Abstract
There is a pressing need for the development of novel approaches to treat and prevent hepatocellular carcinoma (HCC). The S100 calcium-binding protein S100A4 is associated with poor prognosis and metastasis in several human cancers. In addition, a role for S100A4 in modulating cancer-initiating cells stemness properties was recently proposed in head and neck and gastric cancers. Whether S100A4+ stromal cells contribute to tumor onset remains, however, an unanswered question. To address that question, we generated a new mouse model allowing for the depletion of S100A4+ cells in a mouse model of HCC with stemness properties, by crossing mice with hepatic deletion of phosphatase and tensin homolog (PTEN) with mice expressing viral thymidine kinase under the control of S100A4 promoter. Depletion of S100A4+ cells by ganciclovir injection did not prevent the development of HCC but reduced the stemness phenotype of the tumor as measured by the expression of progenitor cell, biliary cell and hepatocyte markers. The results were further confirmed by histology analysis showing reduction of cholangiolar tumor components and degree of oval cell hyperplasia in the adjacent liver. Depletion of S100A4+ cells had also some beneficial effect on the underlying liver disease with a reduction of NAS score, largely due to the reduction of inflammation. In conclusion, this study demonstrated that S100A4+ cells do not contribute to HCC onset but maintain the stemness phenotype of the tumor. This study also suggests for the first time a crosstalk between inflammation and stemness.
Highlights
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide.[1]
These results suggest that S100 calcium-binding protein A4 (S100A4) expression correlates with stemness properties in HCC
Generation of Pten-S100A4 double transgenic mice To assess the role of S100A4+ cells in the development of liver cancer, we generated Pten-S100A4 double transgenic mice that were derived from crossing S100A4-tk mice with liver-specific Pten − / − mice
Summary
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide.[1] the highest rates of liver cancer are found in certain areas of Asia and Africa, liver cancer incidence and mortality rates are increasing strikingly in western countries, including the United States.[2,3] Liver cirrhosis due to hepatitis B virus, hepatitis C virus, high alcohol consumption or non-alcoholic steatohepatitis is the main risk factor associated with HCC and most patients with HCC have compromised liver function, limiting treatment options.[4] Survival rates are low, remaining at 15% at. There is a pressing need for the development of novel approaches to treat and prevent HCC.[5]. A role in metastasis and epithelial-mesenchymal transition for S100A4 was proposed in HCC16–19 as well as in cholangiocarcinoma.[20,21,22] S100A4 induced liver fibrosis and activation of hepatic stellate cells, suggesting that S100A4 could be a marker for liver fibrogenesis and a target for novel antifibrotic strategies.[23,24]
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