Hepatocellular carcinoma: novel molecular targets in carcinogenesis for future therapies

Abstract

Background: Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy.

Materials and methods: A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: "hepatocellular carcinoma," "molecular hepatocarcinogenesis," "targeted therapy," and "immunotherapy."

Discussion and conclusion: Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.

Figure 1

Cellular signaling pathways implicated in the pathogenesis of hepatocellular carcinoma.

Figure 2

Mechanisms responsible for inefficient T-cell responses in HCC. Failure of TAA processing and presentation; suppression of CD4+ and CD8+ cells by Treg; insufficient levels of CD4 help; negative regulation by PD-1/PDL1 pathway.

Figure 3

Molecular sites of action of active biochemical agents in hepatocellular carcinoma treatment.