Catecholamines Activate a Tumour Progression Program in Differentiated Tumour Hepatocytes.

Abstract

Background and aims: The sympathetic nervous system is involved in the progression and aggressiveness of several cancers, including hepatocellular carcinoma (HCC). However, the specific effects of sympathetic innervation and catecholamines on tumour hepatocyte behaviour remain poorly understood. In this study, we aimed to investigate the role of sympathetic fibres and catecholamines in the progression of HCC.

Methods: The distribution of sympathetic nerves was mapped in 10 human HCC samples using multiplex immunofluorescence labeling. Adrenergic receptors (ADR) and enzymes involved in catecholamine degradation were assessed in three HCC (HepaRG, BC2, Huh-7) and one hepatoblastoma (HepG2) cell lines. The impact of catecholamines on gene and protein expression and metabolic pathways was assessed in differentiated HepaRG-hepatocytes, and the results were verified in primary human hepatocyte (PHH) cultures. The clinical relevance of the findings was evaluated in two transcriptomics datasets.

Results: Abundant and tortuous sympathetic fibres were detected in non-tumour liver tissues adjacent to the HCC invasion front. Differentiated HepaRG-hepatocytes expressed both α₁- and β₂-ADR and metabolized catecholamines to normetanephrine, metanephrine, and vanillylmandelic acid. In these cells, catecholamine exposure activated inflammation, cell proliferation, and extracellular matrix remodelling pathways associated with retro-differentiation and primed epithelial-to-mesenchymal transition. The catecholamine-induced program was detected in aggressive, ECM/STEM HCC subclasses with poor patient prognosis.

Conclusions: Catecholamines induce an aggressive phenotype in differentiated tumour hepatocytes localized at the invasive front, suggesting their involvement in cancer progression. Understanding the interplay between the sympathetic nervous system and HCC may offer novel therapeutic opportunities.