Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma
Authors: Jiwen Cheng, MuXing Li, Yi Lv
Journal: Hepatology (2013)

Yoshida et al.1 reported that they exposed three human HCC cell lines (HEPG2, HuH7, and HEP3B) to 45°C-55°C for 10 minutes, simulating the marginal zone of radiofrequency ablation (RFA) treatment. They demonstrated that sublethal heat treatment skews hepatocellular carcinoma (HCC) cells towards epithelial-mesenchymal transition (EMT) and transforms them to a progenitor-like, highly proliferative cellular phenotype in vitro and in vivo. Of note, the expression of two central EMT markers (Snail and procollagen-α1(I)) and EMT-related transcript levels increased at day 5 after heat exposure, which returned to baseline at day 12. However, this study raises several confusing questions. First, the experimental protocol used to simulate the marginal zone of RFA treatment was notably different from the conditions in the clinical setting to some extent. For example, a single ablation takes from 8 to 25 minutes,2 but the durations of heat treatments are always less or more than 10 minutes in the clinical setting. What's more, the temperatures in the remainder of the ablation zone cannot maintain a constant temperature for 10 minutes. Because water vaporization and char act as electrical insulators, the increase in impedance with tissue boiling and charring can significantly reduce the thermal conductivity.3 Second, Yoshida et al.1 reported that the Shc expression dramatically increased in HCC tissue, but was absent in healthy liver. However, the HCC specimens studied may not equal that which patients with recurrence of HCC after RFA treatment have. Therefore, it cannot reflect the true expression level of Shc in HCC tissue after RFA treatment. Third, this study indicated that HEPG2 cells pretreated at 48°C and 50°C were subcutaneously implanted on day 3 after heating and displayed faster HCC growth compared to tumors arising from untreated cells. Moreover, early proliferation and EMT-like changes were observed in hepatoma cells at day 3 after heat treatment. Since all these changes clearly found in heat-exposed HCC cells at day 5 returned to baseline at day 12, we wonder whether the transplant heat-pretreated HCC cells at day 5 into nude mice with HCC cells exposed to 48°C and 50°C display faster growth compared to tumors arising from untreated cells or HCC cells at day 3 after heat treatment. Furthermore, to transplant heat-pretreated HCC cells at day 12 into nude mice, we wonder whether the HCC growth will slow down or even stop compared to heat-pretreated HCC cells at day 3 and 5 in nude mice. We believe the answers to the above questions will help clarify the underlying mechanism of the rapid growth of residual HCC after sublethal heat treatment. Jiwen Cheng, Ph.D.1,2 MuXing Li, M.D.1,2 Yi Lv, M.D., Ph.D.1,2 1Department of Hepatobiliary Surgery First Affiliated Hospital of Medical College Xi'an Jiaotong University Xi'an, Shaanxi Province, China 2Institute of Advanced Surgical Technology and Engineering Xi'an Jiaotong University Xi'an, Shaanxi Province, China