Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Their 623, Boston, MA, 02114, USA.
Department of Surgery, Marien Hospital Herne, University Hospital of Ruhr University Bochum, Hölkeskampring 40, 44625, Herne, Germany.
Angiogenesis. 2020 Aug;23(3):479-492. doi: 10.1007/s10456-020-09725-x. Epub 2020 May 22.
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.
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.
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.
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.
在胰腺导管腺癌 (PDAC) 中抑制 Hedgehog (Hh) 信号通路可减少细胞外基质并促进血管生成增加。与这些发现相反，Hh 配体 Sonic Hedgehog (SHH) 在非肿瘤模型中是一种强有力的促血管生成因子。本研究旨在确定 SHH 影响肿瘤基质和血管生成的分子机制。
用针对 SHH 的中和抗体处理携带三种不同异种移植人 PDAC 的小鼠（每组 n = 5）。治疗 7 天后，评估肿瘤并评估肿瘤细胞及其基质中 38 种促血管生成和抗血管生成因子的表达。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和抗血管生成因子的调节作用及其对内皮细胞的影响。
抑制 SHH 影响肿瘤生长、基质含量和血管生成。它对 Hh 信号通路的影响仅限于三种癌症的基质区室。SHH 通过减少基质细胞中抗血管生成 THBS2 和 TIMP2 间接刺激血管生成。SHH 对内皮细胞的额外直接作用取决于 VEGF 的存在。
抑制 Hh 信号通路可降低肿瘤血管生成，表明 Hh 在维持或形成肿瘤血管方面发挥作用。上皮细胞中观察到的肿瘤生长和活力的减少是 Hh 途径抑制的直接后果，还是其对基质和血管生成的间接影响所致，仍有待评估。
