{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:13:43Z","timestamp":1792653223423,"version":"4.5.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":518,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01-CA080124"],"award-info":[{"award-number":["P01-CA080124"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Sorafenib\u2014a broad kinase inhibitor\u2014is 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\u2014and its consequences on treatment resistance\u2014remain 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-1\u03b1) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen\u2013positive (Gr-1\n                      <jats:sup>+<\/jats:sup>\n                      ) myeloid cell infiltration. The SDF-1\u03b1\/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-1\u03b1 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-1\u03b1 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\n                      <jats:sup>+<\/jats:sup>\n                      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\u2014despite persistently elevated hypoxia\u2014in part by reducing Gr-1\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                      <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                      : Blocking SDF-1\u03b1\/CXCR4 or Gr-1\n                      <jats:sup>+<\/jats:sup>\n                      myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment. (HEPATOLOGY 2014;59:1435-1447)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.26790","type":"journal-article","created":{"date-parts":[[2013,11,14]],"date-time":"2013-11-14T22:07:36Z","timestamp":1384466856000},"page":"1435-1447","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":194,"title":["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\u2013positive myeloid cell infiltration in mice"],"prefix":"10.1097","volume":"59","author":[{"given":"Yunching","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Reiberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annique 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