Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model.
Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model.
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DOI：
10.1016/j.canlet.2016.05.037
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发表时间：
2016-08-28
期刊：
影响因子：
9.7
通讯作者：
Korc M
中科院分区：
文献类型：
--
作者：
Gore J;Imasuen-Williams IE;Conteh AM;Craven KE;Cheng M;Korc M
胰腺导管腺癌(PDAC)是一种侵袭性疾病，淋巴扩散频繁。通过分析来自癌症基因组图谱的数据，我们确定∼35%的PDAC具有促血管生成基因特征。我们现在发现，同样的PDAC表现出淋巴管生成基因和淋巴管内皮细胞(LEC)标记的表达增加，并且LEC在人PDAC中的丰度与内皮细胞微血管密度相关。在KRC(突变的Kras；缺失的Rb)和KIC(突变的Kras；缺失的INK4a)遗传模型中产生的小鼠PDAC中，淋巴管生成基因和LECs也升高。此外，KRC肿瘤来源的胰腺癌细胞(PCCs)表达和分泌高水平的淋巴管生成因子，包括EGF受体配体、双调节蛋白。重要的是，转化生长因子-β1增加了KRCPCCs中淋巴管生成基因和双调节素的表达，但在缺乏Smad4的小鼠PCCs中不增加，并且联合靶向转化生长因子-βI型受体(TβRI)与LY2157299和EGFRHER2与拉帕替尼联合抑制同种原位模型中的肿瘤生长和转移，减少肿瘤淋巴管生成和血管生成，同时减少淋巴管生成基因和两调节素并促进细胞凋亡。因此，这种结合对于具有淋巴管生成或血管生成基因特征的PDAC可能是有益的。
Pancreatic ductal adenocarcinomas (PDAC) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ∼35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density. Lymphangiogenic genes and LECs are also elevated in murine PDACs arising in the KRC (mutated Kras; deleted RB) and KIC (mutated Kras; deleted INK4a) genetic models. Moreover, pancreatic cancer cells (PCCs) derived from KRC tumors express and secrete high levels of lymphangiogenic factors, including the EGF receptor ligand, amphiregulin. Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatanib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis. Therefore, this combination could be beneficial in PDACs with lymphangiogenic or angiogenic gene signatures.