Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer
Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer
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DOI：
10.1007/s10456-020-09725-x
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发表时间：
2020-05-22
期刊：
影响因子：
9.8
通讯作者：
Liss, Andrew S.
中科院分区：
文献类型：
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作者：
Bausch, Dirk;Fritz, Stefan;Liss, Andrew S.
前言：胰腺导管腺癌(PDAC)中Hedgehog(HH)信号的抑制减少了促结缔组织增生，促进了血管的增加。与这些发现相反，HH配体Sonic Hedgehog(SHH)在非肿瘤模型中是一种有效的促血管生成因子。本研究的目的是确定SHH影响肿瘤间质和血管生成的分子机制。方法用SHH中和抗体治疗3种不同类型的人PDAC移植小鼠(n=5/组)。治疗7d后，对肿瘤进行评估，并检测38种促血管生成因子和抗血管生成因子在肿瘤细胞及其间质中的表达。然后在体外模型系统中进一步评估SHH对成纤维细胞中促血管生成因子和抗血管生成因子的调节作用及其对内皮细胞的影响。结果抑制SHH对肿瘤生长、间质含量和血管生成均有影响。它对HH信号通路的影响仅限于三种癌的间质间质。Shh通过减少基质细胞中抗血管生成的THBS2和TIMP2，间接促进血管生成。SHH对血管内皮细胞的另一个直接作用依赖于血管内皮生长因子的存在。结论抑制HH信号通路可减少肿瘤血管生成，提示HH在维持或形成肿瘤血管中起重要作用。上皮细胞中肿瘤生长和活性的降低是HH途径抑制的直接结果，还是由其对间质和血管系统的影响间接引起的，仍有待评估。
Introduction The inhibition of Hedgehog (Hh) signaling in pancreatic ductal adenocarcinoma (PDAC) reduces desmoplasia and promotes increased vascularity. In contrast to these findings, the Hh ligand Sonic Hedgehog (SHH) is a potent proangiogenic factor in non-tumor models. The aim of this study was to determine the molecular mechanisms by which SHH affects the tumor stroma and angiogenesis. Methods Mice bearing three different xenografted human PDAC (n = 5/group) were treated with neutralizing antibodies to SHH. After treatment for 7 days, tumors were evaluated and the expression of 38 pro- and antiangiogenic factors was assessed in the tumor cells and their stroma. The effect of SHH on the regulation of pro- and antiangiogenic factors in fibroblasts and its impact on endothelial cells was then further assessed in in vitro model systems. Results Inhibition of SHH affected tumor growth, stromal content, and vascularity. Its effect on the Hh signaling pathway was restricted to the stromal compartment of the three cancers. SHH-stimulated angiogenesis indirectly through the reduction of antiangiogenic THBS2 and TIMP2 in stromal cells. An additional direct effect of SHH on endothelial cells depended on the presence of VEGF. Conclusion Inhibition of Hh signaling reduces tumor vascularity, suggesting that Hh plays a role in the maintenance or formation of the tumor vasculature. Whether the reduction in tumor growth and viability seen in the epithelium is a direct consequence of Hh pathway inhibition, or indirectly caused by its effect on the stroma and vasculature, remains to be evaluated.