Targeting FGFR/PDGFR/VEGFR Impairs Tumor Growth, Angiogenesis, and Metastasis by Effects on Tumor Cells, Endothelial Cells, and Pericytes in Pancreatic Cancer
Targeting FGFR/PDGFR/VEGFR Impairs Tumor Growth, Angiogenesis, and Metastasis by Effects on Tumor Cells, Endothelial Cells, and Pericytes in Pancreatic Cancer
复制标题
DOI：
10.1158/1535-7163.mct-11-0312
复制
发表时间：
2011-11-01
影响因子：
5.7
通讯作者：
Lang, Sven A.
中科院分区：
文献类型：
--
作者：
Taeger, Johannes;Moser, Christian;Lang, Sven A.
成纤维细胞生长因子受体(FGFR)、血小板衍生生长因子受体(PDGFR)和血管内皮生长因子受体(VEGFR)等受体酪氨酸激酶的激活与胰腺癌的进展和转移密切相关。在这项研究中，我们研究了FGFR、PDGFR和VEGFR的酪氨酸激酶抑制剂TKI258对胰腺癌细胞系(HPAF-II、BxPC-3、MiaPaCa2和L3.6pl)、内皮细胞和血管平滑肌细胞(VSMC)的影响。结果表明，TKI258治疗削弱了胰腺癌细胞、内皮细胞和VSMCs的信号中间产物的激活，即使在成纤维细胞生长因子-1、成纤维细胞生长因子-2、血管内皮生长因子-A和血小板衍生生长因子-B的刺激下也是如此。此外，阻断FGFR/PDGFR/VEGFR降低了胰腺癌细胞中Survivin的表达，提高了吉西他滨的活性。此外，TKI258治疗后癌细胞、血管内皮细胞和VSMCs的运动能力降低。在体内，TKI258治疗导致剂量依赖地抑制皮下(HPAF-II)和原位(L3.6pl)肿瘤生长。免疫组织化学分析显示对肿瘤细胞增殖[溴脱氧尿嘧啶核苷(BrdUrd)]和肿瘤血管形成(CD31)的影响。此外，在原位肿瘤模型中，当早期开始使用TKI258(30 mg/kg/d)治疗时，淋巴结转移显著减少。在已建立的肿瘤模型中，TKI258(30 mg/kg/d)分别在皮下和原位模型中导致显著的生长延迟和提高存活率。这些数据提供了TKI258靶向FGFR/PDFGR/VEGFR治疗人胰腺癌的证据，并值得进一步的临床评估。摩尔癌症治疗；10(11)；2157-67。(C)2011年AACR。
Activation of receptor tyrosine kinases, such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and VEGF receptor (VEGFR), has been implicated in tumor progression and metastasis in human pancreatic cancer. In this study, we investigated the effects of TKI258, a tyrosine kinase inhibitor to FGFR, PDGFR, and VEGFR on pancreatic cancer cell lines (HPAF-II, BxPC-3, MiaPaCa2, and L3.6pl), endothelial cells, and vascular smooth muscle cells (VSMC). Results showed that treatment with TKI258 impaired activation of signaling intermediates in pancreatic cancer cells, endothelial cells, and VSMCs, even upon stimulation with FGF-1, FGF-2, VEGF-A, and PDGF-B. Furthermore, blockade of FGFR/PDGFR/VEGFR reduced survivin expression and improved activity of gemcitabine in MiaPaCa2 pancreatic cancer cells. In addition, motility of cancer cells, endothelial cells, and VSMCs was reduced upon treatment with TKI258. In vivo, therapy with TKI258 led to dose-dependent inhibition of subcutaneous (HPAF-II) and orthotopic (L3.6pl) tumor growth. Immunohistochemical analysis revealed effects on tumor cell proliferation [bromodeoxyuridine (BrdUrd)] and tumor vascularization (CD31). Moreover, lymph node metastases were significantly reduced in the orthotopic tumor model when treatment was initiated early with TKI258 (30 mg/kg/d). In established tumors, TKI258 (30 mg/kg/d) led to significant growth delay and improved survival in subcutaneous and orthotopic models, respectively. These data provide evidence that targeting FGFR/PDFGR/VEGFR with TKI258 may be effective in human pancreatic cancer and warrants further clinical evaluation. Mol Cancer Ther; 10(11); 2157-67. (C) 2011 AACR.