Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice

Hepatology. 2014 Apr;59(4):1435-47. doi: 10.1002/hep.26790. Epub 2014 Feb 18.


Sorafenib--a broad kinase inhibitor--is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia--and its consequences on treatment resistance--remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen-positive (Gr-1(+)) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway. This is consistent with the association between SDF-1α expression with fibrotic septa in cirrhotic liver tissues as well as with desmoplastic regions of human HCC samples. We demonstrate that after treatment with sorafenib, SDF-1α increased the survival of HSCs and their alpha-smooth muscle actin and collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1(+) myeloid cells mediate HSC differentiation and activation in a paracrine manner. CXCR4 inhibition, using AMD3100 in combination with sorafenib treatment, prevents the increase in tumor fibrosis--despite persistently elevated hypoxia--in part by reducing Gr-1(+) myeloid cell infiltration and inhibits HCC growth. Similarly, antibody blockade of Gr-1 reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment.

Conclusion: Blocking SDF-1α/CXCR4 or Gr-1(+) myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11b Antigen / metabolism*
  • Carbon Tetrachloride / adverse effects
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Chemokine CXCL12 / metabolism*
  • Disease Models, Animal
  • Hepatocyte Growth Factor / deficiency
  • Hepatocyte Growth Factor / genetics
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Receptors, CXCR4 / metabolism*
  • Receptors, Chemokine / metabolism*
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Receptors, Platelet-Derived Growth Factor / drug effects
  • Signal Transduction / physiology
  • Sorafenib


  • CD11b Antigen
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Gr-1 protein, mouse
  • Phenylurea Compounds
  • Proto-Oncogene Proteins
  • Receptors, CXCR4
  • Receptors, Chemokine
  • macrophage stimulating protein
  • Niacinamide
  • Hepatocyte Growth Factor
  • Sorafenib
  • Carbon Tetrachloride
  • Receptors, Platelet-Derived Growth Factor