Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection

Abstract

Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.

Keywords: epidermal growth factor; growth factors; hepatocyte growth factor; insulin-like growth factor-1; liver cancer; liver resection; regeneration.

Figure 1

Liver carcinogenesis and regeneration involving HGF, IGF-1, and EGF. (A) Normal regeneration after resection. (B) Cancer recurrence after resection. Abbreviations: EGF; epidermal growth factor; HCC, hepatocarcinoma; HGF, Hepatocyte growth factor; IGF-1, Insulin-like growth factor-1; IGFR-1, Insulin-like growth factor receptor-1.

Figure 2

Molecular pathways underlying liver regeneration and tumorigenesis. Proposed pathways of HGF, EGF, IGF-1, and their link to VEGF in inducing regeneration and/or tumorigenesis. Abbreviations: Akt, Protein kinase B; c-Met, Mesenchymal–epithelial transition factor; DKK1, Dickkopf-1; ECM, Extracellular matrix; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; ERK, Extracellular signal-regulated kinase; FasL, Fas Ligand; FoxO3a, Forkhead box protein O3a; HGF, Hepatocyte growth factor; HMGA2, High-mobility group protein A2; IGF-1, Insulin-like growth factor 1; IGF-1 R, Insulin-like growth factor receptor; MAPK, Mitogen-activated protein kinase; MET, Mesenchymal–epithelial transition factor; mTOR, mammalian target of rapamycin; PERK, protein kinase R-like endoplasmic reticulum kinase; PI3K, Phosphoinositide 3-kinase; PD-L1, Programmed death-ligand 1; ROS, Reactive oxygen species. SIRT1, Deacetylase sirtuin1; STAT, Signal transducer and activator of transcription; TNFα, Tumor necrosis factor-alpha; VEGF, Vascular endothelial growth factor. →: induce the expression; ⇥: blockadge of expression; ↑: increment; ↓: decrease.

Figure 3

Pharmacological regulation of growth factors and its effect on regeneration and cancer recurrence. (A) According to the limited number of studies, treatment with Sorafenib seems does not to affect liver regeneration and could provide benefits to patients after liver resection. (B) No other drugs targeting HGF, EGF, and IGF-1 have been tested with similar objectives. ? means unknown. Abbreviations: EGF; epidermal growth factor; HGF, Hepatocyte growth factor; IGF-1, Insulin-like growth factor 1; PH, partial hepatectomy.