Abstract
BackgroundHepatocellular carcinoma (HCC) is a malignancy with poor survival outcome. New treatment options for the disease are needed. In this study, we identified and evaluated tumor vascular PLVAP as a therapeutic target for treatment of HCC.MethodsGenes showing extreme differential expression between paired human HCC and adjacent non-tumorous liver tissue were investigated. PLVAP was identified as one of such genes with potential to serve as a therapeutic target for treatment of HCC. A recombinant monoclonal anti-PLVAP Fab fragment co-expressing extracellular domain of human tissue factor (TF) was developed. The potential therapeutic effect and toxicity to treat HCC were studied using a Hep3B HCC xenograft model in SCID mice.ResultsPLVAP was identified as a gene specifically expressed in vascular endothelial cells of HCC but not in non-tumorous liver tissues. This finding was confirmed by RT-PCR analysis of micro-dissected cells and immunohistochemical staining of tissue sections. Infusion of recombinant monoclonal anti-PLVAP Fab-TF into the main tumor feeding artery induced tumor vascular thrombosis and extensive tumor necrosis at doses between 2.5 μg and 12 μg. Tumor growth was suppressed for 40 days after a single treatment. Systemic administration did not induce tumor necrosis. Little systemic toxicity was noted for this therapeutic agent.ConclusionsThe results of this study suggest that anti-PLVAP Fab-TF may be used to treat HCC cases for which transcatheter arterial chemoembolization (TACE) is currently used and potentially avoid the drawback of high viscosity of chemoembolic emulsion for TACE to improve therapeutic outcome. Anti-PLVAP Fab-TF may become a viable therapeutic agent in patients with advanced disease and compromised liver function.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-815) contains supplementary material, which is available to authorized users.
Highlights
Hepatocellular carcinoma (HCC) is a malignancy with poor survival outcome
Identification of Plasmalemmal vesicle associated protein (PLVAP) as a therapeutic target for HCC To identify genes expressed in HCC and not in non-tumorous liver tissue, we compared the gene expression profiles of 18 pairs of HCC and adjacent nontumorous liver tissues
After further examining PLVAP expression in all 18 tissue pairs (Figure 3A), we found that all pairs but one showed higher PLVAP expression in the HCC tissues
Summary
Hepatocellular carcinoma (HCC) is a malignancy with poor survival outcome. New treatment options for the disease are needed. We identified and evaluated tumor vascular PLVAP as a therapeutic target for treatment of HCC. Primary liver cancer is the fifth most common cancer in men and the seventh in women. An estimated 748,300 new liver cancer cases occurred during 2008 [1]. 695,500 people died from liver cancer that same year. HCC is the second leading cause of cancer death in men and the sixth leading cause among women. HCC accounts for 85% of primary liver cancer [2] and is endemic in Southeast Asia and Sub-Saharan Africa.
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