Mast cell–derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors
Takayuki Nakayama, … , Lei Yao, Giovanna Tosato
Takayuki Nakayama, … , Lei Yao, Giovanna Tosato
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1317-1325. https://doi.org/10.1172/JCI22089.
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Article Oncology

Mast cell–derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors

Abstract

Multiple myeloma in humans is frequently associated with mast cell infiltration and neovascularization, which correlate directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that primary murine mast cells express angiopoietin-1 (Ang-1) and low levels of VEGF-A but not Ang-2 and that 2 established murine plasmacytoma cell lines express high levels of VEGF-A but little or no Ang-1 or Ang-2. An in vivo angiogenesis assay using extracellular matrix components shows that mast cells and plasmacytoma cells, together, promote marked neovascularization composed of dilated vessels, which is prevented by neutralization of VEGF-A and Ang-1 but is only partially reduced by neutralization of either VEGF-A or Ang-1. Mast cells within extracellular matrix components express Ang-1, and recombinant Ang-1 together with plasmacytoma cells promotes extracellular matrix neovascularization similar to that induced by mast cells. A transplantation assay shows that primary mast cells accelerate tumor growth by established plasmacytoma cell lines and that neutralization of Ang-1 alone or with VEGF-A reduces significantly the growth of plasmacytomas containing mast cells. These results demonstrate that mast cell–derived Ang-1 promotes the growth of plasmacytomas by stimulating neovascularization and provide further evidence supporting a causal relationship between inflammation and tumor growth.

Authors

Takayuki Nakayama, Lei Yao, Giovanna Tosato

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Evidence supporting a contribution of mast cell–derived Ang-1 to neovasc...
Evidence supporting a contribution of mast cell–derived Ang-1 to neovascularization in vivo. Matrigel plugs (0.5 ml) containing plasmacytoma cells (TEPC2027 cells, 0.5 × 106) alone or with BMMCs (0.5 × 106) were inoculated s.c. into mice (3–5 mice per group) without additives or with anti–VEGF-A antibody (5 μg/ml), Tie-2/Fc (5 μg/ml), anti–VEGF-A antibody plus Tie-2/Fc (5 μg/ml each), control (Ctr) goat IgG plus control B7-1/Fc (5 μg/ml each), or recombinant Ang-1 (500 ng/ml). (A) Representative histological images of Matrigel plugs stained with Masson’s trichrome (top row), showing different degrees of neovascularization; and immunostained for κ light chain (bottom row), showing differing degrees of plasmacytoma cell infiltration under the experimental conditions tested. Original magnification, ×20. (B) Quantitative analysis (as described in the legend to Figure 2) of Matrigel neovascularization (top) and plasmacytoma cell infiltration (bottom) under the experimental conditions tested (3–5 plugs per group; 1 plug per mouse). (C) Representative microscopic images of Matrigel plugs containing plasmacytoma cells alone or with recombinant Ang-1, stained with Masson’s trichrome (top row) or immunostained for κ chain (bottom row), showing differing degrees of neovascularization and plasmacytoma cell infiltration. (D) Quantitative analysis (as described in the legend to Figure 2) of Matrigel neovascularization (top) and plasmacytoma cell infiltration (bottom) in the presence of plasmacytoma cells alone or with recombinant Ang-1 (3–5 plugs per group; 1 plug per mouse).