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

BMC Cancer

Kuo-Jang Kao³  Vincent P Chuang¹  Kai-Ming Chang³  Ta-Yuan Chen³  Tsung-Yen Cheng²  Yun-Hsin Wang³ 

[1]Department of Radiology, Koo Foundation Sun Yat-Sen Cancer Center, Lih-Der Road, Taipei, Taiwan

[2]Department of Surgery, Koo Foundation Sun Yat-Sen Cancer Center, Lih-Der Road, Taipei, Taiwan

[3]Department of Research, Koo Foundation Sun Yat-Sen Cancer Center, Lih-Der Road, Taipei, Taiwan

关键词: Thrombotic treatment;    Tissue factor;    Monoclonal antibody;    Hepatocellular carcinoma;    PLVAP;   

Others  :  1120230
DOI  :  10.1186/1471-2407-14-815

 received in 2014-04-16, accepted in 2014-10-27,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:1-21.
• [2]Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP: The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006, 45:529-538.
• [3]Simard EP, Ward EM, Siegel R, Jemal A: Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 2012, 62:118-128.
• [4]Siegel R, Naishadham D, Jemal A: Cancer Statistics, 2012. CA Cancer J Clin 2012, 62:10-29.
• [5]American Cancer Society: Survival rates for liver cancer. http://www.cancer.org/cancer/livercancer/detailedguide/liver-cancer-survival-rates webcite
• [6]Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003, 37:429-442.
• [7]Murata S, Mine T, Ueda T, Nakazawa K, Onozawa S, Yasui D, Kumita S: Transcatheter arterial chemoembolization on hepatic hemodynamics for hepatocellular carcinoma. Sci World J 2013, 2013:479805.
• [8]Leung TW, Lau WY, Ho SK, Ward SC, Chow JH, Chan MS, Metreweli C, Johnson PJ, Li AK: Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys 1995, 33:919-924.
• [9]Iñarrairaegui M, Bilbao JI, Rodríguez M, Benito A, Sangro B: Liver radioembolization using 90 y resin microspheres in elderly patients: tolerance and outcome. Hosp Pract 2010, 38:103-109.
• [10]Strigari L, Sciuto R, Rea S, Carpanese L, Pizzi G, Soriani A, Iaccarino G, Benassi M, Ettorre GM, Maini CL: Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR Spheres: Radiobiologic Considerations. J Nucl Med 2010, 51:1377-1385.
• [11]Simonetti RG, Cammà C, Fiorello F, Politi F, D’Amico G, Pagliaro L: Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 1991, 36:962-972.
• [12]Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology 2011, 53:1020-1022.
• [13]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. New Eng J Med 2008, 359:378-390.
• [14]Hung YJ, Lin ZHY, Cheng TI, Liang CT, Kuo TM, Kao KJ: Serum midkine as a prognostic biomarker for patients with hepatocellular carcinoma. Am J Clin Pathol 2011, 136:594-603.
• [15]Leppink DM, Bishop DK, Sedmak DD, Henry ML, Ferguson RM, Streeter PR, Butcher EC, Orosz CG: Inducible expression of an endothelial cell antigen on murine myocardial vasculature in association with interstitial cellular infiltration. Transplantation 1989, 48:874-877.
• [16]Philipp J, Dienst A, Unruh M, Wagener A, Grunow A, Engret A, Fries JW, Gottstein C: Soluble tissue factor induces coagulation on tumor endothelial cells in vivo if coadministered with low-dose lipopolysaccharides. Arterioscler Thromb Vasc Biol 2003, 23:905-910.
• [17]Pinheiro JC, Bates DM: Mixed-Effects Models in S and S-plus. New York: Spinger Verlag; 2000:1-521.
• [18]Stan RV, Kubitza M, Palade GE: PV-1 is a component of the fenestral and stomatal diaphragms in fenestrated endothelia. Proc Natl Acad Sci U S A 1999, 96:13203-13207.
• [19]Stan RV: Structure of caveolae. BBA-Mol Cell Res 2005, 1746:334-348.
• [20]Mackman N: Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol 2004, 24:1015-1022.
• [21]Snyder LA, Rudnick KA, Tawadros R, Volk A, Tam SH, Anderson GM, Bugelski PJ, Yang J: Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in mice. J Thromb Haemost 2008, 6:306-314.
• [22]Cotran RS, Kuma V, Robbins SL: Chapter 1. Cellular Injury And Cellular Death. In Robbins Pathologic Basis of Disease. 5th edition. Edited by Shoen FJ. Philadelphia: WB Saunders; 1994:15-16.
• [23]Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE: Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 1997, 275:547-550.
• [24]Madden SL, Cook BP, Nacht M, Weber WD, Callahan MR, Jiang Y, Dufault MR, Zhang X, Zhang W, Walter-Yohrling J, Rouleau C, Akmaev VR, Wang CJ, Cao X, St Martin TB, Roberts BL, Teicher BA, Klinger KW, Stan RV, Lucey B, Carson-Walter EB, Laterra J, Walter KA: Vascular gene expression in non-neoplastic and malignant brain. Am J Pathol 2004, 165:601-608.
• [25]Strickland LA, Jubb AM, Hongo J-A, Zhong F, Burwick J, Fu L, Frantz GD, Koeppen H: Plasmalemmal vesicle-associated protein (PLVAP) is expressed by tumour endothelium and is upregulated by vascular endothelial growth factor-A (VEGF). J Pathol 2005, 206:466-475.
• [26]Bertino G, Di Carlo I, Ardiri A, Calvagno GS, Demma S, Malaguarnera G, Bertino N, Malaguarnera M, Toro A, Malaguarnera M: Systemic therapies in hepatocellular carcinoma: present and future. Future Oncol 2013, 9:1533-1548.
• [27]Bertino G, Demma S, Ardiri A, Proiti M, Gruttadauria S, Toro A, Malaguarnera G, Bertino N, Malaguarnera M, Malaguarnera M, Di Carlo I: Hepatocellular carcinoma: Novel molecular targets in carcinogenesis for future therapies. Biomed Res Int 2014, 2014:203693.