Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.
Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.
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DOI：
10.1158/1078-0432.ccr-11-1185
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发表时间：
2011-09-01
期刊：
影响因子：
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通讯作者：
Melisi D
中科院分区：
文献类型：
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作者：
Carbone C;Moccia T;Zhu C;Paradiso G;Budillon A;Chiao PJ;Abbruzzese JL;Melisi D
肿瘤对抗血管生成疗法的抗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，可以确定哪些逃逸途径应针对肿瘤后发展抗血管内皮生长因子（VEGF）治疗的耐药性。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，其机制和介导者尚未确定。因此，本研究旨在直接确定胰腺癌对抗VEGF治疗耐药的肿瘤细胞启动机制。我们建立并验证了两种对VEGF特异性抗体贝伐单抗体内耐药的人胰腺癌小鼠模型。我们使用全基因组分析来直接鉴定哪些肿瘤分泌因子被对抗VEGF治疗有抗性的胰腺癌细胞过表达。而不是直接的促血管生成因子，我们确定了几个促炎因子，在抗VEGF治疗抵抗细胞中的表达水平高于治疗敏感的对照细胞。这些促炎因子以旁分泌方式刺激CD 11b+促血管生成髓样细胞的募集。此外，我们发现抗VEGF治疗抗性胰腺癌细胞过表达的分泌因子以自分泌方式起作用以诱导上皮向间充质转化（EMT），并因此导致贝伐珠单抗抗性胰腺肿瘤的侵袭性增加。我们的研究结果确定了促炎因子和EMT标志物作为选择胰腺癌患者进行抗血管生成治疗的潜在生物标志物。
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 anti-vascular endothelial growth factor (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. Therefore, we aimed the present study at directly identifying the tumor cell-initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment. 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. Rather then 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. Our results identified proinflammatory factors and EMT markers as potential biomarkers for selecting patients with pancreatic cancer for antiangiogenic therapy.