PO.TB02.01 · 肿瘤生物学
开发生物发光成像引导的CTC液体活检流程以确定实现更优光热治疗疗效的最佳时间窗
Development of a bioluminescence imaging-guided CTC liquid biopsy procedure to identify the optimal time window for achieving superior photothermal therapy efficacy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
全球癌症负担是公共卫生领域最重大的挑战之一。对于主流治疗流程而言，一个值得关注的问题是接受这些治疗的大多数患者复发率较高。这一问题通常归因于癌细胞播散的演变状态，即循环肿瘤细胞（CTC）开始出现在血液循环中。然而，由于需要富集CTC，在初始或随访诊断期间反复大量抽血引发了伦理问题，因此CTC检测在临床实践中并未成为常规。鉴于在使用小鼠模型的临床前实验中CTC应用稀少（小鼠总血量仅限于1.5 ml/只），本研究挑战了这一传统观念，利用临床前小鼠肿瘤模型建立了一种基于发光的CTC检测方法。经优化的、采用生物发光成像引导的液体活检流程能够从低至100 μl的血量中检测到多达两个细胞，使我们能够从极低的血量中追踪CTC激增动态。我们在荷有高度侵袭性4T1-FLuc2和相对惰性ZR-75-1-Nanoluc原位乳腺癌模型的小鼠中，考察了CTC动态和转移潜能。为验证这一情形，我们进一步采用了标准化程度很高的光热治疗（PTT）流程，使用金包被固体脂质纳米材料（Au-SLN），并证明当在时间上优化的窗口期进行PTT时，无论在高度侵袭性还是低侵袭性乳腺癌模型中，该治疗的应用均不会诱导可检测到的CTC通量（p < 0.05），也不会导致恶性肿瘤向重要器官的远处扩散。CTC的成像信号进一步通过分子生物标志物和转录组学表征得到确认，揭示了EpCAM阳性CTC与肿瘤侵袭性及其转移倾向的密切关联。这些效应显著改善了小鼠的寿命和无复发生存期。我们的研究结果强调，当在活的CTC释放之前进行时，Au-SLN介导的PTT可提供无复发的有效治疗，并突出了整合灵敏的液体活检方法以监测转移风险和疾病复发可能性的重要性。
查看英文原文 English abstract
Global cancer burden represents one of the most significant challenges in public health. Notable concern for the mainframe therapeutic procedures is the high incidence of relapsed disease among majority patients availing those. This problem is frequently attributed to the evolving state of cancer cell dissemination, where circulating tumor cells (CTCs) begin to appear in the blood circulation. However, due to CTC enrichment requirement, high-volume blood withdrawal repeatedly during initial or follow up diagnosis, raises an ethical concern, and therefore CTC determination not integral in practice. Given the sparse nature of CTC applications in preclinical experiments using mouse model, where the total blood volume is limited to only 1.5 ml/mouse, in this study we challenged this dogma, and established a luminescence-based CTC detection method using preclinical mouse tumor models. The optimized liquid biopsy process using bioluminescence imaging-guidance allowed detection of up to two cells from as low as 100μl blood volumes, allowing us to follow the CTC surge dynamics from a very low blood volume. We examined both CTC dynamics and metastatic potential in mice bearing highly aggressive 4T1-FLuc2 and a relatively indolent ZR-75-1-Nanoluc orthotopic breast cancer models. To test the case, we further used our well-standardized photothermal therapy (PTT) procedure using gold-coated solid lipid nanomaterial (Au-SLN) and demonstrate that when PTT is performed in a temporally optimized window, the therapy application does not induce a detectable CTC flux (p< 0.05), nor distant spread of malignant tumors in the vital organs, both in highly aggressive and less aggressive breast cancer models. Imaging signal from CTC was confirmed further by molecular biomarker and transcriptomic characterization, revealing a close association of EpCAM positive CTCs with tumor aggressiveness and their metastatic propensity. These effects essentially improve mice longevity and relapse-free survival of the mice. Our findings highlight that Au-SLN mediated PTT could provide a relapse-free efficacious treatment, when performed before viable CTCs are released and underscore the importance of integrating a sensitive liquid biopsy method for monitoring metastatic risk and chance of disease relapse.
利益披露 Disclosure
A. De, None..
C. Patnaik, None.