Sorafenib, the first molecular targeted agent for HCC, has been shown to be clinically effective in global clinical trials. Although overall survival of HCC patients has been extended by a few months, these results are not satisfactory. Clinical studies involving other molecular targeted therapies and combination therapies are ongoing, but no clearly effective therapy has yet emerged. While we were exploring new targets related to epithelial-mesenchymal transition (EMT), which is involved in metastasis and ivasion of advanced cancers, we found the EMT-inducing potential of the tropo-myosine-related kinase B (TrkB) receptor, whose ligands include brain-derived neurotrophic factor (BDNF).

We observed by phase contrast microscopy that K252a, a Trk inhibitor, induced alterations in cell shape of several HCC cell lines (HAK-1A, HAK-1B, KYN-2, Huh7, and HLF). The morphological change was most obvious in HAK-1B cells, which have been proven to have mesenchymal features: the K252a-treated HAK-1B turned to polygonal epithelial-like cells. In Western blot analysis, the E-cadherin expression level was increased in the K252a-treated HAK-1B cells. Similar findings were demonstrated also in HAK-1A, which is a sister cell line of HAK-1B. The mechanistic basis for the “mesenchymal-epithelial transition (MET)” was down-regulation of E2A, an EMT-regulating transcriptional factor. Although the down-regulation of E2A was universally found in other cell lines, such as KYN-2, Huh7, and HLF, their expression levels of E-cadherin were not apparently increased.

Our findings suggest that inhibition of TrkB signaling may be a new therapeutic approach for advanced HCC, since the inhibition may give rise to “MET” in aggressive tumors. In addition, the present data are impressive insofar as they imply a relationship between the liver and neurosystem.

Citation Format: Mitsuhiko Abe, Hironori Koga, Takafumi Yoshida, Hiroshi Masuda, Masahiro Sakata, Yu Ikezono, Toru Nakamura, Eitaro Taniguchi, Takumi Kawaguchi, Hirohisa Yano, Takuji Torimura, Michio Sata. Inhibition of Trk receptor leads to mesenchymal-epithelial transition in human hepatocellular carcinoma cell lines. [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 289. doi:10.1158/1538-7445.AM2013-289