Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Roche Innovation Center Munich, Roche Pharma Research and Early Development, 82377 Penzberg, Germany.
Cell Rep. 2018 Mar 6;22(10):2530-2540. doi: 10.1016/j.celrep.2018.02.035.
Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs.
抗血管生成药物的耐药性限制了它们在癌症治疗中的应用。在这里，我们表明，在血管内皮生长因子 A（VEGFA）阻断的延长作用下，胰腺神经内分泌肿瘤（PNET）的新生血管形成和进展依赖于骨膜蛋白（POSTN），这是一种由基质细胞表达的细胞外基质蛋白。在 RIP1-Tag2 小鼠中，Postn 的基因缺失削弱了对延长 VEGFA 抑制的反应性 M2 样巨噬细胞和αSMA 基质细胞的肿瘤反弹，并抑制了治疗中的 PNET 新生血管形成和进展。POSTN 缺乏也阻碍了碱性成纤维细胞生长因子（FGF2）的上调，这是一种先前被认为参与 PNET 逃避抗血管生成治疗的适应性机制。在人类 PNET 中，较高的 POSTN 表达与 M2 样巨噬细胞标志物相关，并且在用集落刺激因子 1 受体（CSF1R）抗体耗尽巨噬细胞后，尽管继续产生 POSTN，但仍能抑制 VEGFA 阻断下的 PNET 新生血管形成和进展。这些发现表明 POSTN 在协调 PNET 对抗 VEGFA 治疗的耐药性方面发挥作用。
