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Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P
We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HC...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589653/ https://www.ncbi.nlm.nih.gov/pubmed/28903414 http://dx.doi.org/10.18632/oncotarget.19339 |
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author | Liu, Yewei Yin, Ting Keyzer, Frederik De Feng, Yuanbo Chen, Feng Liu, Jianjun Song, Shaoli Yu, Jie Vandecaveye, Vincent Swinnen, Johan Bormans, Guy Himmelreich, Uwe Oyen, Raymond Zhang, Jian Huang, Gang Ni, Yicheng |
author_facet | Liu, Yewei Yin, Ting Keyzer, Frederik De Feng, Yuanbo Chen, Feng Liu, Jianjun Song, Shaoli Yu, Jie Vandecaveye, Vincent Swinnen, Johan Bormans, Guy Himmelreich, Uwe Oyen, Raymond Zhang, Jian Huang, Gang Ni, Yicheng |
author_sort | Liu, Yewei |
collection | PubMed |
description | We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HCCs of 2.8–20.9 mm in size on liver cirrhosis received CA4P intravenously at 10 mg/kg. Tumor-diameter was measured by T2-weighted imaging (T2WI) to define microcancers (< 5 mm) versus larger HCCs. Vascular responses and tissue necrosis were detected by diffusion-weighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1WI) and dynamic contrast enhanced (DCE-) MRI, which were validated by microangiography and histopathology. MRI revealed nearly complete necrosis in 5 out of 7 micro-HCCs, but diverse therapeutic necrosis in larger HCCs with a positive correlation with tumor size. Necrosis in micro-HCCs was 36.9% more than that in larger HCCs. While increased diffusion coefficient (ADC(diff)) suggested tumor necrosis, perfusion coefficient (ADC(perf)) indicated sharply decreased blood perfusion in cirrhotic liver together with a reduction in micro-HCCs. DCE revealed lowered tumor blood flow from intravascular into extravascular extracellular space (EES). Microangiography and histopathology revealed hypo- and hypervascularity in 4 and 3 micro-HCCs, massive, partial and minor degrees of tumoral necrosis in 5, 1 and 1 micro-HCCs respectively, and patchy necrotic foci in cirrhotic liver. CD34-PAS staining implicated that poorly vascularized micro-HCCs growing on liver cirrhosis tended to respond better to CA4P treatment. In this study, more complete CA4P-response occurred unexpectedly in micro-HCCs in rats, along with CA4P-induced necrotic foci in cirrhotic liver. These may help to plan clinical applications of VDAs in patients with HCCs and liver cirrhosis. |
format | Online Article Text |
id | pubmed-5589653 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-55896532017-09-12 Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P Liu, Yewei Yin, Ting Keyzer, Frederik De Feng, Yuanbo Chen, Feng Liu, Jianjun Song, Shaoli Yu, Jie Vandecaveye, Vincent Swinnen, Johan Bormans, Guy Himmelreich, Uwe Oyen, Raymond Zhang, Jian Huang, Gang Ni, Yicheng Oncotarget Research Paper We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HCCs of 2.8–20.9 mm in size on liver cirrhosis received CA4P intravenously at 10 mg/kg. Tumor-diameter was measured by T2-weighted imaging (T2WI) to define microcancers (< 5 mm) versus larger HCCs. Vascular responses and tissue necrosis were detected by diffusion-weighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1WI) and dynamic contrast enhanced (DCE-) MRI, which were validated by microangiography and histopathology. MRI revealed nearly complete necrosis in 5 out of 7 micro-HCCs, but diverse therapeutic necrosis in larger HCCs with a positive correlation with tumor size. Necrosis in micro-HCCs was 36.9% more than that in larger HCCs. While increased diffusion coefficient (ADC(diff)) suggested tumor necrosis, perfusion coefficient (ADC(perf)) indicated sharply decreased blood perfusion in cirrhotic liver together with a reduction in micro-HCCs. DCE revealed lowered tumor blood flow from intravascular into extravascular extracellular space (EES). Microangiography and histopathology revealed hypo- and hypervascularity in 4 and 3 micro-HCCs, massive, partial and minor degrees of tumoral necrosis in 5, 1 and 1 micro-HCCs respectively, and patchy necrotic foci in cirrhotic liver. CD34-PAS staining implicated that poorly vascularized micro-HCCs growing on liver cirrhosis tended to respond better to CA4P treatment. In this study, more complete CA4P-response occurred unexpectedly in micro-HCCs in rats, along with CA4P-induced necrotic foci in cirrhotic liver. These may help to plan clinical applications of VDAs in patients with HCCs and liver cirrhosis. Impact Journals LLC 2017-07-18 /pmc/articles/PMC5589653/ /pubmed/28903414 http://dx.doi.org/10.18632/oncotarget.19339 Text en Copyright: © 2017 Liu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Liu, Yewei Yin, Ting Keyzer, Frederik De Feng, Yuanbo Chen, Feng Liu, Jianjun Song, Shaoli Yu, Jie Vandecaveye, Vincent Swinnen, Johan Bormans, Guy Himmelreich, Uwe Oyen, Raymond Zhang, Jian Huang, Gang Ni, Yicheng Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P |
title | Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P |
title_full | Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P |
title_fullStr | Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P |
title_full_unstemmed | Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P |
title_short | Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P |
title_sort | micro-hccs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent ca4p |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589653/ https://www.ncbi.nlm.nih.gov/pubmed/28903414 http://dx.doi.org/10.18632/oncotarget.19339 |
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