Ex vivo explant model of adenoma and colorectal cancer to explore mechanisms of action and patient response to cancer prevention therapies.

IF 2.5 4区 医学 Q3 GENETICS & HEREDITY
Mutagenesis Pub Date : 2022-12-08 DOI:10.1093/mutage/geac020
Sam Khan, Gareth J Miles, Constantinos Demetriou, Zahirah Sidat, Nalini Foreman, Kevin West, Ankur Karmokar, Lynne Howells, Catrin Pritchard, Anne L Thomas, Karen Brown
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引用次数: 1

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer death in the UK. Novel therapeutic prevention strategies to inhibit the development and progression of CRC would be invaluable. Potential contenders include low toxicity agents such as dietary-derived agents or repurposed drugs. However, in vitro and in vivo models used in drug development often do not take into account the heterogeneity of tumours or the tumour microenvironment. This limits translation to a clinical setting. Our objectives were to develop an ex vivo method utilizing CRC and adenoma patient-derived explants (PDEs) which facilitates screening of drugs, assessment of toxicity, and efficacy. Our aims were to use a multiplexed immunofluorescence approach to demonstrate the viability of colorectal tissue PDEs, and the ability to assess immune cell composition and interactions. Using clinically achievable concentrations of curcumin, we show a correlation between curcumin-induced tumour and stromal apoptosis (P < .001) in adenomas and cancers; higher stromal content is associated with poorer outcomes. B cell (CD20+ve) and T cell (CD3+ve) density of immune cells within tumour regions in control samples correlated with curcumin-induced tumour apoptosis (P < .001 and P < .05, respectively), suggesting curcumin-induced apoptosis is potentially predicted by baseline measures of immune cells. A decrease in distance between T cells (CD3+ve) and cytokeratin+ve cells was observed, indicating movement of T cells (CD3+ve) towards the tumour margin (P < .001); this change is consistent with an immune environment associated with improved outcomes. Concurrently, an increase in distance between T cells (CD3+ve) and B cells (CD20+ve) was detected following curcumin treatment (P < .001), which may result in a less immunosuppressive tumour milieu. The colorectal tissue PDE model offers significant potential for simultaneously assessing multiple biomarkers in response to drug exposure allowing a greater understanding of mechanisms of action and efficacy in relevant target tissues, that maintain both their structural integrity and immune cell compartments.

腺瘤和结直肠癌离体移植模型探讨作用机制和患者对癌症预防治疗的反应。
结直肠癌(CRC)是英国癌症死亡的第二大原因。新的治疗预防策略抑制结直肠癌的发展和进展将是非常宝贵的。潜在的竞争者包括低毒性制剂,如膳食衍生制剂或重新利用的药物。然而,用于药物开发的体外和体内模型通常没有考虑肿瘤或肿瘤微环境的异质性。这限制了对临床环境的翻译。我们的目标是开发一种利用结直肠癌和腺瘤患者源性外植体(PDEs)的体外方法,以促进药物筛选,评估毒性和疗效。我们的目的是使用多重免疫荧光方法来证明结直肠组织PDEs的生存能力,以及评估免疫细胞组成和相互作用的能力。使用临床可达到的姜黄素浓度,我们发现在腺瘤和癌症中,姜黄素诱导的肿瘤和基质凋亡之间存在相关性(P < 0.001);基质含量越高,预后越差。对照样本中肿瘤区域免疫细胞的B细胞(CD20+ve)和T细胞(CD3+ve)密度与姜黄素诱导的肿瘤凋亡相关(分别为P < 0.001和P < 0.05),表明姜黄素诱导的肿瘤凋亡可能通过免疫细胞的基线测量来预测。T细胞(CD3+ve)与细胞角蛋白+ve之间的距离减小,表明T细胞(CD3+ve)向肿瘤边缘移动(P < 0.001);这一变化与免疫环境的改善是一致的。同时,姜黄素治疗后,T细胞(CD3+ve)和B细胞(CD20+ve)之间的距离增加(P < 0.001),这可能导致免疫抑制较低的肿瘤环境。结直肠组织PDE模型为同时评估多种生物标志物对药物暴露的反应提供了巨大的潜力,从而更好地了解相关靶组织的作用机制和疗效,同时保持其结构完整性和免疫细胞区室。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Mutagenesis
Mutagenesis 生物-毒理学
CiteScore
5.90
自引率
3.70%
发文量
22
审稿时长
6-12 weeks
期刊介绍: Mutagenesis is an international multi-disciplinary journal designed to bring together research aimed at the identification, characterization and elucidation of the mechanisms of action of physical, chemical and biological agents capable of producing genetic change in living organisms and the study of the consequences of such changes.
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