Department of Medicine 1, FAU Erlangen-Nürnberg, Erlangen, Germany.
Fritz Lipmann Institute, Leibniz Institute for Age Research, Jena, Germany.
Gastroenterology. 2015 Jul;149(1):177-189.e10. doi: 10.1053/j.gastro.2015.03.016. Epub 2015 Mar 19.
BACKGROUND & AIMS: Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC).
CAC was induced in VEGFR2(ΔIEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate. Tumor development and inflammation were determined by endoscopy. Colorectal tissues were collected for immunoblot, immunohistochemical, and quantitative polymerase chain reaction analyses. Findings from mouse tissues were confirmed in human HCT116 colorectal cancer cells. We analyzed colorectal tumor samples from patients before and after treatment with bevacizumab.
After colitis induction, VEGFR2(ΔIEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(ΔIEC) mice were in senescence than tumor cells from control mice. We found VEGFR2 to activate phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, resulting in inactivation of p21 in HCT116 cells. Inhibitors of VEGFR2 and AKT induced senescence in HCT116 cells. Tumor cell senescence promoted an anti-tumor immune response by CD8(+) T cells in mice. Patients whose tumor samples showed an increase in the proportion of senescent cells after treatment with bevacizumab had longer progression-free survival than patients in which the proportion of senescent tumor cells did not change before and after treatment.
Inhibition of VEGFR2 signaling leads to senescence of human and mouse colorectal cancer cells. VEGFR2 interacts with phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT to inactivate p21. Colorectal tumor senescence and p21 level correlate with patient survival during treatment with bevacizumab.
衰老可阻止细胞转化。我们研究了血管内皮生长因子（VEGF）通过其受体 VEGFR2 信号传导是否调节结肠炎相关癌症（CAC）小鼠中肿瘤细胞的衰老和增殖。
通过给予氧化偶氮甲烷（azoxymethane）随后给予葡聚糖硫酸钠（dextran sodium sulfate），在缺乏肠道上皮细胞中 VEGFR2 表达的 VEGFR2（ΔIEC）小鼠和 VEGFR2（fl/fl）对照小鼠中诱导 CAC。通过内窥镜检查确定肿瘤发生和炎症情况。收集结直肠组织进行免疫印迹、免疫组织化学和定量聚合酶链反应分析。在人类 HCT116 结直肠癌细胞中证实了小鼠组织的发现。我们分析了接受贝伐单抗治疗前后患者的结直肠肿瘤样本。
在结肠炎诱导后，VEGFR2（ΔIEC）小鼠比对照小鼠形成的肿瘤明显更少。VEGFR2（ΔIEC）小鼠的肠肿瘤细胞中衰老细胞的数量比对照小鼠中的肿瘤细胞多。我们发现 VEGFR2 可激活磷脂酰肌醇-4,5-二磷酸-3-激酶和 AKT，导致 HCT116 细胞中 p21失活。VEGFR2 和 AKT 的抑制剂可诱导 HCT116 细胞衰老。肿瘤细胞衰老通过 CD8（+）T 细胞在小鼠中促进抗肿瘤免疫反应。与治疗前相比，贝伐单抗治疗后肿瘤样本中衰老细胞比例增加的患者的无进展生存期比治疗前后衰老肿瘤细胞比例未发生变化的患者更长。
抑制 VEGFR2 信号传导可导致人类和小鼠结直肠癌细胞衰老。VEGFR2 与磷脂酰肌醇-4,5-二磷酸-3-激酶和 AKT 相互作用，使 p21失活。结直肠肿瘤衰老和 p21 水平与贝伐单抗治疗期间患者的生存相关。
