Hydrocortisone Suppresses Early Paraneoplastic Inflammation And Angiogenesis To Attenuate Early Hepatocellular Carcinoma Progression In Rats

BACKGROUND: Inflammation is implicated in both hepatic cirrhosis development and hepatocellular carcinogenesis, and treatment with long-acting glucocorticoid dexamethasone prevented liver carcinogenesis in mice. However, it is unclear whether glucocorticoids have anti-inflammatory effect on hepatocellular carcinoma (HCC) and if short-acting glucocorticoids (with fewer adverse effects) inhibit paraneoplastic inflammation and HCC progression. METHODS: To investigate whether different types of anti-inflammatory agents attenuate HCC progression, the current study compared effects of treatments with hydrocortisone (a short-acting glucocorticoid) or aspirin on HCC progression. HCC was induced in diethylnitrosamine-treated rats which were randomly divided into 4 groups (n=8), respectively receiving orally once daily vehicle, glucuronolactone, glucuronolactone+hydrocortisone, and glucuronolactone+aspirin. Diethylnitrosamine (DEN) was given to rats in drinking water (100mg/L) to induce HCC. At weeks 12 and 16 post-induction, effects were compared on HCC nodule formation, microvessel density, and macrophage infiltration, and levels of paraneoplastic protein expression of tumor necrosis factor (TNF)-α, p38 mitogen-activated protein kinase (p38), phosphorylated p38 (p-p38), nuclear factor (NF)-κB, interleukin (IL)-10, hepatocyte growth factor (HGF), transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF). RESULTS: Compared to the model and glucuronolactone alone groups, HCC nodule number and microvessel density in the glucuronolactone+hydrocortisone group were significantly lower at week 12. At week 12 but not week 16, significantly lower levels of macrophages, TNF-α, p-p38, NF-κB, IL-10, HGF, TGF-β1 and VEGF were observed in the paraneoplastic tissue of the glucuronolactone+hydrocortisone group when compared with the control and glucuronolactone groups. CONCLUSION: The results suggest that hydrocortisone treatment reduces macrophage polarization, expression of inflammatory and anti-inflammatory cytokines, and angiogenesis in paraneoplastic tissue, and attenuates early HCC progression. Although hydrocortisone did not have attenuation effect on advanced solid tumor, the current study shows the potential benefits and supports potential clinical use of hydrocortisone in attenuating early progression of HCC, which is through suppressing paraneoplastic inflammation and angiogenesis.