Xu Lei, Duda Dan G, di Tomaso Emmanuelle, Ancukiewicz Marek, Chung Daniel C, Lauwers Gregory Y, Samuel Rekha, Shellito Paul, Czito Brian G, Lin Pei-Chun, Poleski Martin, Bentley Rex, Clark Jeffrey W, Willett Christopher G, Jain Rakesh K
Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Cancer Res. 2009 Oct 15;69(20):7905-10. doi: 10.1158/0008-5472.CAN-09-2099. Epub 2009 Oct 13.
Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.
临床研究一致观察到，在大多数癌症患者中，抗血管内皮生长因子（VEGF）治疗会使循环细胞因子升高。然而，这些分子的来源及其在肿瘤逃逸中的相关性仍不清楚。我们检测了直肠癌患者在接受抗VEGF抗体贝伐单抗单药治疗前及治疗12天后肿瘤活检中癌细胞和肿瘤相关巨噬细胞的基因表达谱。贝伐单抗上调了癌细胞中基质细胞衍生因子1α（SDF1α）、其受体CXCR4和CXCL6，并下调了PlGF、Ang1和Ang2。此外，贝伐单抗降低了肿瘤相关巨噬细胞中的Ang1并诱导了神经纤毛蛋白1（NRP1）的表达。贝伐单抗治疗期间较高的SDF1α血浆水平与三年时的远处转移显著相关。这些数据表明，VEGF阻断会上调炎症通路和NRP1，应将其作为改善抗VEGF治疗的潜在靶点进行评估。
