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.
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.


CONCLUSIONS
Blocking SDF-1α/CXCR4 or Gr-1(+) myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.
Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Boston, MA.
Yunching
Y
Chen
Yuhui
Y
Huang
Thomas
T
Reiberger
Annique M
AM
Duyverman
Peigen
P
Huang
Rekha
R
Samuel
Lotte
L
Hiddingh
Sylvie
S
Roberge
Christina
C
Koppel
Gregory Y
GY
Lauwers
Andrew X
AX
Zhu
Rakesh K
RK
Jain
Dan G
DG
Duda
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology; D000077157:Sorafenib
D039481:CD11b Antigen; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C503133:Gr-1 protein, mouse; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; C082332:macrophage stimulating protein; D009536:Niacinamide; D017228:Hepatocyte Growth Factor; D000077157:Sorafenib; D002251:Carbon Tetrachloride; D017479:Receptors, Platelet-Derived Growth Factor