Abstract
The stroma of carcinomas shares several characteristics with inflamed tissues including a distorted vasculature, active angiogenesis and macrophage infiltration. In addition, the tumor interstitial fluid pressure (P(IF)) of the stroma is pathologically elevated. We show here that bevacizumab [rhuMab vascular endothelial growth factor (VEGF), Avastin], a monoclonal antibody to VEGF, at a dose of 5 mg/kg modulated inflammation in KAT-4 xenograft human anaplastic thyroid carcinoma tissue. At this dose, bevacizumab reduced the density of macrophages, MHC class II antigen expression by macrophages and IL-1beta mRNA expression. Furthermore, bevacizumab lowered tumor extracellular fluid volume, plasma protein leakage from tumor vessels, the number of CD31-positive structures and tumor P(IF). The tumor plasma volume and the number of alpha-smooth muscle actin-positive vessels, however, remained unchanged. Our data suggest that carcinoma cell-derived VEGF either directly or indirectly participates in maintaining an inflammatory microenvironment in experimental KAT-4 carcinoma. Furthermore, our data indicate that the reduction of inflammation resulting in reduced vascular permeability and decrease in the tumor extracellular fluid volume by bevacizumab contributes to reduced tumor P(IF).
Copyright 2006 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Monoclonal, Humanized
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Bevacizumab
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Blood Vessels / drug effects
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Blood Vessels / metabolism
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Blood Vessels / pathology
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Cell Count
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Cell Line, Tumor
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Chemokines / genetics
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Cytokines / genetics
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay
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Extracellular Fluid / drug effects
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Extracellular Fluid / metabolism
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Gene Expression / drug effects
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Humans
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Inflammation / metabolism
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Inflammation / pathology
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Inflammation / prevention & control*
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Macrophages / drug effects
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Macrophages / pathology
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Mice
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Mice, SCID
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / prevention & control
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Plasma Volume / drug effects
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Platelet Endothelial Cell Adhesion Molecule-1 / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Thyroid Neoplasms / metabolism
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Thyroid Neoplasms / pathology
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Thyroid Neoplasms / prevention & control*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / immunology*
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Vascular Endothelial Growth Factor A / metabolism
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Xenograft Model Antitumor Assays*
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Chemokines
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Cytokines
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Platelet Endothelial Cell Adhesion Molecule-1
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RNA, Messenger
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Vascular Endothelial Growth Factor A
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Bevacizumab