Inhibition of carcinoma cell-derived VEGF reduces inflammatory characteristics in xenograft carcinoma.
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).
Salnikov
Alexei V
AV
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Heldin
Nils-Erik
NE
Stuhr
Linda B
LB
Wiig
Helge
H
Gerber
Hanspeter
H
Reed
Rolf K
RK
Rubin
Kristofer
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010953:Plasma Volume / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018925:Chemokines; D016207:Cytokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab