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.

Abstract

UNLABELLED:

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.

• Authors: Yunching Chen, Yuhui Huang, Thomas Reiberger, Annique M Duyverman, Peigen Huang, Rekha Samuel, Lotte Hiddingh, Sylvie Roberge, Christina Koppel, Gregory Y Lauwers, Andrew X Zhu, Rakesh K Jain, Dan G Duda
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 59 Issue 4 Pg. 1435-47 (Apr 2014) ISSN: 1527-3350 [Electronic] United States
• PMID: 24242874 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Association for the Study of Liver Diseases.

Chemical References

• 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

Topics

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