Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of death due to cancer. Although there are different treatment options, these strategies are not efficient in terms of restricting the tumor cell’s proliferation and metastasis. The liver tumor microenvironment contains the non-parenchymal cells with supportive or inhibitory effects on the cancerous phenotype of HCC. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of liver carcinoma cells. Recent studies have established new approaches for the prevention and treatment of HCC using small molecules. Small molecules are compounds with a low molecular weight that usually inhibit the specific targets in signal transduction pathways. These components can induce cell cycle arrest, apoptosis, block metastasis, and tumor growth. Devising strategies for simultaneously targeting HCC and the non-parenchymal population of the tumor could lead to more relevant research outcomes. These strategies may open new avenues for the treatment of HCC with minimal cytotoxic effects on healthy cells. This study provides the latest findings on critical signaling pathways governing HCC behavior and using small molecules in the control of HCC both in vitro and in vivo models.

Immunotherapies for hepatocellular carcinoma

“…), Wnt/ß‐catenin, MAPK/ERK, PI3K/AKT/mTOR, and the JAK/STAT signalling pathways. 68 , 69 , 70 , 71 , 72 They are associated with decreased intratumoural infiltration and effector function of T‐cells and dendritic cells (DCs), and increased T‐cell exhaustion. 64 , 65 , 66 , 67 Furthermore, cytokines such as interleukin (IL)‐10 and TGF‐ß promote tumour cell proliferation and immune evasion through a reduction in the recruitment of APCs and antigen presentation, along with overexpression of alternative co‐inhibitory cell‐surface ligands such as T‐cell immunoglobulin domain and mucin domain 3 and lymphocyte‐activation gene 3.…”

“…Oncogenic cell signalling pathways that are upregulated in HCC include receptor tyrosine kinases (EGFR, FGFR, c‐MET, VEGFR, etc. ), Wnt/ß‐catenin, MAPK/ERK, PI3K/AKT/mTOR, and the JAK/STAT signalling pathways 68–72 . They are associated with decreased intratumoural infiltration and effector function of T‐cells and dendritic cells (DCs), and increased T‐cell exhaustion 64–67 .…”

Prevention and Treatment of Hepatocellular Carcinoma Using miRNAs

“…[25][26][27] Targeting these signaling pathways may promote the treatment of the disease. [28][29][30] Recent studies have established new approaches for the prevention and treatment of HCC using miRNA technology. [31][32][33] microRNAs are a branch of RNA interference (RNAi) technology that contain about 20 nucleotides and target the specific mRNA in the cells.…”

Immune signature-based hepatocellular carcinoma subtypes may provide novel insights into therapy and prognosis predictions

“…The risk factors for HCC include viral infections (e.g., hepatitis B and C), alcohol consumption, obesity with non-alcohol fatty liver disease, and the high intake of aflatoxins [ 4 ]. Despite recent advances in HCC management, liver resection, transplantation, chemotherapy, radiotherapy, and molecular-targeting therapies that have improved HCC clinical outcomes to a certain degree [ 5 ], most patients are still diagnosed at advanced HCC stages and have limited therapeutic options [ 6 – 8 ]. Current curative rates are still poor for HCC because of its heterogeneity, high morbidity, high recurrence rate, metastases, and poor responsiveness to chemotherapy [ 9 ].…”