Exp Mol Med.  2018 Jan;50(1):e422. 10.1038/emm.2017.175.

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

Affiliations
  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lberetta@mdanderson.org
  • 2Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • 3Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.


MeSH Terms

Animals
Carcinoma, Hepatocellular
Ganciclovir
Head
Hepatocytes
Humans
Hyperplasia
Inflammation
Liver
Liver Diseases
Mice
Neck
Neoplasm Metastasis
Phenotype*
Prognosis
Stem Cells
Stomach Neoplasms
Stromal Cells*
Thymidine Kinase
Ganciclovir
Thymidine Kinase
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