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.

Yunching Chen,Lotte Hiddingh,Sylvie Roberge,Yuhui Huang,Rekha Samuel,Andrew X Zhu,Gregory Y Lauwers,Annique M Duyverman,Christina Koppel,Dan G Duda,Peigen Huang,Thomas Reiberger,Rakesh K Jain

doi:10.1002/hep.26790

Abstract

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

Highlights

Hepatocellular carcinoma (HCC) almost exclusively arises in cirrhotic livers, and the preexisting chronic inflammation and fibrosis fuel hepatocarcinogenesis and HCC growth [1,2,3]
Fibrosis is the consequence of hepatic stellate cell (HSC) activation and proliferation, and myofibroblast differentiation leading to increased collagen deposition [4]
The tyrosine kinase inhibitor (TKI) sorafenib has emerged as the first systemic therapy for HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) almost exclusively arises in cirrhotic livers, and the preexisting chronic inflammation and fibrosis fuel hepatocarcinogenesis and HCC growth [1,2,3]. Fibrosis is the consequence of hepatic stellate cell (HSC) activation and proliferation, and myofibroblast differentiation leading to increased collagen deposition [4]. This dual pathology of the liver contributes to an aggressive and systemic treatment-refractory characteristic in HCCs [1]. Sorafenib is an antiangiogenic drug that has a broad tyrosine kinase inhibition spectrum [5] Despite this progress, the mortality rate from HCC remains high, making this disease the third leading cause of cancer-related death worldwide [6,7,8,9,10]

Results

Discussion

Conclusion