Sass Dilorom, Fitzgerald Wendy, Wolff Brian S, Torres Isaias, Pagan-Mercado Glorivee, Armstrong Terri S, Miaskowski Christine, Margolis Leonid, Saligan Leorey, Kober Kord M
National Institute of Nursing Research, National Institutes of Health (NIH), Bethesda, MD, United States.
Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, United States.
Front Genet. 2022 Apr 25;13:869044. doi: 10.3389/fgene.2022.869044. eCollection 2022.
Because extracellular vesicle (EV)-associated cytokines, both encapsulated and surface bound, have been associated with symptom severity, and may vary over the lifespan, they may be potential biomarkers to uncover underlying mechanisms of various conditions. This study evaluated the associations of soluble and EV-associated cytokine concentrations with distinct symptom profiles reported by 290 women with breast cancer prior to surgery. Patients were classified into older (≥60 years, = 93) and younger (< 60 years, = 197) cohorts within two previously identified distinct symptom severity profiles, that included pain, depressive symptoms, sleep disturbance, and fatigue (i.e., High Fatigue Low Pain and All Low). EVs were extracted using ExoQuick. Cytokine concentrations were determined using Luminex multiplex assay. Mann Whitney test evaluated the differences in EV and soluble cytokine levels between symptom classes and between and within the older and younger cohorts adjusting for Karnofsky Performance Status (KPS) score, body mass index (BMI), and stage of disease. Partial correlation analyses were run between symptom severity scores and cytokine concentrations. Results of this study suggest that levels of cytokine concentrations differ between EV and soluble fractions. Several EV and soluble pro-inflammatory cytokines had positive associations with depressive symptoms and fatigue within both age cohorts and symptom profiles. In addition, in the older cohort with High Fatigue Low Pain symptom profile, EV GM-CSF concentrations were higher compared to the All Low symptom profile ( < 0.05). Albeit limited by a small sample size, these exploratory analyses provide new information on the association between cytokines and symptom profiles of older and younger cohorts. Of note, unique EV-associated cytokines were found in older patients and in specific symptom classes. These results suggest that EVs may be potential biomarker discovery tools. Understanding the mechanisms that underlie distinct symptom class profiles categorized by age may inform intervention trials and offer precision medicine approaches.
由于细胞外囊泡（EV）相关的细胞因子，包括包裹在内的和表面结合的，都与症状严重程度相关，并且可能在整个生命周期中有所变化，因此它们可能是揭示各种疾病潜在机制的潜在生物标志物。本研究评估了290名乳腺癌女性术前报告的可溶性和EV相关细胞因子浓度与不同症状特征之间的关联。患者被分为年龄较大（≥60岁，n = 93）和年龄较小（<60岁，n = 197）的队列，这两个队列属于之前确定的两种不同症状严重程度特征，包括疼痛、抑郁症状、睡眠障碍和疲劳（即高疲劳低疼痛和全低）。使用ExoQuick提取EV。使用Luminex多重分析法测定细胞因子浓度。Mann Whitney U检验评估了症状类别之间以及年龄较大和较小队列之间和内部的EV和可溶性细胞因子水平差异，并对卡诺夫斯基功能状态（KPS）评分、体重指数（BMI）和疾病分期进行了调整。对症状严重程度评分和细胞因子浓度进行了偏相关分析。本研究结果表明，细胞因子浓度水平在EV和可溶性组分之间存在差异。几种EV和可溶性促炎细胞因子在两个年龄队列和症状特征中均与抑郁症状和疲劳呈正相关。此外，在高疲劳低疼痛症状特征的老年队列中，EV GM-CSF浓度高于全低症状特征（P < 0.05）。尽管样本量有限，但这些探索性分析提供了关于细胞因子与老年和年轻队列症状特征之间关联的新信息。值得注意的是，在老年患者和特定症状类别中发现了独特的EV相关细胞因子。这些结果表明，EV可能是潜在的生物标志物发现工具。了解按年龄分类 的不同症状类别特征背后的机制可能为干预试验提供信息，并提供精准医学方法。
