Work

Depletion of S100A4+ stromal cells does not prevent HCC development but reduces the stem cell-like phenotype of the tumors

Year: 2018

Type: article

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. Targeting a protein that promotes cancer cell self-renewal could be a promising strategy for the treatment of liver cancer. The expression of S100 calcium-binding protein A4 (S100A4) in tumor tissues has been associated with poor prognosis in several human cancers. To determine the contribution of S100A4 to the development of liver cancer, Laura Beretta and colleagues at the University of Texas, USA, generated a mouse model of the disease in which the expression of the S100A4 gene could be turned off in otherwise healthy connective tissue cells. Although S100A4 depletion had no effect on cancer onset, it reduced the cancer cells' ability to proliferate and self-renew compared with controls. A decrease in inflammation was also observed, suggesting an interplay between inflammation and cancer cell self-renewal that may be key for developing more successful therapies.

Source: Experimental & Molecular Medicine

DOI: 10.1038/emm.2017.175