Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature
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DOI：
10.1158/0008-5472.can-16-0300
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Cascone, Ilaria
中科院分区：
文献类型：
--
作者：
Gilles, Maud-Emmanuelle;Maione, Federica;Cascone, Ilaria
胰腺癌是一种高度侵袭性的肿瘤，大多数对标准治疗有抵抗力。核仁素在癌症中过表达，其抑制会损害肿瘤生长。在此，我们发现核仁素在胰腺导管腺癌（PDAC）的人类标本中过表达，并且核仁素水平低的患者的总生存率显著增加。核仁素拮抗剂N6 L在原位小鼠PDAC模型（mPDAC）中强烈损害原发性肿瘤和肝转移的生长。在胰腺神经内分泌肿瘤RIP-Tag 2的高度血管生成小鼠模型中观察到N6 L的类似抗肿瘤作用。N6 L显著抑制人和小鼠胰腺细胞的增殖和侵袭。值得注意的是，肿瘤脉管系统的分析揭示了mPDAC和RIP-Tag 2肿瘤中周细胞覆盖和血管灌注的强烈增加，与肿瘤缺氧的抑制平行。核仁素抑制直接影响内皮细胞（EC）的激活，并改变了促血管生成的签名。在血管激活剂中，核仁素抑制显著降低血管生成素-2（Ang-2）在内皮细胞、肿瘤和mPDAC小鼠血浆中的分泌和表达。作为观察到的N6 L诱导的肿瘤血管正常化的结果，用N6 L预处理有效地改善了化疗药物递送并增加了吉西他滨在PDAC小鼠中的抗肿瘤特性。总之，核仁素抑制是一种新的抗胰腺癌治疗策略，其双重阻断肿瘤进展并使肿瘤血管正常化，从而改善化疗药物的递送和功效。此外，我们揭示了Ang-2作为胰腺癌N6 L治疗的潜在靶点和合适的反应生物标志物。(C)2016年AACR。
Pancreatic cancer is a highly aggressive tumor, mostly resistant to the standard treatments. Nucleolin is overexpressed in cancers and its inhibition impairs tumor growth. Herein, we showed that nucleolin was overexpressed in human specimens of pancreatic ductal adenocarcinoma (PDAC) and that the overall survival significantly increased in patients with low levels of nucleolin. The nucleolin antagonist N6L strongly impaired the growth of primary tumors and liver metastasis in an orthotopic mouse model of PDAC (mPDAC). Similar antitumor effect of N6L has been observed in a highly angiogenic mouse model of pancreatic neuroendocrine tumor RIP-Tag2. N6L significantly inhibited both human and mouse pancreatic cell proliferation and invasion. Notably, the analysis of tumor vasculature revealed a strong increase of pericyte coverage and vessel perfusion both inmPDAC and RIP-Tag2 tumors, in parallel to an inhibition of tumor hypoxia. Nucleolin inhibition directly affected endothelial cell (EC) activation and changed a proangiogenic signature. Among the vascular activators, nucleolin inhibition significantly decreased angiopoietin-2 (Ang-2) secretion and expression in ECs, in the tumor and in the plasma of mPDAC mice. As a consequence of the observed N6L-induced tumor vessel normalization, pre-treatment with N6L efficiently improved chemotherapeutic drug delivery and increased the antitumor properties of gemcitabine in PDAC mice. In conclusion, nucleolin inhibition is a new anti-pancreatic cancer therapeutic strategy that dually blocks tumor progression and normalizes tumor vasculature, improving the delivery and efficacy of chemotherapeutic drugs. Moreover, we unveiled Ang-2 as a potential target and suitable response biomarker for N6L treatment in pancreatic cancer. (C) 2016 AACR.