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Abstract：
Hepatocellular carcinoma (HCC), as a well-vascularized tumor, has attracted increasing attention in antiangiogenic therapies. Notably, emerging studies reveal that the long-term administration of antiangiogenic drugs induces hypoxia in tumors. Pericytes, which play a vital role in vascular stabilization and maturation, have been documented to be associated with antiangiogenic drug-induced tumor hypoxia. However, the role of antiangiogenic agents in regulating pericyte behavior still remains elusive. In this study, by using immunostaining analysis, we first demonstrated that tumors obtained from HCC patients were highly angiogenic, in which vessels were irregularly covered by pericytes. Therefore, we established a new 3D model of tumor-driven angiogenesis by culturing endothelial cells, pericytes, cancer stem cells (CSCs) and mesenchymal stem cells (MSCs) with microcarriers in order to investigate the effects and mechanisms exerted by antiangiogenic agents on pericyte recruitment during tumor angiogenesis. Interestingly, microcarriers, as supporting matrices, enhanced the interactions between tumor cells and the extracellular matrix (ECM), promoted malignancy of tumor cells and increased tumor angiogenesis within the 3D model, as determined by qRT-PCR and immunostaining. More importantly, we showed that zoledronic acid (ZA) reversed the inhibited pericyte recruitment, which was induced by sorafenib (Sora) treatment, through fostering the expression and activation of ErbB1/ErbB2 and PDGFR-β in pericytes, in both an in vitro 3D model and an in vivo xenograft HCC mouse model. Hence, our model provides a more pathophysiologically relevant platform for the assessment of therapeutic effects of antiangiogenic compounds and identification of novel pharmacological targets, which might efficiently improve the benefits of antiangiogenic treatment for HCC patients.
摘要：
肝细胞癌（HCC），作为一种血管化良好的肿瘤，在抗血管生成疗法中引起了越来越多的关注。值得注意的是,新出现的研究表明，长期服用抗血管生成药物会导致肿瘤缺氧。周细胞,在血管稳定和成熟中起着至关重要的作用，已被证明与抗血管生成药物诱导的肿瘤缺氧有关。然而,抗血管生成剂在调节周细胞行为中的作用仍然难以捉摸。在这项研究中,通过使用免疫染色分析，我们首先证明了从HCC患者获得的肿瘤是高度血管生成的，其中血管不规则地被周细胞覆盖。因此,我们通过培养内皮细胞建立了一个新的肿瘤驱动血管生成的3D模型，周细胞,肿瘤干细胞（CSCs）和间充质干细胞（MSCs）与微载体，以研究抗血管生成剂对肿瘤血管生成过程中周细胞募集的影响和机制。有趣的是,微载体,作为支持矩阵，增强肿瘤细胞与细胞外基质（ECM）之间的相互作用，在3D模型中促进肿瘤细胞的恶性和增加肿瘤血管生成，如通过qRT-PCR和免疫染色确定的。更重要的是,我们发现唑来膦酸（ZA）逆转了被抑制的周细胞募集，这是由索拉非尼（Sora）治疗诱导的，通过促进ErbB1/ErbB2和PDGFR-β在周细胞中的表达和激活，在体外3D模型和体内异种移植HCC小鼠模型中。因此，我们的模型为评估抗血管生成化合物的治疗效果和鉴定新的药理靶点提供了更多的病理生理学相关平台。这可能有效地提高抗血管生成治疗肝癌患者的益处。
