by ecancer reporter Janet Fricker

The senescence-associated secretory phenotype (SASP) plays a crucial role in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice, finds a study published in Nature.

Although obesity is well known as a major risk factor for several common types of cancer, the exact mechanisms whereby it promotes tumours have been unclear.

In the study Eiji Hara and colleagues, from The Japanese Foundation for Cancer Research, Koto-Ku, Tokyo, explored how obesity enhances the development of tumours in mouse models of HCC.

Dietary or genetic obesity, they found, induces alterations in gut micro bacteria, increasing levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause damage to DNA.

The team went on to show that enterohepatic circulation of DCA provokes SASP in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver. Following exposure to chemical carcinogens it is these inflammatory and tumour promoting factors that facilitate HCC development in mice.

The team showed that blocking DCA production or reducing gut bacteria in obese mice both prevented HCC development.

Furthermore similar results were observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA–SASP axis in HSCs plays a key role in the development of obesity-associated HCC.

“A greater understanding of the molecular mechanisms linking gut microbial metabolite to SASP will therefore provide valuable new insights into how to bypass this undesirable side effect of cellular senescence,” write the authors.

Reference

S Yoshimoto, T Mun Loo, K Atarashi, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.  Nature doi:10.1038/nature12347