloma is mediated by VEGF, as well as other angiogenic factors.⁴

Reprinted with permission from Podar K, Anderson KC. Blood. 2005;105:1383-1395. Figure 2.

The diagram below shows how VEGF from plasma cells stimulates bone marrow stroma cells to release more VEGF (2a), creating a paracrine loop that promotes myeloma cell growth (2). VEGF can also stimulate multiple myeloma cell growth through an autocrine loop in plasma cells (3). Endothelial cells also produce VEGF, which contributes to the growth and survival of plasma cells in bone marrow (5).⁴

VEGF and other angiogenic factors in the bone marrow microenvironment in multiple myeloma⁴

Reprinted with permission from Jakob C, Sterz J, Zavrski I, et al. Eur J Cancer. 2006;42:1581-1590. Figure 1.

VEGF is produced by multiple sources. In a preclinical study, Podar and colleagues found that VEGF is secreted by both multiple myeloma cells and bone marrow stromal cells and that these 2 cell types can bind together to enhance VEGF, as well as interleukin-6 (IL-6) secretion. Within the bone marrow, stromal cells secrete IL-6, which stimulates multiple myeloma cells to produce VEGF. Increased VEGF then stimulates more IL-6 production by bone marrow stromal cells, thereby creating a positive feedback loop.²

VEGF production within bone marrow by multiple myeloma cells and stromal cells²

Reprinted with permission from Podar K, Tai YT, Davies FE, et al. Blood. 2001;98:428-435. Figure 8.

In addition to stimulating angiogenesis in bone marrow, VEGF triggers cell growth directly through the Raf-1–MEK-1–ERK signaling cascade. It also promotes cell migration through the PKC-dependent pathway, which is ERK independent.²

VEGF-mediated pathways in proliferation and migration of multiple myeloma cells²

Reprinted with permission from Podar K, Tai YT, Davies FE, et al. Blood. 2001;98:428-435. Figure 8.

Podar and colleagues also investigated VEGF signal transduction within multiple myeloma cells. They showed that VEGF mediates cell proliferation through MEK-1 and ERK signaling, and cell survival through the upregulation of survivin and Mcl-1. They also found that VEGF could induce multiple myeloma cell migration via fibronectin, a process mostly dependent on the localization of VEGFR-1 within caveolae, followed by Src tyrosine kinase family–dependent phosphorylation of caveolin-1, PI3-kinase, and PKCα.³

VEGF signal transduction in multiple myeloma cells³

Reprinted with permission from Podar K, Anderson KC. Blood. 2005;105:1383-1395. Figure 4.

Six factors modulating VEGF secretion in multiple myeloma³

A. Bone marrow stromal cells and tumor cells secrete IL-6 or VEGF directly
B. Hypoxia and the presence of mutant oncogenes upregulate VEGF via
HIF-1α
C. IGF-1 upregulates VEGF production and secretion in tumor cells
(paracrine loop)
D. C-maf–driven expression of tumor integrin β7 that results in enhanced adhesion to bone marrow stroma
E. ICAM1 and LFA1 modulate adhesion of tumor cells to extracellular matrix and bone marrow stromal cells to increase VEGF production and secretion
F. CD40 activation induces p53-dependent VEGF secretion

Reprinted with permission from Podar K, Anderson KC. Blood. 2005;105:1383-1395. Figure 4.

References:

1.

Ria R, Roccaro AM, Merchionne F, et al. Leukemia. 2003;17:1961-1966.

2.

Podar K, Tai YT, Davies FE, et al. Blood. 2001;98:428-435.

3.

Podar K, Anderson KC. Blood. 2005;105:1383-1395.

4.

Jakob C, Sterz J, Zavrski I, et al. Eur J Cancer. 2006;42:1581-1590.