Abstract 3748: Clinicopathological characterization of non-alcoholic Steatohepatitis (NASH)-derived hepatocellular carcinoma (HCC) as a patient stratification model in mice

Abstract

Therapeutic strategy against Hepatocellular carcinoma (HCC) is determined by tumor stage and liver function. Improvement of patient stratification thus contributes to improved survival of patients as well as to provide insights into the usage of anti-HCC drugs. Distinct from current clinical strategy, however, stratification has been paid a little attention in tumor animal models largely due to the lack of suitable model. Given the importance of animal study for the development of anti-HCC therapeutics, it is needed to consider stratification also in an animal HCC model. Here we investigate the clinicopathological features of HCC in a recently reported, non-transgenic Nonalcoholic steatohepatitis (NASH)-derived HCC model (STAM model, Fujii et al, Med Mol Morphol, 2013) and show that STAM model is the first murine model to which the patient stratification concept is applicable. STAM mice showed following characteristics; 1) all male mice developed well differentiated HCC without exception, 2) HCC was developed in the fibrotic, but not intact liver, 3) at least 4 tumor nodules were detectable, 4) space occupied lesions were observed from 14 weeks of age by multiphase dynamic-enhance computed tomography (CT), 5) average tumor growth rate from 14 to 20 weeks of age was 200% by CT, 6) hypervascular in arterial phase and washout in delayed phase, 7) mice did not exhibit ascites and visible metastasis, 8) liver function was relatively preserved corresponding to Child-Pugh grade A or B in human, 9) expression levels of human HCC markers such as Glypican-3 were elevated. These observations suggest that HCC in STAM mice are equivalent to stage B to C of Barcelona Clinic Liver Cancer (BCLC) staging system in human. Moreover, whether Sorafenib, which is selected as a first line drug for patients with stage C HCC in BCLC, also shows anti-HCC activity in this murine model or not, we evaluated the effect of Sorafenib on HCC in STAM mice. We demonstrated that Sorafenib reduced HCC growth rate in STAM mice. Taken together, our results indicate that STAM model is suitable to evaluate the drug efficacy on HCC associated with NASH. Application of stratification concept to murine study would also open new avenue to establish fine pharmacological intervention against HCC. Citation Format: Kazuki Takakura, Masato Fujii, Taishi Hashiguchi, Yuichiro Shibazaki, Hiroyuki Yoneyama, Shigeo Koido, Sadamu Homma, Toshifumi Ohkusa, Hisao Tajiri. Clinicopathological characterization of non-alcoholic Steatohepatitis (NASH)-derived hepatocellular carcinoma (HCC) as a patient stratification model in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3748. doi:10.1158/1538-7445.AM2014-3748

Tie‐ing Up Angiogenesis to Treat Nonalcoholic Steatohepatitis

“…They show that MCD diet-fed mice exhibit increased serum ANG2 levels, confirming the expected findings alluded to above. They also studied another NASH model, namely neonatal streptozotocin and 16 weeks of western diet exposure, (9) and confirmed that ANG2 serum levels were increased in that model also. Administration of L1-10 reduced inflammation, ballooning, and fibrosis in MCD diet-fed mice but did not change the degree of steatosis.…”

Identification of chromatin‐accessible domains in non‐alcoholic steatohepatitis‐derived hepatocellular carcinoma

“…The Stelic Animal Model (STAM) of NASH-derived HCC is the first mouse model to depict the sequential evolution of clinical and pathomorphological features of the development of HCC in diabetesassociated NASH patients. 13,14 Briefly, 2-day-old male C57BL/6J mice were injected with streptozotocin (200 µg/mouse). Starting from 4 weeks of age, the mice were continuously fed a high-fat diet (HFD-32; Clea, Tokyo, Japan).…”

Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

“…It is also notable that female mice undergoing the same treatment did not develop NASH, fibrosis and HCC, which indicates that estrogen may play a protective role in susceptibility to NASH initiation and progression, as well as its malignant transformation in diabetic mice [58]. This group further characterized the tumor nodule size and metastatic status at 20 weeks of induction, and claimed that the stage of HCC seen in these mice corresponds to stages B to C of the Barcelona Clinic Liver Cancer (BCLC) staging system for humans [60]. This stratification could be helpful in assessing the efficacy of a therapeutic algorithm in the treatment of liver cancer with this model.…”