Abstract
The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.
Highlights
Liver transplantation (LT) remains an unsolved problem in clinical practice, due to the lack of donor grafts and because of the risk factors of liver dysfunction or failure that show steatotic livers [1] or livers from a brain-dead (BD) donor [2]
Future studies with much better models of cancer induction and cell types to simulate as much as possible the clinical conditions are required. Another possible explanation for that change to the behavior of FGF19/FGFR4 is provided by Heinzle et al, who suggested that the tumor-suppressive function probably depends on the lineage-specific expression of β-klotho, which belongs to a protein family known for its role in anticancer processes [76]
The benefits of exogenous FGF15 administration in liver donors with steatotic and non-steatotic grafts, as well as the benefits of FGF15/19 inhibitors in patients with hepatocellular carcinoma (HCC), have been reported. These controversial effects of FGF15/19 depend on the type of pathology and the surgical conditions. This reveals the difficulty of managing a liver disease targeting FGF15/19 or its downstream signaling pathways or receptors: if the same pharmacological strategies are applied indiscriminately to different liver pathologies in patients with different liver phenotypes or different pathology, the effects may be very different
Summary
Liver transplantation (LT) remains an unsolved problem in clinical practice, due to the lack of donor grafts and because of the risk factors of liver dysfunction or failure that show steatotic livers (present in 30% of total liver grafts) [1] or livers from a brain-dead (BD) donor (the 80% of deceased donors) [2]. Future studies with much better models of cancer induction and cell types to simulate as much as possible the clinical conditions are required Another possible explanation for that change to the behavior of FGF19/FGFR4 is provided by Heinzle et al, who suggested that the tumor-suppressive function probably depends on the lineage-specific expression of β-klotho, which belongs to a protein family known for its role in anticancer processes [76]. Given the physiological functions of the FGF19-FGFR4 pathway in BA synthesis [84], the blockade of FGF19, FGFR4, or β-klotho, as a potential strategy to reduce the risk of cancer progression, would result in hepatic deregulation of BA synthesis This is relevant because bile salts can elicit a hepatocellular proliferative response mediated by ileumderived FGF15 according to preclinical and clinical data reported by Uriarte et al in the mouse model [85]. Intensive investigations on the possible relationship between HDAC2 and FGFR4 could be of scientific and clinical interest in hepatic tumorigenesis
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