Abstract
Background and Aims: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown.Methods: We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx). We also performed TP using human liver biopsies (n = 5) taken from the occluded lobe and the future liver remnant (FLR) during the first step of ALPPS surgery (4–5 h apart). We used Oncofinder computational tools, which covers 378 ISPs, for unsupervised, unbiased quantification of ISP activity.Results: Gene expression cluster analysis revealed an ALPPS specific signature: the IGF1R Signaling Pathway (Cell survival), the ILK Pathway (Induced cell proliferation), and the IL-10 Pathway (Stability determination) were significantly enriched, whereas the activity of the Interferon Pathway (Transcription) was reduced (p < 0.05). Further, the PAK- and ILK-associated ISPs were activated at an earlier time point, reflecting significant acceleration of liver regeneration (p < 0.001). These pathways, which were also recovered in human liver biopsies, control cell growth and proliferation, inflammatory response, and hypoxia-related processes.Conclusions: ALPPS is not a straightforward addition of portal vein ligation (PVL) plus transection—it is more. The early stages of normal and accelerated liver regeneration are clearly discernible by a significantly increased and earlier activation of a small number of signaling pathways. Compounds mimicking these responses may help to improve the ALPPS method and further reduce the hospitalization time of the patient.
Highlights
Liver regeneration is controlled by a cooperating, redundant system of biological networks performing an assortment of tasks, which together result in a coordinated response to replenish lost liver tissue
To elucidate the molecular pathways responsible for accelerated liver regeneration, hepatic RNA isolated at several time points after ALPPS, portal vein ligation (PVL), transection, left lateral lobe resection (LLLx), and sham operation was deep-sequenced
We identified the common and unique intracellular signaling pathway (ISP) for ALPPS and normal liver regeneration as induced by standard hepatectomy
Summary
Liver regeneration is controlled by a cooperating, redundant system of biological networks performing an assortment of tasks, which together result in a coordinated response to replenish lost liver tissue. A novel two-staged strategy has been introduced: ALPPS (for: Associating Liver Partition and Portal vein ligation for Staged hepatectomy) [3]. In the first stage of the ALPPS procedure, the portal vein is ligated, followed by removal of any tumor in the future liver and an in situ split of the parenchyma between the healthy and diseased liver (partition or transection) is performed. The main advantage of the ALPPS strategy is that the accelerated regeneration of the liver remnant, which reaches a body-sustaining size within 7–10 days, enables the prompt elimination of the major tumor load [4, 7]. ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown
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