Over the past several decades, obesity has become more prevalent in most developed countries, and is increasingly recognized as a major risk factor for several common types of cancers. Although several events are proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Recently, we found that cellular senescence and senescence-associated secretory phenotype (SASP) have crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Therefore, we are currently focusing on the role and mechanisms of SASP in cancer development in an obesity-associated HCC mouse model in vivo. We found that myofibroblasts in the tumor microenvironment of obesity-associated liver cancer showed tumor-promoting SASP. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut microbial metabolite known to cause DNA damage. The enterohepatic circulation of DCA produces the SASP phenotype in hepatic stellate cells (HSCs), which in turn secrete various inflammatory and tumor-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogens. Notably, blocking DCA production or reducing gut microbiota efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has a key role in obesity-associated HCC development. Moreover, signs of SASP were also observed in HSCs from HCC patients with non-alcoholic steatohepatitis (NASH), indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. We are continuing to conduct clinical studies on the relationship between gut microbial metabolites and human obesity-associated HCC.
We have been studying how cellular senescence, an irreversible arrest of cell proliferation is provoked by oncogenic impulses that cause DNA damage. Cellular senescence is thought to be a fail-safe mechanism preventing the proliferation of abnormal cells that might transform into cancer cells. Unlike apoptotic cells, senescent cells do not die immediately, and survive for a long time. Recently, it has been shown that senescent cells have the potential to secrete inflammatory cytokines, chemokines, matrix remodeling factors and growth factors. This phenotype of cellular senescence is called senescence-associated secretory phenotype (SASP) and is sometimes beneficial or deleterious depending on the biological context. We focus on the role of SASP in vivo.
As mentioned, senescent cells secrete inflammatory cytokines, chemokines, matrix remodeling factors and growth factors called SASP factors. However, the precise mechanisms of how a variety of SASP factors concurrently upregulate senescent cells are still unknown. We are currently conducting research to elucidate these mechanisms.