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However, the responses are variable, reflecting heterogeneity of the disease, while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient\u2010derived xenografts and cell line\u2013derived xenografts and that the therapeutic effect of the drug inversely covaries to the ratio of epithelial cell adhesion molecule\u2013positive cells, which may be tumor initiating cells in HCC. The TSC2\u2010AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1\/2 complex is enhanced, causing increased phosphorylation of AKT, which contributes to up\u2010regulation of \u201cstemness\u201d\u2010related genes in epithelial cell adhesion molecule\u2013positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all\u2010\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    retinoic acid decreased AKT activity, reduced the epithelial cell adhesion molecule\u2013positive cell population enriched by sorafenib, and potentiated the therapeutic effect of sorafenib in the patient\u2010derived xenograft model.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy; this resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of tumor initiating cells (e.g., all\u2010\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    retinoic acid) should improve the prognosis of this subtype of HCC.(H\n                    <jats:sc>epatology<\/jats:sc>\n                    2015;62:1791\u20131803)\n                  <\/jats:p>","DOI":"10.1002\/hep.28117","type":"journal-article","created":{"date-parts":[[2015,8,7]],"date-time":"2015-08-07T19:25:42Z","timestamp":1438975542000},"page":"1791-1803","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["Sorafenib enriches epithelial cell adhesion molecule\u2013positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2\u2010AKT cascade"],"prefix":"10.1097","volume":"62","author":[{"given":"Dong\u2010Xian","family":"Guan","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Shi","sequence":"additional","affiliation":[{"name":"Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Hospital of Anhui Medical University,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang\u2010Sha","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling\u2010Yun","family":"Long","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian\u2010Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Er\u2010Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010Yuan","family":"Feng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Dai","family":"Bao","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue\u2010Zhen","family":"Deng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Qiu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology,Institute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery of FenXian Hospital,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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