A hormone secreted by fat cells can curb the growth of liver tumors in mice, according to a new study from the Institute of Life Sciences of the University of Michigan.
Results offer proof of concept for the development of therapies for hepatocellular carcinoma, the most common form of liver cancer .
Jiandie Lin and her team are using mice as a model to study how molecular and cellular changes are affected by non-alcoholic fatty liver disease, and how these changes consequently lead to the progression of this disease. Although it begins with a relatively mild buildup of fat in the liver, the condition can progress to non-alcoholic steatohepatitis, or NASH, which increases the risk of most liver cancers.
The liver contains dozens of different cell types, including various immune cells. Using single-cell RNA sequencing, a technology to probe the gene expression of individual cells in complex tissues, Lin and his team previously constructed a liver cell atlas and intercellular signaling technique in healthy mouse livers. and NASH.
For this latest study, which is scheduled for publication on 15 August in Cell Metabolic process, the scientists wanted to identify specific molecular changes in the NASH state that disrupt the balance and interactions of these cell types, as potential therapeutic targets to reverse the progression of NASH to cancer.
“The most cancers of the liver in NASH patients are different from cancers caused by viral hepatitis, in that they often develop in the absence of cirrhosis of the liver,” said Lin, a member of the faculty of UM Everyday living Sciences Institute e t lead author of the study. “We suspect that different disease mechanisms may be involved in NASH-related liver cancers.”
Lin and colleagues observed changes in two styles of immune cells in particular that appear to contribute to the development of HCC. In the livers of mice with NASH, T cells – immune cells that normally fight off infected or damaged cells, such as cancer cells – showed features of functional deficiencies. At the same time, the team discovered that a second type of immune cell, called macrophages, acquired molecular characteristics commonly associated with cancers.
“These changes we observed in macrophages and T cells resemble the tumor microenvironment, but they occur even before a cancer becomes evident,” Lin said. , who is also a professor of cell and developmental biology at the UM Professional Medical School. “This gives us a clue that perhaps these changes in the liver microenvironment could provide fertile ground for the emergence and growth of liver cancer cells. It almost seems that the liver, once it develops NASH, is already preparing for cancer cells to grow.”
The team also identified a hormone which serves as a control outlet for disease progression and which appears to have potential treatment: neuregulin 4 or NRG4.
Lin’s team previously disclosed that NRG4 – a hormone secreted primarily by fat cells – may protect the livers of mice against NASH, and that a decrease or loss of this hormone leads to more severe levels of liver disease.
Now the team has found that the hormone can suppress hepatocellular carcinoma in NASH mice. Their findings show that mice lacking the NRG4 hormone develop more severe NASH and more liver tumors than mice with normal levels of NRG4.
When scientists increased levels of the hormone in mice – either by genetically elevating NRG4 expression in fatty tissue or by treating mice with a recombinant NRG4 fusion – increased levels of NRG4 suppressed the development of liver cancer NASH.
“Many liver cancer studies focus on cancerous liver cells themselves: how they proliferate and how they evade the immune system,” Lin said. “But our findings fall outside of this liver-centric framework, showing that a fat-derived hormone could actually reprogram the liver’s environment and have a very significant effect on the development of liver cancer.”
Further research is needed before NRG4 can be pursued as a therapeutic for hepatocellular carcinoma. Lin and his team now plan to study approaches to improve the hormone’s efficacy and better understand the nature underlying its regulation of macrophages and T cells in the liver.
The research was supported by funding from the National Institutes of Overall health and a pilot grant from the University of Michigan Rogel Cancer Heart.
In addition to Lin, study authors are: Peng Zhang, Zhimin Chen, Henry Kuang, Tongyu Liu, Jiaqiang Zhu, Linkang Zhou, Qiuyu Wang, Xuelian Xiong, Ziyi Meng, Xiaoxue Qiu, Ramiah Jacks, Lu Liu, Siming Li, Carey N Lumeng, Qing Li and Xiang Zhou from the University of Michigan.