Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma
Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma
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DOI：
10.1053/j.gastro.2019.01.039
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发表时间：
2019-05-01
期刊：
影响因子：
29.4
通讯作者：
Chari, Suresh T.
中科院分区：
文献类型：
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作者：
Sah, Raghuwansh P.;Sharma, Ayush;Chari, Suresh T.
背景与目的：在胰腺导管腺癌(PDAC)诊断前发现代谢异常可以增加早期发现的机会。我们收集了患者在接受PDAC诊断前5年的代谢参数(葡萄糖、血脂、甘油三酯；总、低密度和高密度胆固醇；以及总体重)和软组织(腹部皮下脂肪、脂肪组织、内脏脂肪组织[VAT]和肌肉)的变化数据。方法：我们收集了从2000年到2015年罗切斯特流行病学项目的219名诊断为PDAC的患者(患者)和657名健康人(对照)的数据。我们比较了患者与年龄和性别匹配的对照组的代谢情况，建立了诊断为PDAC(指数日期)前60个月的空腹血糖、血脂(包括甘油三酯)、胆固醇曲线、体重和体温的时间曲线。为了构建软组织变化的时间轮廓，我们收集了68名患者的计算机断层扫描，比较了基线(诊断前18个月)L2/L3椎体的SAT、VAT和肌肉区域与后来扫描的区域，直到诊断时为止。从健康个体分离的SAT和VAT与从PDAC细胞系分离的外切体接触，并进行RNA测序分析。收集KRAS(+/LSL)G12D P53(FLOX/FLOX)小鼠、C57/BL6(对照)小鼠和5例患者的唾液酸，进行组织学和免疫组织化学分析。结果：直到PDAC诊断前30个月，患者的代谢或软组织特征与对照组没有显著差异。在PDAC诊断前30至18个月(阶段1，高血糖)，与对照组相比，相当大比例的患者出现高血糖，没有软组织变化。在PDAC诊断前18至6个月(2期，恶病质前期)，患者在保留VAT和肌肉的情况下，高血糖显著升高，而血脂、体重和SAT显著下降。在PDAC诊断前6至0个月(3期，恶病质)，与对照组相比，相当大比例的患者有高血糖，患者的所有血脂、SAT、VAT和肌肉显著降低。根据体温升高，我们认为患者在PDAC诊断前18个月开始出现SAT褐变。我们观察到解偶联蛋白1(UCP1)在暴露于PDAC外切体的SAT、患有PDAC的小鼠的SAT和所有5名患者的SAT中的表达，但只有4名对照中的1名。结论：在诊断为PDAC之前，我们确定了代谢和软组织改变的三个阶段。SAT的丢失在PDAC识别前18个月开始，很可能是由于褐变。UCP1在SAT中的过度表达可能是早期PDAC的生物标志物，但尚需进一步研究。
BACKGROUND & AIMS: Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. METHODS: We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age-and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS(+/LSL)G12D P53(flox/flox) mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry. RESULTS: There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. CONCLUSIONS: We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early- stage PDAC, but further studies are needed.