Risk Factors, Pathogenesis, and Strategies for Hepatocellular Carcinoma Prevention: Emphasis on Secondary Prevention and Its Translational Challenges

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.

Keywords: NASH; chemoprevention; hepatitis; hepatocellular carcinoma.

Figure 1

Mechanisms of hepatocellular carcinoma. Molecular pathways of HCC carcinogenesis are summarized. Risk factors include viral hepatitis, NAFLD, alcohol and toxins. HCC tumors develop as dysplastic nodules through the gaining of molecular aberrations and mutations. The cirrhotic microenvironment in the liver promotes HCC carcinogenesis through the activation of hepatic stellate cells into myofibroblasts. The cirrhotic background also promotes inflammation leading to the upregulation of pro-carcinogenic genes and pathways (text for details).

Figure 2

Reverse engineering for HCC chemoprevention. Traditionally, chemoprevention targets are verified in both in vitro and experimental animal models and then introduced into clinical trials (top panel). The reverse-engineering identifies targets for chemoprevention in human cohorts already followed for decades. Samples are genetically profiled into molecular signatures and then experimentally evaluated for mechanisms and therapeutic strategies (bottom panel).

Figure 3

Lysophosphatidic acid (LPA) pathway as a novel chemoprevention target. Reverse engineering transcriptome analysis revealed the LPA pathway as a target for HCC prevention. LPA and its G protein-coupled receptors, lysophosphatidic acid receptors (LPARs), promote fibrosis, inflammation, and carcinogenesis through the activation of down-stream RhoA, Ras/mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), and Akt/PI3K. LPA activation has been observed in human and rodent cirrhotic livers at risk for HCC.

Figure 4

HCC-prevention strategies through the progression of HCC development. HCC prevention strategies, primary, secondary, and tertiary prevention, target various stages of liver disease progression (text for details).

Figure 5

Etiology-specific and independent secondary HCC prevention. Etiology-specific secondary prevention targets the various risk factors of HCC development, including HBV, HCV, NAFLD/NASH, and ALD. Etiology independent prevention strategies include agents that have anti-fibrosis or anti-inflammatory activities.