背景:长期抗血管生成导致血管修剪,致密沉积的细胞外基质(ECM),并因此减少了食管胃癌(EGC)的化疗递送。为了解决这个问题,我们评估了在化疗和抗血管生成药物方案中加入透明质酸酶或NO供体的疗效.
方法:建立了患者来源的EGC异种移植模型。将移植的小鼠随机分配到四个实验组和一个对照组。实验组接受小鼠血管生成抑制剂DC101,和nab-紫杉醇(NPTX),添加透明质酸酶(PEGPH20),或NO供体(硝化甘油,NTG),或它们的组合,分别。我们比较了17天治疗期间的肿瘤生长。我们对ECM成分透明质酸(HA)和胶原蛋白进行了免疫组织化学,CD31为内皮细胞,和γH2AX用于DNA损伤。对阳性染色区域进行定量,使用QuPath软件测量血管直径。
结果:延长DC101处理诱导HA(p<0.01)和胶原(p<0.01)的沉积。HA被PEGPH20有效降解(p<0.001),但不是预期的NTG。PEGPH20(p<0.05)和NTG(p<0.01)扩张的血管都响应于长期DC101治疗而塌陷。然而,发现仅PEGPH20(而不是NTG)与NPTX和DC101组合显著抑制肿瘤生长(p<0.05)。
结论:这些发现表明,HA的机械屏障是导致EGC中长期抗血管生成过程中产生耐药性的主要原因。将PEGPH20纳入现有治疗方案有望改善EGC患者的预后。
BACKGROUND: Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a
hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs.
METHODS: A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of
hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software.
RESULTS: Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101.
CONCLUSIONS: These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.