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

Wang YH, Cheng TY, Chen TY, Chang KM, Chuang VP, Kao KJ - BMC Cancer (2014)

Bottom Line: Systemic administration did not induce tumor necrosis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Research, Koo Foundation Sun Yat-Sen Cancer Center, Lih-Der Road, Taipei, Taiwan. kjkao@kfsyscc.org.

ABSTRACT

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.

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Related in: MedlinePlus

Tumor growth after infusing MECA32-Fab-TF or control MECA32 mAb into a tumor feeding artery. The results of two different studies were shown here. In study A, tumor bearing mice were treated with 5 or 10 μg MECA32-Fab-TF or 10 μg MECA32 mAb. All mice were euthanized 24 days after treatment. The growth rates between the treatment groups and the control group were compared using a linear mixed-effects model. Significant differences in tumor growth between controls and 5 μg or 10 μg treatment groups were noted (p = 0.003 and 0.001). In study B, tumor bearing mice were treated with 10 μg MECA32-Fab-TF (n = 4) or control MECA32 mAb (n = 2). Mice were sacrificed when tumors grew large enough to interfere with movement and food intake. The average numbers of days required to reach a tumor size of 1600 mm3 for control and treatment groups were 9.8 and 51.8 days, respectively. Different rates of tumor growth were noted between experiments and between mice within the same experiments. Therefore, effort was made to match tumor sizes between control and treatment groups in each study.
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Fig5: Tumor growth after infusing MECA32-Fab-TF or control MECA32 mAb into a tumor feeding artery. The results of two different studies were shown here. In study A, tumor bearing mice were treated with 5 or 10 μg MECA32-Fab-TF or 10 μg MECA32 mAb. All mice were euthanized 24 days after treatment. The growth rates between the treatment groups and the control group were compared using a linear mixed-effects model. Significant differences in tumor growth between controls and 5 μg or 10 μg treatment groups were noted (p = 0.003 and 0.001). In study B, tumor bearing mice were treated with 10 μg MECA32-Fab-TF (n = 4) or control MECA32 mAb (n = 2). Mice were sacrificed when tumors grew large enough to interfere with movement and food intake. The average numbers of days required to reach a tumor size of 1600 mm3 for control and treatment groups were 9.8 and 51.8 days, respectively. Different rates of tumor growth were noted between experiments and between mice within the same experiments. Therefore, effort was made to match tumor sizes between control and treatment groups in each study.

Mentions: We then studied the effect of MECA32-Fab-TF treatment on tumor growth. Two different studies were conducted. The first study followed tumor growth for 25 days after treatment, at which point the tumors in the control group grew too large and the study was stopped. Tumor growth was monitored using 3D sonography. SCID mice bearing Hep3B xenografts were treated with 5 μg or 10 μg of MECA32-FAb-TF and controls were treated with 10 μg of MECA32 mAb without tissue factor. The results, shown in Figure 5A, demonstrate that a single dose of 5 μg or 10 μg MECA32-Fab-TF effectively suppressed tumor growth; this effect was not observed in mice given 10 μg MECA32 mAb as a control. Power Doppler study again revealed significant reduction of tumor blood flow 2 hours after treatment with MECA32-Fab-TF, but not in control mice treated with MECA32 mAb.Figure 5


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

Wang YH, Cheng TY, Chen TY, Chang KM, Chuang VP, Kao KJ - BMC Cancer (2014)

Tumor growth after infusing MECA32-Fab-TF or control MECA32 mAb into a tumor feeding artery. The results of two different studies were shown here. In study A, tumor bearing mice were treated with 5 or 10 μg MECA32-Fab-TF or 10 μg MECA32 mAb. All mice were euthanized 24 days after treatment. The growth rates between the treatment groups and the control group were compared using a linear mixed-effects model. Significant differences in tumor growth between controls and 5 μg or 10 μg treatment groups were noted (p = 0.003 and 0.001). In study B, tumor bearing mice were treated with 10 μg MECA32-Fab-TF (n = 4) or control MECA32 mAb (n = 2). Mice were sacrificed when tumors grew large enough to interfere with movement and food intake. The average numbers of days required to reach a tumor size of 1600 mm3 for control and treatment groups were 9.8 and 51.8 days, respectively. Different rates of tumor growth were noted between experiments and between mice within the same experiments. Therefore, effort was made to match tumor sizes between control and treatment groups in each study.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4233082&req=5

Fig5: Tumor growth after infusing MECA32-Fab-TF or control MECA32 mAb into a tumor feeding artery. The results of two different studies were shown here. In study A, tumor bearing mice were treated with 5 or 10 μg MECA32-Fab-TF or 10 μg MECA32 mAb. All mice were euthanized 24 days after treatment. The growth rates between the treatment groups and the control group were compared using a linear mixed-effects model. Significant differences in tumor growth between controls and 5 μg or 10 μg treatment groups were noted (p = 0.003 and 0.001). In study B, tumor bearing mice were treated with 10 μg MECA32-Fab-TF (n = 4) or control MECA32 mAb (n = 2). Mice were sacrificed when tumors grew large enough to interfere with movement and food intake. The average numbers of days required to reach a tumor size of 1600 mm3 for control and treatment groups were 9.8 and 51.8 days, respectively. Different rates of tumor growth were noted between experiments and between mice within the same experiments. Therefore, effort was made to match tumor sizes between control and treatment groups in each study.
Mentions: We then studied the effect of MECA32-Fab-TF treatment on tumor growth. Two different studies were conducted. The first study followed tumor growth for 25 days after treatment, at which point the tumors in the control group grew too large and the study was stopped. Tumor growth was monitored using 3D sonography. SCID mice bearing Hep3B xenografts were treated with 5 μg or 10 μg of MECA32-FAb-TF and controls were treated with 10 μg of MECA32 mAb without tissue factor. The results, shown in Figure 5A, demonstrate that a single dose of 5 μg or 10 μg MECA32-Fab-TF effectively suppressed tumor growth; this effect was not observed in mice given 10 μg MECA32 mAb as a control. Power Doppler study again revealed significant reduction of tumor blood flow 2 hours after treatment with MECA32-Fab-TF, but not in control mice treated with MECA32 mAb.Figure 5

Bottom Line: Systemic administration did not induce tumor necrosis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Research, Koo Foundation Sun Yat-Sen Cancer Center, Lih-Der Road, Taipei, Taiwan. kjkao@kfsyscc.org.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus