Development of a unique pre-tumor microenvironment in hepatocarcinogenesis: key factors and metformin prevention

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Liver cancer is the fifth most common and the fourth most deadly cancer worldwide, and it is one of the few types of cancer for which the incidence and death rate are rising in the United States. The most common type of liver cancer is hepatocellular carcinoma (HCC), patients with early-stage HCC were often symptomless and there is no reliable biomarker available for patient screening and diagnosing at this stage. As a result, most patients with HCC being diagnosed at time were in advanced stages and not amenable to curative resection or liver transplantation. Moreover, efficacious molecule-targeting therapies and systemic chemotherapies for advanced HCC are very limited, where the two molecule-targeting therapies available for the patients only prolong survival for less than 3 months. In fact, the 5-year survival rate for HCC is still below 19% in the US. Thus, understanding the key events in the early development of HCC to help with the prevention and early detection of this disease has been one of our focuses here in Dr. Hua Xiao’s laboratory at Michigan State University.

Our laboratory reported that genetically-engineered Ncoa5 heterozygous deletion mouse exhibits glucose intolerance, chronic hepatic inflammation and a high incidence of HCC in a male-gender dependent manner. Ncoa5+/- male mouse mimics many characteristics of human non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, which are believed as the major risk factors for HCC in developed countries. Thus, we proposed that Ncoa5+/- male mouse is a unique model for both investigating molecular basis of HCC and addressing a provocative question of why metformin, a drug for patients with type 2 diabetes, might reduce the incidence of HCC. Utilizing this mouse model, in the article entitled “NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21WAF1/CIP1 overexpression, which is reversed by metformin”, we identified a pre-tumor microenvironment (pre-TME) in livers of Ncoa5+/- male mice, featuring increased proinflammatory cytokines and p21WAF1/CIP1 expression, increased intrahepatic infiltrations of macrophages and activated CD8 T cells, and myeloid derived suppressor cells. Through analyzing two TCGA datasets collected from HCC adjacent livers from human patients, we found that the pre-TME in the liver of Ncoa5+/- male mice is very likely to present in about 1/3 of HCC patients, and such patients had significantly worse survival. This is interesting because our findings raise the possibility to use non-cancerous liver tissue to predict the recurrence and prognosis of human HCC. Moreover, we were able to alleviate the pre-TME by heterozygously deleting the p21WAF1/CIP1 gene in Ncoa5+/- mice, indicating an essential role of p21WAF1/CIP1 in the formation of the pre-TME.  Thus, we propose that p21WAF1/CIP1 may drive oncogenesis through promoting the development of pre-TME and tumor microenvironment (TME). 

To investigate how we can correct this pre-TME and prevent HCC, we treated a cohort of Ncoa5+/+ and Ncoa5+/- mice with or without prophylactic metformin, a safe medication that is widely used to treat patients with type 2 diabetes. Noteworthy, to assess the possibility of developing a long-term protection by metformin even after treatment termination, metformin was given in drinking water to treated mice for a period of time and then withdrawn. We found that prophylactic metformin treatment reversed the pre-TME including the crucial p21WAF1/CIP1 overexpression and subsequently reduced HCC incidence in Ncoa5+/- mice. Thus, we have identified a safe medication that may be used to prevent HCC, given the minimal side-effect of metformin. Also, we showed the preventing function of metformin in transcriptome level and generated a Metformin Reversal Score, which can be used to stratify patients and identify who can benefit the most from metformin treatment. Together, our findings highlight the importance of targeting the precancerous microenvironment for the prevention and treatment of HCC, and suggest p21WAF1/CIP1 as a potential target for chemopreventive and therapeutic strategies against HCC development. 

By: Yueqi Zhang and Hua Xiao

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Yueqi Zhang

Graduate student, Michigan State University

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