Plasmalemmal Vesicle Associated Protein (PLVAP) as a therapeutic target for treatment of hepatocellular carcinoma.
BACKGROUND
Hepatocellular 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.


METHODS
Genes 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.


RESULTS
PLVAP 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.


CONCLUSIONS
The 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.
Yun-Hsin
YH
Wang
Tsung-Yen
TY
Cheng
Ta-Yuan
TY
Chen
Kai-Ming
KM
Chang
Vincent P
VP
Chuang
Department of Research, Koo Foundation Sun Yat-Sen Cancer Center, Lih-Der Road, Taipei, Taiwan. kjkao@kfsyscc.org.
Kuo-Jang
KJ
Kao
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000188:drug therapy* / Q000235:genetics; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D064593:Heterografts; D006801:Humans; D008099:Liver / Q000737:chemistry; D008113:Liver Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D002352:Carrier Proteins; C095910:MECA-32 antigen, mouse; D008565:Membrane Proteins; C486771:PLVAP protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins