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

// Yewei Liu 1, 2, 3, 4 , Ting Yin 1 , Frederik De Keyzer 1 , Yuanbo Feng 1 , Feng Chen 1 , Jianjun Liu 2 , Shaoli Song 2 , Jie Yu 1 , Vincent Vandecaveye 1 , Johan Swinnen 1 , Guy Bormans 1 , Uwe Himmelreich 1 , Raymond Oyen 1 , Jian Zhang 5 , Gang Huang 2, 3, 4 and Yicheng Ni 1, 5 1 Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium 2 Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China 3 Shanghai University of Medicine and Health Sciences, Shanghai 201318, China 4 Institute 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 5 Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China Correspondence to: Yicheng Ni, email: yicheng.ni@kuleuven.be Gang Huang, email: huang2802@163.com Keywords: vascular-disrupting agents, combretastatin A4 phosphate, therapeutic response, microcancer, hepatocellular carcinoma Received: February 28, 2017      Accepted: June 27, 2017      Published: July 18, 2017 ABSTRACT 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.