Salnikov Alexei V, Heldin Nils-Erik, Stuhr Linda B, Wiig Helge, Gerber Hanspeter, Reed Rolf K, Rubin Kristofer
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Int J Cancer. 2006 Dec 15;119(12):2795-802. doi: 10.1002/ijc.22217.
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).
癌组织的基质与炎症组织有几个共同特征，包括血管系统扭曲、活跃的血管生成和巨噬细胞浸润。此外，基质的肿瘤间质液压力（P(IF)）在病理上升高。我们在此表明，贝伐单抗[rhuMab血管内皮生长因子（VEGF），阿瓦斯汀]，一种VEGF单克隆抗体，以5mg/kg的剂量调节KAT-4异种移植人未分化甲状腺癌组织中的炎症。在此剂量下，贝伐单抗降低了巨噬细胞密度、巨噬细胞MHC II类抗原表达和IL-1βmRNA表达。此外，贝伐单抗降低了肿瘤细胞外液体积、肿瘤血管的血浆蛋白渗漏、CD31阳性结构的数量和肿瘤P(IF)。然而，肿瘤血浆体积和α-平滑肌肌动蛋白阳性血管的数量保持不变。我们的数据表明，癌细胞衍生的VEGF直接或间接参与维持实验性KAT-4癌中的炎症微环境。此外，我们的数据表明，贝伐单抗导致的炎症减轻，进而导致血管通透性降低和肿瘤细胞外液体积减少，有助于降低肿瘤P(IF)。
