基于超声成像平台的胰腺癌新生血管相关PAUF基因突变及靶向抑制研究

Pancreatic cancer is known as neither reluctant to conventional chemotherapy nor radiotherapy either. The poor survival has not been significantly improved. Targeted treatment, such as vascular endothelial growth factor (VEGF) antibody bevacizumab to inhibit tumor angiogenesis, is viewed as possible solutions and thus become research focus. Unfortunately, the treatment effect was not improved as expected. PAUF (pancreatic adenocarcinoma up-regulated factor), a new regulation of angiogenesis through endothelial cells activation other than VEGF, has been considered as the new promising target foci recently. Moreover, few researches were taken on to evaluate pancreatic angiogenesis with imaging modality in vivo longitudinally. By our preliminary study, we demonstrated that pancreatic cancer presented as hypo-perfusion versus hyper-perfusion pattern on ultrasound (US) microvessel imaging. These two distinguished perfusion patterns implied that an US platform could be a potential imaging modality to evaluate pancreatic angiogenesis in vivo..Our project is designed to investigate the difference of PAUF expression level between hypo- and hyper perfusion tumors. The perfusion pattern might also serve as an important prognostic factor of pancreatic cancer, which in turn providing the solid theoretical support for PAUF targeted therapy. Secondly, a PDX1-PAUF transgenic mice model would be made to observe the tumor angiogenesis inversed by AMD3100 blocking PAUF SDF-1 /CXCR4 pathway, thus to provide solid evidence of PAUF regulatory mechanism. By a multi-modality US imaging research platform, we might verify the value of US on observing mice model longitudinally and dynamically. Our research could achieved in setting up an US imaging platform both for clinical application and basic researches, verifying the imaging predictor and prognosis markers of pancreatic cancer, and promoting translational individualized treatment.

胰腺癌对常规化疗、放疗不敏感，患者生存率尚无显著改善。靶向抑制肿瘤血管生成改善预后已成为研究热点，但抗血管内皮生长因子（VEGF）抗体的疗效却不尽人意。胰腺癌上调因子（PAUF）作为非VEGF介导的人类内皮细胞激活剂可促进血管的生成，是靶向治疗的新曙光。目前尚缺乏胰腺癌新生血管在体评价的影像学研究，本课题组前期工作显示胰腺癌超声微血管灌注成像表现出两种不同模式（乏血供和富血供），有望成为在体评价的技术手段。本课题将研究不同灌注模式肿瘤的PAUF表达差异，探讨胰腺癌影像学预后因子，为PAUF靶向治疗提供关键理论支撑；同时构建PDX1-PAUF转基因小鼠模型，观察AMD3100靶向阻断PAUF-SDF-1/CXCR4通路后肿瘤微血管变化，验证PAUF对胰腺癌微血管形成及超声表型的调控机制。研究成果将建立超声微血管成像平台，筛选胰腺癌微血管生成及疗效监测的影像学标记物，推进个体化精准治疗。

胰腺癌起病隐匿，对常规放化疗均不敏感，严重影响了人类生命健康，是当前医疗事业亟需解决的重大问题。靶向研究是近年来的研究热点，然而当前诸如抗血管内皮生长因子(VEGF)抗体等研究的疗效结果差强人意。胰腺癌上调因子(PAUF)作为非VEGF介导的人类内皮细胞激活剂可促进血管的生成，为靶向治疗提供了新的方向。超声造影弥补了传统超声的不足，在胰腺癌的诊断中发挥了巨大价值。本研究构建了国际最大胰腺疾病数据库，探讨了胰腺癌的超声造影表型谱，明确胰腺癌的超声造影的富血供、乏血供以及快速廓清模式，为其诊断提供了最精准的标准，大幅提升了超声造影在胰腺癌鉴别诊断中的准确率，为胰腺癌的早期发现提供了重要依据。同时，通过超声造影定量和定性分析，探讨其与胰腺癌代谢组学及预后的关系，挖掘胰腺癌影像学表型的内部代谢基础，筛选出与胰腺癌患者的预后相关的影像学参数，为临床提供了更加丰富的信息，进而为获益患者群制定靶向治疗方案提供可靠依据。为了更近一步明确胰腺癌超声造影表型的病理学基础及其与肿瘤侵袭性的内在机制，研究构建PAUF高表达裸鼠模型。结果显示，胰腺癌的超声造影表型与其病理学基础息息相关，PAUF高表达组倾向于富血供表型，靶向药物AMD3100较单独使用吉西他滨明显抑制了瘤体的生长，荷瘤小鼠对AMD3100的耐受性也高于吉西他滨。同时，化疗前后胰腺癌的超声造影表现存在差异，为其进一步检测化疗疗效的临床实验提供了重要依据，极大程度探索了超声造影在胰腺癌诊疗监测中的应用范围。综上所述，本研究证明了超声微血管显像平台作为预测胰腺癌微环境和评价治疗疗效的影像学标志物的可行性，验证了PAUF与胰腺癌微血管形成及超声表型的相关性，实现从肿瘤新生血管角度提供生物靶向治疗信息，为胰腺癌患者的个体化精准治疗方案提供了重要参考价值，为患者带来新的希望。

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