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

Jingjing Jiao, Weibo Niu, Heather Stevenson, Mihai Gagea, H sugimoto, R kalluri, Laura Beretta

Research output: Contribution to journalArticle

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.
Original languageEnglish (US)
JournalExperimental and Molecular Medicine
StatePublished - 2018

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Stromal Cells
Stem cells
Tumors
Hepatocellular Carcinoma
Stem Cells
Phenotype
Liver
Neoplasms
Ganciclovir
Histology
Calcium-Binding Proteins
Thymidine Kinase
Crosstalk
Phosphoric Monoester Hydrolases
Inflammation
Head and Neck Neoplasms
Stomach Neoplasms
Hyperplasia
Liver Diseases
Hepatocytes

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Depletion of S100A4+ stromal cells does not prevent HCC development but reduces the stem cell-like phenotype of the tumors. / Jiao, Jingjing; Niu, Weibo; Stevenson, Heather; Gagea, Mihai; sugimoto, H; kalluri, R; Beretta, Laura.

In: Experimental and Molecular Medicine, 2018.

Research output: Contribution to journalArticle

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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.",
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AU - Jiao, Jingjing

AU - Niu, Weibo

AU - Stevenson, Heather

AU - Gagea, Mihai

AU - sugimoto, H

AU - kalluri, R

AU - Beretta, Laura

PY - 2018

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