It should be considered, however, that fibrosis, inflammation, and increased cell turnover are key processes implicated in the development
selleck chemical of liver cancer.28 Therefore, by reducing liver fibrosis and exerting antiinflammatory effects this therapy might in fact reduce the risk of liver carcinogenesis. Interestingly, multifocal bile duct proliferation, a process that precedes carcinogenesis in the TAA model, was markedly decreased in SVIGF-I-treated rats.29 Moreover, in rats with CCl4-induced cirrhosis, IGF-I therapy favors hepatocellular differentiation (up-regulation of HNF4α and down-regulation of WT-1), which may oppose tumorigenesis (Fig. 7). In fact, up-regulation of WT-1 has been shown to be associated with HCC development,18 suggesting that the effect of IGF-I in suppressing its expression may inhibit tumor formation. According to this idea it has been shown that a sharp decrease of IGF-I production by the cirrhotic liver increases the risk of hepatocellular carcinoma (HCC).30 Although there is activation of IGF-IR in HCC, the levels of IGF-I in tumor tissue are markedly diminished, whereas there is check details up-regulation of IGF-II, suggesting that the latter, and not the former, is the ligand involved in IGF-IR signaling in the tumor.31 As shown above, our data indicate that
in the cirrhotic liver IGF-IR is mainly expressed by nonparenchymal cells present in fibrous septa. The very poor expression of this receptor in hepatocytes would minimize any direct effect of the molecule on these cells. However, IGF-I gene therapy should not be administered to patients with cirrhosis who have already developed HCC because this therapy may
enhance tumor growth due to the abundance of IGF-IR in already transformed hepatocytes. In summary, we show that gene transfer of IGF-I to the cirrhotic liver sets in motion a curative process involving 17-DMAG (Alvespimycin) HCl increased expression of cytoprotective and antifibrogenic molecules and reduced expression of profibrogenic factors. IGF-I seems to be able to reprogram the liver from a “scar formation” response, which leads to cirrhosis, to a “tissue repair” circuit that favors cirrhosis regression. According to these findings IGF-I gene therapy might be of value for patients with advanced cirrhosis who do not have access to timely liver transplantation. We thank Pilar Peréz and Uxue Latasa for help with liver cells isolation, Maria Vera for SVIGF-I production, Ana Sandoval for the thioacetamide model, and Monica Enguita and Erkuden Casales. Additional Supporting Information may be found in the online version of this article. “
“Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses.