Treatment with the steroid dexamethasone reduces the formation of liver tumours in a mouse model of hepatocellular carcinoma (HCC), according to new research. Crucially, dexamethasone restored gluconeogenesis in malignant hepatocytes, which indicates that targeting altered metabolism in liver cancer could prove useful as a therapeutic strategy for HCC.

Glucocorticoids such as dexamethasone are widely used in clinical practice as anti-inflammatory agents and can also be given to patients with cancer to counteract some of the adverse effects of chemotherapy (for example, anorexia and nausea). Increased glycolysis is a key feature of cancers to support tumour growth, and the study authors reasoned that altering cancer metabolism might be an alternative therapeutic strategy, especially in liver cancer, given the fundamental role of hepatocytes in metabolism.

...glucose metabolism was altered in ... malignant hepatocytes...

In their study published in Nature Communications, Bo Huang and colleagues first demonstrated that glucose metabolism was altered in mouse and human malignant hepatocytes. Importantly, altered expression of two important enzymes that regulate endogenous glucocorticoids and gluconeogenesis were observed in malignant hepatocytes; expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was downregulated, whilst 11β-HSD2 was upregulated in tumour cells from mice and humans.

Interestingly, this 11β-HSD1:11β-HSD2 expression ratio was linked with prognosis and survival in patients with HCC, with the authors noting its potential as a prognostic marker. Individuals with a high 11β-HSD1:11β-HSD2 ratio had markedly increased survival time and reduced rates of relapse compared with those patients with a low ratio.

Finally, in mouse models of HCC, treatment with dexamethasone (an active synthetic glucocorticoid) effectively restored glucose metabolism and inhibited growth of liver tumours. Notably, withdrawal of dexamethasone resulted in rebound tumour growth in the livers of the mice, and treatment with another steroid (prednisone, an inactive glucocorticoid) did not have an antitumour effect.

“This study just discloses the tip of the iceberg in liver cancer metabolism,” says Huang who plans further research to understand the metabolism of cancer and cancer stem cells in a bid to develop new diagnostic and therapeutic strategies for HCC.