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.
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.
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DOI：
10.1002/hep.26790
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发表时间：
2014-04
期刊：
影响因子：
13.5
通讯作者：
Duda, Dan G.
中科院分区：
文献类型：
--
作者：
Chen, Yunching;Huang, Yuhui;Reiberger, Thomas;Duyverman, Annique M.;Huang, Peigen;Samuel, Rekha;Hiddingh, Lotte;Roberge, Sylvie;Koppel, Christina;Lauwers, Gregory Y.;Zhu, Andrew X.;Jain, Rakesh K.;Duda, Dan G.
索拉非尼是一种广泛的激酶激活剂，是晚期肝细胞癌（HCC）的标准治疗药物，并已被证明在肝硬化（HCC的前体）中发挥抗纤维化作用。然而，索拉非尼对肿瘤结缔组织增生的作用及其对治疗耐药性的影响仍然未知。我们证明索拉非尼对小鼠原位肝癌模型中的肿瘤纤维化与肝纤维化具有不同的作用。索拉非尼可加剧肿瘤缺氧，从而增加肿瘤和基质细胞中基质衍生因子1α（SDF 1 α）的表达，随后增加Gr-1+髓样细胞浸润。SDF 1 α/CXCR 4通路通过MAP激酶通路直接促进肝星状细胞（HSC）的分化和活化。这与SDF 1 α表达与肝硬化组织中纤维化间隔以及人HCC样本中促纤维增生区域之间的相关性一致。我们证明，索拉非尼治疗后，SDF 1 α增加了HSC的存活率及其α-SMA和胶原蛋白I的表达，从而增加了肿瘤纤维化。最后，我们表明，Gr-1+髓样细胞介导的HSC分化/活化的旁分泌方式。使用AMD 3100联合索拉非尼治疗的CXCR 4抑制可部分通过减少Gr-1+髓样细胞浸润来防止肿瘤纤维化的增加（尽管持续缺氧），并抑制HCC生长。类似地，当与索拉非尼治疗组合时，Gr-1的抗体阻断减少肿瘤纤维化并抑制HCC生长。阻断SDF 1 α/CXCR 4或Gr-1+髓样细胞浸润可减少缺氧介导的HCC纤维组织增生，并增加索拉非尼治疗的疗效。
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. Blocking SDF1α/CXCR4 or Gr-1+ myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.
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影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
25.7
作者：
Kim, Seung Up;Oh, Hyun Jung;Park, Young Nyun
通讯作者：
Park, Young Nyun
索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen