Anti-VEGF Treatment-Resistant Pancreatic Cancers Secrete Proinflammatory Factors That Contribute to Malignant Progression by Inducing an EMT Cell Phenotype

IF 0.1 Q4 GASTROENTEROLOGY & HEPATOLOGY Journal of the Pancreas Pub Date : 2013-09-15 DOI:10.6092/1590-8577/1865
C. Carbone, G. Piro, Anna Tamburrino, M. M. Mina, Silvia Zanini, G. Tortora, D. Melisi
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引用次数: 2

Abstract

Context The resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. There are currently no validated predictive biomarkers for selecting which cancer patients will benefit from antiangiogenic therapy. Also lacking are resistance biomarkers that can identify which escape pathways should be targeted after tumors develop resistance to VEGF treatment. Recent studies showed that anti-VEGF treatment can make tumor cells more aggressive and metastatic. However, the mechanisms and mediators of this are unidentified. Objective We aimed this study at directly identifying the tumor cell-initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment. Methods We established and validated two murine models of human pancreatic cancer resistant to the VEGF-specific antibody bevacizumab in vivo . We used a genome-wide analysis to directly identify which tumor-secreted factors were overexpressed by pancreatic cancer cells that were resistant to anti-VEGF treatment. Results Rather than direct proangiogenic factors, we identified several proinflammatory factors that were expressed at higher levels in cells resistant to anti-VEGF treatment than in treatment-sensitive control cells. These proinflammatory factors acted in a paracrine manner to stimulate the recruitment of CD11b + proangiogenic myeloid cells. Also, we found that secreted factors overexpressed by anti-VEGF treatment-resistant pancreatic cancer cells acted in an autocrine manner to induce epithelial-to-mesenchymal transition (EMT) and were thus responsible for increased aggressiveness of bevacizumab-resistant pancreatic tumors. Conclusions Our results identified proinflammatory factors and EMT markers as potential biomarkers for selecting patients with pancreatic cancer for antiangiogenic therapy.
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抗vegf治疗抵抗胰腺癌分泌促炎因子,通过诱导EMT细胞表型促进恶性进展
肿瘤对抗血管生成治疗的耐药性正变得越来越重要。目前还没有经过验证的预测性生物标志物来选择哪些癌症患者将从抗血管生成治疗中受益。同样缺乏的是耐药生物标志物,这些标志物可以识别肿瘤对VEGF治疗产生耐药性后应该靶向哪些逃逸途径。最近的研究表明,抗vegf治疗可以使肿瘤细胞更具侵袭性和转移性。然而,其机制和介质尚未确定。目的本研究旨在直接确定胰腺癌对抗vegf治疗产生耐药性的肿瘤细胞启动机制。方法建立并验证两种人胰腺癌小鼠模型对vegf特异性抗体贝伐单抗的体内耐药。我们使用全基因组分析来直接确定哪些肿瘤分泌因子在抗vegf治疗的胰腺癌细胞中过度表达。与直接的促血管生成因子不同,我们发现了几种促炎症因子,它们在抗vegf治疗的细胞中表达的水平高于在治疗敏感的对照细胞中表达的水平。这些促炎因子以旁分泌的方式刺激CD11b +促血管生成髓样细胞的募集。此外,我们发现抗vegf治疗抵抗性胰腺癌细胞过度表达的分泌因子以自分泌方式诱导上皮细胞向间质转化(EMT),从而导致贝伐单抗抵抗性胰腺肿瘤的侵袭性增加。结论:我们的研究结果确定了促炎因子和EMT标志物是选择胰腺癌患者进行抗血管生成治疗的潜在生物标志物。
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Journal of the Pancreas
Journal of the Pancreas GASTROENTEROLOGY & HEPATOLOGY-
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