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
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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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Contribution of Ang-1–secreting mast cells to plasmacytoma tumor growth....
Contribution of Ang-1–secreting mast cells to plasmacytoma tumor growth. (A) Tumor tissues were stained with toluidine blue for detection of mast cells and/or immunostained with Tie-2/Fc for detection of Ang-1. Top row: Representative tumor tissue from a mouse inoculated with TEPC1165SZ plasmacytoma cells alone, showing no toluidine-positive cells (original magnification, ×20), and from a mouse inoculated with TEPC1165SZ cells plus SPMCs, showing infiltration with toluidine-positive cells (original magnifications, ×20 and ×40). Bottom row: Immunostaining for Ang-1 fails to detect positive cells in representative tumor tissue from a mouse inoculated with TEPC1165SZ cells alone, but detects scattered Ang-1–positive (brown) cells in a representative tumor tissue from a mouse inoculated with SPMCs (original magnification, ×20 and ×40). Inset: Cell colocalization of toluidine blue staining and Ang-1 immunostaining (original magnification, ×63). (B) Tumor size in mice injected s.c. with TEPC1165SZ plus BMMCs alone, Tie-2/Fc (50 μg per mouse), goat anti–mouse VEGF-A antibodies (50 μg per mouse), Tie-2/Fc plus goat anti–mouse VEGF-A antibodies (50 μg each per mouse), or human IgG Fc plus control goat IgG (50 μg each per mouse). There were 4 mice per group. Tumor size was estimated in square millimeters on day 14 after injection; the results are expressed as the mean percent tumor size (± SD) of tumors derived from inoculation of TEPC1165SZ plus BMMCs.