A group of researchers led by Drs Isabel Fabregat, form the Bellvitge Biomedical Research Institute (IDIBELL), and Aranzazu Sanchez, from the Complutense University of Madrid, have developed a genetically modified mouse model that allows, for the first time, to study specifically on hepatocytes (the most majority of liver cells) the role of the receptor catalytic activity of a critical cell signaling pathway: the epidermal growth factor (EGF). The study, published in the prestigious journal Hepatology, provides new findings about the involvement of this pathway in liver diseases such as hepatocarcinogenesis (liver cancer), liver fibrosis and inflammation, all of them highly interesting due to their clinical relevance and often severe prognosis that patients receive. Work has been performed in straight collaboration with researchers from the CIEMAT and two CSIC centers: CNB and IIB-Alberto Sols, in Madrid, as well as with clinicians of the Bellvitge University Hospital, in Barcelona.
The transgenic mouse where the experiments of the recently published work has been performed, expresses a truncated form (without a domain called tyrosine kinase) of the EGF receptor (EGFR). This model produces a significant (but not total) and permanent attenuation of its signaling pathway. Because the transgen control is exercised by the albumin gene promoter, only the hepatocytes of these animals express the mutant form of EGFR, a completely new aspect of the model, which provides researchers a unique tool for studying the relevance of this signaling pathway in liver pathophysiological processes, without alterations in the pathway in other cell types of the body.
The results show, on one hand, that the activation of the EGFR pathway is crucial during the early stages of liver regeneration following surgical resection of a large part of the organ. Indeed, mice with the mutated form of this receptor show a delayed liver regeneration, which correlates with low activation of proliferative signals and a predominance of cytostatic mechanisms. On the other hand, the same animal model has demonstrated, for the first time, that the EGFR pathway plays a major role in the primary stages of developing prenodules will lead to liver tumors. Therefore, the attenuation of the studied signaling pathway causes a significant delay in tumor appearance. Surprisingly, the responsible mechanism for the observed effects is not related to the inhibition of cell proliferation nor with an increase in programmed cell death, but correlates with alterations in inflammatory processes. Indeed, the attenuation of the EGFR pathway decreases the inflammatory environment that encourages the emergence of prenodules and subsequent development of tumors. This result suggests that the pharmacological use of EGFR pathway inhibitors may contribute to reduce the inflammation associated with chronic liver diseases and, therefore, to delay the onset of tumors.
The achievement of this work is a clear example of how advances in biomedicine are nourished by the effort to coordinate basic research and clinical aspects of the diseases against which society faces. The project is conducted with funding from the catalan and spanish governments, and European Community (ITN-Marie Curie action).
Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis. López-Luque J, Caballero-Díaz D, Martinez-Palacián A, Roncero C, Moreno-Càceres J, García-Bravo M, Grueso E, Fernández A, Crosas-Molist E, García-Álvaro M, Addante A, Bertran E, Valverde AM, González-Rodríguez Á, Herrera B, Montoliu L, Serrano T, Segovia JC, Fernández M, Ramos E, Sánchez A, Fabregat I. Hepatology. 2016 Feb;63(2):604-19. doi: 10.1002/hep.28134. Epub 2015 Oct 10. PMID: 26313466