Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Bio-TDR, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
Sci Rep. 2018 Oct 3;8(1):14724. doi: 10.1038/s41598-018-33037-2.
VEGF signaling through its tyrosine kinase receptor, VEGFR2 (FLK1), is critical for tumor angiogenesis. Previous studies have identified a critical gene dosage effect of VegfA in embryonic development and vessel homeostasis, neovascularization, and tumor growth, and potent inhibitors of VEGFR2 have been used to treat a variety of cancers. Inhibition of FGFR signaling has also been considered as an antiangiogenic approach to treat a variety of cancers. Inhibition of VEGFR2 with neutralizing antibodies or with pharmacological inhibitors of the VEGFR tyrosine kinase domain has at least short-term efficacy with some cancers; however, also affects vessel homeostasis, leading to adverse complications. We investigate gene dosage effects of Vegfr2, Fgfr1, and Fgfr2 in three independent mouse models of tumorigenesis: two-stage skin chemical carcinogenesis, and sub-cutaneous transplantation of B16F0 melanoma and Lewis Lung Carcinoma (LLC). Mice heterozygous for Vegfr2 display profound defects in supporting tumor growth and angiogenesis. Unexpectedly, additional deletion of endothelial Fgfr1 and Fgfr2 in Vegfr2 heterozygous mice shows similar tumor growth and angiogenesis as the Vegfr2 heterozygous mice. Notably, hematopoietic deletion of two alleles of Vegfr2 had minimal impact on tumor growth, with little effect on angiogenesis, reinforcing the importance of endothelial Vegfr2 heterozygosity. These studies reveal previously unrecognized Vegfr2 gene dosage effects in tumor angiogenesis and a lack of synergy between VEGFR2 and endothelial FGFR1/2 signaling during tumor growth.
VEGF 通过其酪氨酸激酶受体 VEGFR2（FLK1）进行信号转导，对于肿瘤血管生成至关重要。先前的研究已经确定了 VegfA 在胚胎发育和血管稳态、新血管生成和肿瘤生长中的关键基因剂量效应，并且已经使用了强效的 VEGFR2 抑制剂来治疗多种癌症。FGFR 信号的抑制也被认为是一种抗血管生成方法，用于治疗多种癌症。用中和抗体或 VEGFR 酪氨酸激酶结构域的药理学抑制剂抑制 VEGFR2 在一些癌症中至少具有短期疗效；然而，它也会影响血管稳态，导致不良反应。我们在三种独立的肿瘤发生小鼠模型中研究了 Vegfr2、Fgfr1 和 Fgfr2 的基因剂量效应：两阶段皮肤化学致癌作用，以及 B16F0 黑色素瘤和 Lewis 肺肿瘤（LLC）的皮下移植。Vegfr2 杂合子小鼠在支持肿瘤生长和血管生成方面存在严重缺陷。出乎意料的是，在 Vegfr2 杂合子小鼠中进一步缺失内皮细胞 Fgfr1 和 Fgfr2 显示出与 Vegfr2 杂合子小鼠相似的肿瘤生长和血管生成。值得注意的是，造血细胞中 Vegfr2 的两个等位基因缺失对肿瘤生长的影响极小，对血管生成的影响也很小，这强调了内皮细胞 Vegfr2 杂合性的重要性。这些研究揭示了肿瘤血管生成中以前未被认识到的 Vegfr2 基因剂量效应，以及 VEGFR2 和内皮 FGFR1/2 信号在肿瘤生长过程中缺乏协同作用。
