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

Sorafenib—a broad kinase inhibitor—is a standard therapy for advanced hepatocellular carcinoma (HCC), and has been shown to exert anti-fibrotic 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 1α (SDF1α) expression in cancer and stromal cells, and subsequently Gr-1+ myeloid cell infiltration. The SDF1α/CXCR4 pathway directly promotes hepatic stellate cell (HSC) differentiation and activation via MAP kinase pathway. This is consistent with the association between SDF1α 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, SDF1α increased the survival of HSCs and their α-SMA and Collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1+ myeloid cells mediate HSC differentiation/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 inhibited HCC growth when combined with sorafenib treatment. Conclusion Blocking SDF1α/CXCR4 or Gr-1+ myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.

Targeting immunosuppression after standard sorafenib treatment to facilitate immune checkpoint blockade in hepatocellular carcinoma – an auto-commentary on clinical potential and future development

“…5 Unfortunately, all Phase III trials of more potent or specific antiangiogenic agents conducted so far have failed. Our data indicate that increased intratumoral hypoxia after sorafenib treatment fuels resistance to treatment by promoting fibrosis and immunosuppression in HCC, 2,3 in line with findings on the role of hypoxia in other cancers. [6][7][8][9] This also raises the concern that the efficacy of immunotherapies against HCC could be hampered by antiangiogenic treatment.…”

Hepatocellular Carcinoma: A Phase II Randomized Controlled Double-Blind Trial of Transarterial Chemoembolization in Combination with Biweekly Intravenous Administration of Bevacizumab or a Placebo

“…There were fewer TACE to immune function and inflammation (31). Experimental data indicate that hypoxia can result in increased infiltration of inflammatory cells in patients with HCC that are not essentially functional but rather lead to resistance and desmoplasia (32). Inflammation leads to stabilization of hypoxia-inducible factor-1a and upregulates hypoxia-inducible factor target genes, including VEGF (33), to counterbalance the increased oxygen and adenosine triphosphate consumption of the inflamed tissue the cTACE-B group was shorter than that in the cTACE-C group in patients with Child-Pugh class A disease but not in those with Child-Pugh B disease.…”

CXCR4 Ligands: The Next Big Hit?

“…The stromal cell-derived factor 1a/CXCR4 pathway mediated stroma polarization toward an immunosuppressive microenvironment and contributed to systemic disease progression after antiangiogenic treatment in a hepatocellular mouse model (65). AMD3100 prevented this immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival (66).…”