Research Papers:

Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P

Yewei Liu, Ting Yin, Frederik De Keyzer, Yuanbo Feng, Feng Chen, Jianjun Liu, Shaoli Song, Jie Yu, Vincent Vandecaveye, Johan Swinnen, Guy Bormans, Uwe Himmelreich, Raymond Oyen, Jian Zhang, Gang Huang and Yicheng Ni _

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Oncotarget. 2017; 8:55204-55215. https://doi.org/10.18632/oncotarget.19339

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Yewei Liu1,2,3,4, Ting Yin1, Frederik De Keyzer1, Yuanbo Feng1, Feng Chen1, Jianjun Liu2, Shaoli Song2, Jie Yu1, Vincent Vandecaveye1, Johan Swinnen1, Guy Bormans1, Uwe Himmelreich1, Raymond Oyen1, Jian Zhang5, Gang Huang2,3,4 and Yicheng Ni1,5

1Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium

2Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

3Shanghai University of Medicine and Health Sciences, Shanghai 201318, China

4Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, China

5Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China

Correspondence to:

Yicheng Ni, email: [email protected]

Gang Huang, email: [email protected]

Keywords: vascular-disrupting agents, combretastatin A4 phosphate, therapeutic response, microcancer, hepatocellular carcinoma

Received: February 28, 2017     Accepted: June 27, 2017     Published: July 18, 2017


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 (ADCdiff) suggested tumor necrosis, perfusion coefficient (ADCperf) 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.

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