Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Cancer Cell. 2014 Mar 17;25(3):350-65. doi: 10.1016/j.ccr.2014.02.005.
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.
肿瘤内皮细胞 (ECs) 在促进癌症进展方面的作用超出了它们作为支持代谢的管道的作用。然而，血管生态位衍生的旁分泌因子（定义为血管生成因子）如何引发肿瘤侵袭性尚不清楚。在这里，我们表明，B 细胞淋巴瘤细胞 (LCs) 通过激活 FGFR1 产生的成纤维细胞生长因子 4 (FGF4) 上调相邻 ECs 上的 Notch 配体 Jagged1 (Jag1)。反过来，Jag1 在 ECs 上的上调又诱导 LCs 中的 Notch2-Hey1。这种串扰强制形成侵袭性的 CD44(+)IGF1R(+)CSF1R(+)LC 表型，包括结外侵犯和化疗耐药性。在 Eμ-Myc 淋巴瘤模型中，诱导性 EC 选择性敲除 Fgfr1 或 Jag1，或在小鼠和人 LCs 中损害 Notch2 信号通路，可降低淋巴瘤侵袭性并延长小鼠存活时间。因此，靶向血管生成因子 FGF4-FGFR1/Jag1-Notch2 环可抑制 LC 的侵袭性并增强化疗敏感性。
