Abstract 177: Inhibition of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway for chemoprevention of hepatocellular carcinoma.
Authors: Lan Wei, Yujin Hoshida, Gretchen Bain, Jamie Swaney, Gregory Y. Lauwers, Esperance A. Schaefer, Suguru Yamada, Michael Lanuti, Raymond T. Chung, Kenneth K. Tanabe, Bryan C. Fuchs
Journal: Cancer Research (2013)

Abstract Background: Hepatocellular carcinoma (HCC) is increasing in incidence both in the United States and worldwide. Due to the limited treatment options for HCC, prevention in high-risk patients with cirrhosis has been proposed as an alternative strategy. Aberrant activation of the autotoxin-lysophosphatidic acid (ATX-LPA) pathway, an upstream activator of RhoA signaling, has been associated with fibrosis in several organs. Here, we hypothesized that inhibition of the ATX-LPA pathway in fibrotic liver would reduce progression to cirrhosis and HCC occurrence. Methods: Rats were treated weekly with 50 mg/kg diethylnitrosamine (DEN) to induce sequential development of fibrosis, cirrhosis and HCC. After establishment of liver fibrosis (8 weeks), rats were treated daily by oral gavage with either vehicle control, 5 mg/kg AM063 (an ATX inhibitor) or 30 mg/kg AM095 (a LPA receptor 1 (LPA1) antagonist). At the end of the study, rats were sacrificed, livers were sectioned and stained to analyze disease progression, and tumor nodules were counted. In addition, the effect of LPA on RhoA signaling was investigated in hepatic stellate cell lines (TWNT4 and LX-2). Results: Gene set enrichment analysis revealed that a RhoA activation gene signature, which was associated with poor prognosis in human cirrhosis patients, increased in DEN-injured rat livers. Several members of this gene signature, including pro-fibrogenic connective tissue growth factor (CTGF), were reduced after treatment with either AM063 or AM095. In addition, both AM063 and AM095 significantly (p &amp;lt; 0.01) prevented the development of HCC tumor nodules in DEN-injured livers from a median of 16 in controls to a median of 8 and 6 in AM063 and AM095-treated rats, respectively. Interestingly, the extent of fibrosis in DEN-injured rat livers as measured by Ishak score also significantly (p &amp;lt; 0.01) decreased from a median of 6 in controls to a median of 4 in both AM063 and AM095-treated rats. Examination of hepatic stellate cell lines revealed that LPA increased RhoA-mediated CTGF expression, which was inhibited by AM095. Conclusions: We have identified the ATX-LPA pathway as a major mediator of liver fibrosis progression. Further, AM063 and AM095 are potential chemoprevention strategies for HCC. Citation Format: Lan Wei, Yujin Hoshida, Gretchen Bain, Jamie Swaney, Gregory Y. Lauwers, Esperance A. Schaefer, Suguru Yamada, Michael Lanuti, Raymond T. Chung, Kenneth K. Tanabe, Bryan C. Fuchs. Inhibition of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway for chemoprevention of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 177. doi:10.1158/1538-7445.AM2013-177