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.

The role of gut microbiota in liver regeneration

“…HGF is secreted mainly by hepatic stellate cells, vascular endothelial cells and Kupffer cells. HGF is a ligand for the tyrosine kinase receptor c-Met ( 55 – 57 ). Activation of HGF/Met axis activate several downstream pathways including ERK1/2, JAK/STAT3, PI3K/AKR/NF-κB, MAPK and Ras/Raf ( 55 , 57 , 58 ).…”

“…HGF is a ligand for the tyrosine kinase receptor c-Met ( 55 – 57 ). Activation of HGF/Met axis activate several downstream pathways including ERK1/2, JAK/STAT3, PI3K/AKR/NF-κB, MAPK and Ras/Raf ( 55 , 57 , 58 ). These pathways play a vital role in promoting liver regeneration.…”

Dysregulation of Liver Regeneration by Hepatitis B Virus Infection: Impact on Development of Hepatocellular Carcinoma

“…One of the suggested mechanisms is the overactivation of c-Met and related signals, such as the Akt pathways, resulting in increased proliferation of hepatic tissue, enhanced angiogenesis, and modulation of autophagy [ 126 , 127 , 128 ]. A recent review highlighted the importance of balance between liver regeneration signal and carcinogenesis [ 129 ]. It is reasonable to assume that HBV infection might modulate both regeneration and carcinogenesis processes through the regulation of growth factors and related signaling pathways.…”

Role of Fibrinogen-like Protein 1 in Tumor Recurrence Following Hepatectomy

“…2 Chemotherapy and radiotherapy have controlled this malignancy well, but they typically have serious side effects. 3 Hence, liver transplantation and liver partial resection, also known as partial hepatectomy (PH), are considered as the two main therapeutic approaches for HCC. 4 As finding a transplant organ is a time-consuming process in many countries, PH is known as the primary strategy to control HCC at the early stages.…”

“…Indeed, cancer cells can multiply by exploiting pathways associated with liver regeneration. 3 Tumor recurrence, with a 70% 5-year recurrence, is the most serious PH consequence. 7 The liver secretes proteins called hepatokines, which play crucial roles in diverse medical conditions.…”