Cytokines and Hepatocellular Carcinoma: Biomarkers of a Deadly Embrace

Abstract

Hepatocellular carcinoma (HCC) represents a worldwide health matter with a major care burden, high prevalence, and poor prognosis. Its pathogenesis mainly varies depending on the underlying etiological factors, although it develops from liver cirrhosis in the majority of cases. This review summarizes the role of the most interesting soluble factors as biomarkers for early diagnosis and as recommended targets for treatment in accordance with the new challenges in precision medicine. In the premalignant environment, inflammatory cells release a wide range of cytokines, chemokines, growth factors, prostaglandins, and proangiogenic factors, making the liver environment more suitable for hepatocyte tumor progression that starts from acquired genetic mutations. A complex interaction of pro-inflammatory (IL-6, TNF-α) and anti-inflammatory cytokines (TGF-α and -β), pro-angiogenic molecules (including the Angiopoietins, HGF, PECAM-1, HIF-1α, VEGF), different transcription factors (NF-kB, STAT-3), and their signaling pathways are involved in the development of HCC. Since cytokines are expressed and released during the different stages of HCC progression, their measurement, by different available methods, can provide in-depth information on the identification and management of HCC.

Keywords: biomarkers; cytokines; hepatocellular carcinoma; personalized medicine.

Figure 1

Major pathogenetic events and cytokine network involved in hepatocellular carcinogenesis. Following persistent liver damage, locally activated chronic inflammation favors the release of soluble factors sustaining the proliferation and survival of tumor cells. Angiogenic factors (angiopoietins, VEGF), growth factors for normal and transformed hepatocytes (HGF), adhesion molecules and cytokines for recruitment and activation of leukocytes (PECAM, IL-6), and stellate cells upregulates TGF in the liver and, consequently, regeneration, proliferation, and hepatocyte dysplasia, and, ultimately, the development of HCC.

Figure 2

(A) Hypoxic environment stimulates neoangiogenesis, thanks to a circuit involving HIF-1α -induced VEGF release by tumor cells. (B) A wide range of cellular released growth factors, derived from a tumor, stroma, and leukocytes, ensures the formation of new vascularity and the sustainment of cell growth, allowing the worsening progression of the initial tumor burden.