Oncolytic Ad co-expressing decorin and Wnt decoy receptor overcomes chemoresistance of desmoplastic tumor through degradation of ECM and inhibition of EMT
Oncolytic Ad co-expressing decorin and Wnt decoy receptor overcomes chemoresistance of desmoplastic tumor through degradation of ECM and inhibition of EMT
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DOI：
10.1016/j.canlet.2019.05.033
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Yun, Chae-Ok
中科院分区：
文献类型：
--
作者：
Li, Yan;Hong, JinWoo;Yun, Chae-Ok
胰腺癌是一种高度致命的疾病。肿瘤细胞外基质(ECM)过度积聚和上皮向间充质转化(EMT)表型是促结缔组织增生性胰腺肿瘤耐药的两个主要因素。为了克服胰腺癌的促结缔组织增生和化疗耐药，我们利用共表达核心蛋白聚糖和可溶性Wnt诱骗受体的溶瘤腺病毒(Ad)(HEMT-DCN/sLRP6)。用Mia Paca-2细胞建立裸鼠胰腺原位移植瘤模型，观察HEMT-DCN/sLRP6系统给药的抗肿瘤和抗肿瘤作用。对肿瘤组织进行免疫组织化学分析，以评估ECM降解、诱导细胞凋亡、病毒扩散和抑制WNTA-Catenin信号通路。HEMT-DCN/sLRP6能有效降解肿瘤细胞外基质，抑制EMT，增强病毒在肿瘤组织中的分布，诱导细胞凋亡，抑制肿瘤细胞增殖。HEMT-DCN/sLRP6可预防胰腺癌的转移。重要的是，HEMT-DCN/sLRP6使胰腺肿瘤对吉西他滨治疗增敏。此外，HEMT-DCN/sLRP6增加了药物在胰腺肿瘤移植瘤和患者来源的肿瘤球体中的渗透和分散。综上所述，这些结果表明，HEMT-DCN/sLRP6可以提高溶瘤Ad和化疗药物在化疗耐药和促结缔组织增生性肿瘤中的弥散性，有效地克服了标准治疗的局限性。
Pancreatic cancer is a highly lethal disease. Excessive accumulation of tumor extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) phenotype are two main contributors to drug resistance in desmoplastic pancreatic tumors. To overcome desmoplasia and chemoresistance of pancreatic cancer, we utilized an oncolytic adenovirus (Ad) co-expressing decorin and soluble Wnt decoy receptor (HEmT-DCN/sLRP6). An orthotopic pancreatic xenograft tumor model was established in athymic nude mice using Mia PaCa-2 cells, and the antimetastatic and antitumor efficacy of systemically administered HEmT-DCN/sLRP6 was evaluated. Immunohistochemical analysis of tumor tissues was performed to assess ECM degradation, induction of apoptosis, viral dispersion, and inhibition of the Wnta-catenin signaling pathway. HEmT-DCN/sLRP6 effectively degraded tumor ECM and inhibited EMT, leading to enhanced viral distribution, induction of apoptosis, and attenuation of tumor cell proliferation in tumor tissue. HEmT-DCN/sLRP6 prevented metastasis of pancreatic cancer. Importantly, HEmT-DCN/sLRP6 sensitized pancreatic tumor to gemcitabine treatment. Furthermore, HEmT-DCN/sLRP6 augmented drug penetration and dispersion within pancreatic tumor xenografts and patient derived tumor spheroids. Collectively, these results illustrate that HEmT-DCN/sLRP6 can enhance the dispersion of both oncolytic Ad and a chemotherapeutic agent in chemoresistant and desmoplastic pancreatic tumor, effectively overcoming the preexisting limitations of standard treatments.