ICF: Microfluidic investigation of the role of transcapillary resistance and vascular permeability/normalisation on cancer outcomes via vasodilation

在一项涉及12，456名被诊断患有结直肠癌的男性患者的里程碑式研究中，那些在诊断后服用西地那非（销售为伟哥）的人比那些没有服用的人生存10年的几率高出两倍。西地那非通常用于治疗勃起功能障碍和肺动脉高压，并通过扩张血管（血管舒张）发挥作用。我们认为这种药物通过两种机制影响结直肠癌的结果：a）增加小血管的直径，抑制肿瘤细胞闭塞，这是转移进展的关键步骤; B）改变血管的通透性和结构，这可能有助于药物和免疫细胞向肿瘤的递送（图1）。我们将通过三个关键目标来探索这些假设：1）开发微血管微流体平台，其结合由毛细血管前括约肌收缩诱导的血管舒张，2）研究血管舒张介导的血液动力学阻力如何影响肿瘤细胞截留、侵袭和转移形成，第三章探索内皮渗透性和微血管正常化对抗体治疗剂的肿瘤渗透和分布的影响，微流体和小鼠模型中免疫细胞浸润和活性。血管扩张剂药物在人类中具有长期的安全使用记录，并且了解这种药物如何通过血管系统影响癌症结局可以提供开发下一代血管扩张剂佐剂的途径，而不会对癌症患者产生不必要的副作用。

In a landmark study involving 12,456 male patients diagnosed with colorectal cancer, those who took Sildenafil (marketed as Viagra) after diagnosis had over twice the odds of survivng for 10 years than those who did not. Sildenafil is commonly prescribed for erectile dysfunction and pulmonary arterial hypertension and acts by widening blood vessels (vasodilation). We propose that this drug influences colorectal cancer outcomes via two mechanisms: a) increasing the diameter of small vessels which inhibits tumour cell occlusion, a key step in metastasis progression and b) modification of the permeability and architecture of blood vessels, which may assist drug and immune cell delivery to tumours (Fig. 1). We will explore these hypothesis via 3 key aims: 1) development of a microvascular microfluidic platform that incorporates vasodilation induced by precapillary sphincter contraction, 2) investigate how vasodilation-mediated hemodynamic resistance influences tumour cell entrapment, invasion and metastasis formation, 3) explore the influence of endothelial permeability and microvascular normalisation on the tumour penetration and distribution of antibody therapeutics and immune cell infiltration & activity in microfluidic & mice models. Vasodilator drugs have long track records of safe use in humans and an understanding of how this drug influences cancer outcomes via the vasculature may provide a pathway to develop next generation vasodilator adjuvants without unwanted side effects for patients with cancer.