Project Summary (2011-2017)

A team of researchers led by Michael Karin, Ph.D., are studying how Superfund toxicants and mixtures increase liver cancer risk. Their efforts are focused on specific progenitor cells responsible for generation of hepatocellular carcinoma (HCC), the most common form of liver cancer, in mice administered diethylnitrosamine (DEN), an hepatocarcinogen that represents the nitrosamine class of Superfund substances. DEN and its relative DMN undergo metabolic activation in the liver and give rise to HCC through induction of genetic alterations and compensatory proliferation that is triggered by hepatocyte cell death. They are characterizing HCC initiating cells (HIC) isolated from livers of DEN-treated mice before tumors are detectable and using them to identify marker genes and genetic and epigenetic alterations that distinguish HIC from normal, non-tumorigenic, hepatocytes and fully transformed HCC cells. They are determining whether the same gene set is activated in HIC from mutant mice that spontaneously develop HCC and investigate whether signaling pathways, whose ablation augments HCC development, affect the appearance, growth and progression of HIC. The researchers are also examining whether obesity, which increases HCC risk in humans and acts as a tumor promoter in mice, accelerates the appearance and growth of HIC and affects expression of HIC signature genes. Similar experiments are being conducted with Superfund substances that act as liver tumor promoters, such as carbon tetrachloride, polychlorinated biphenyls (PCBs) and the nuclear receptor CAR, which mediates their biological effects. The researchers will examine whether such chemicals, alone or in combination with DEN, affect HIC formation and growth. These studies are resulting in the identification of genetic, epigenetic and cellular programs responsible for induction and development of HCC. This knowledge and information serves as the foundation for a new approach to rapid assessment of the hepatocarcinogenicity of diverse substances and mixtures found at Superfund sites. Also, the research team works with the Research Translation Core and Community Engagement Core to share their findings pertinent to tumor promotion and obesity. High levels of obesity are a problem in Tribal and low income border communities (the vulnerable populations targeted by the UCSD SRP). These vulnerable communities may face greater risks to their health when obesity is coupled with exposure to Superfund toxicants, a point where the researchers can help the RTC and CEC communicate to broader audiences.