Mongan A M, Lynam-Lennon N, Casey R, Maher S, Pidgeon G, Reynolds J V, O'Sullivan J
Department of Surgery, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
Cancer Biology & Therapeutics Lab, School of Biological, Biomedical & Environmental Sciences, University of Hull, Cottingham road, Hull, HU6 76X, UK.
Clin Transl Oncol. 2016 Jun;18(6):632-40. doi: 10.1007/s12094-015-1411-y. Epub 2015 Oct 16.
Oesophageal adenocarcinoma is an exemplar model of obesity-associated cancer. Locally advanced disease is treated with neoadjuvant chemoradiotherapy, and survival rates are highest in patients demonstrating a pathological response following neoadjuvant therapy. Given that 55 % of oesophageal adenocarcinoma patients are obese, uncovering the effect of adipose tissue on radioresponse is clinically relevant. This study investigates if adipose tissue activates genomic instability events in radioresponsive (OE33P) and radioresistant (OE33R) oesophageal cancer cell lines and tumour samples.
OE33R and OE33P were cultured with adipose-conditioned media derived from oesophageal adenocarcinoma patients (n = 10). Anaphase bridges, a marker of genomic instability, were enumerated in both cell lines following treatment with adipose media, and normalised to cell number. Genomic instability is regulated by the spindle assembly complex. Expression of two spindle assembly complex genes (MAD2L2, BUB1B) was assessed using qPCR, and validated in patient tumour specimens from viscerally obese (n = 46) and nonobese patients (n = 41).
Adipose-conditioned media increased anaphase bridging in OE33R (p < 0.0001), with a threefold increase in OE33R compared to OE33P (p < 0.01). Levels of anaphase bridges in OE33R cells correlated with visceral obesity status as measured by waist circumference (R = 0.709, p = 0.03) and visceral fat area (R = 0.794, p = 0.006). Adipose tissue altered expression of MAD2L2 in vitro. In vivo, MAD2L2 expression was higher in viscerally obese oesophageal adenocarcinoma patients compared with nonobese patients (p < 0.05).
Anaphase bridge levels are influenced by obesity and radiosensitivity status in oesophageal adenocarcinoma. Furthermore, visceral adipose-conditioned media stimulates dysregulation of the spindle assembly complex in oesophageal adenocarcinoma patients.
食管腺癌是肥胖相关癌症的一个典型模型。局部晚期疾病采用新辅助放化疗进行治疗，在新辅助治疗后显示出病理反应的患者中生存率最高。鉴于55%的食管腺癌患者肥胖，揭示脂肪组织对放射反应的影响具有临床相关性。本研究调查脂肪组织是否会激活放射敏感（OE33P）和放射抵抗（OE33R）食管癌细胞系及肿瘤样本中的基因组不稳定事件。
将OE33R和OE33P与来自食管腺癌患者（n = 10）的脂肪条件培养基一起培养。在脂肪培养基处理后的两种细胞系中，对作为基因组不稳定标志物的后期桥进行计数，并将其标准化为细胞数量。基因组不稳定由纺锤体组装复合体调节。使用qPCR评估两个纺锤体组装复合体基因（MAD2L2、BUB1B）的表达，并在内脏肥胖患者（n = 46）和非肥胖患者（n = 41）的肿瘤标本中进行验证。
脂肪条件培养基增加了OE33R中的后期桥接（p < 0.0001），与OE33P相比，OE33R增加了三倍（p < 0.01）。OE33R细胞中的后期桥水平与通过腰围测量的内脏肥胖状态相关（R = 0.709，p = 0.03）以及与内脏脂肪面积相关（R = 0.794，p = 0.006）。脂肪组织在体外改变了MAD2L2的表达。在体内，内脏肥胖的食管腺癌患者中MAD2L2的表达高于非肥胖患者（p < 0.05）。
后期桥水平受食管腺癌中的肥胖和放射敏感性状态影响。此外，内脏脂肪条件培养基会刺激食管腺癌患者纺锤体组装复合体的失调。
