超重/肥胖直肠癌患者体内外泌体蛋白与热放射化学疗法疗效之间的关系:一项前瞻性队列试点研究

N. Yunusova, D. Svarovsky, Artem I. Konovalov, D. Kostromitsky, I. V. Kondakova, A. Usova, I. Frolova, Evgeniya A. Sidenko, G. Kakurina, Lyubov V. Gerdt, A. Grigor’eva, Zhanna A. Startseva
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The presence of transcription/translation/folding factors (heat shock proteins (HSPs), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in exosomes secreted by irradiated cells and cells exposed to hyperthermia, indicates the cell adaptation to the thermal and radiation stress. \nAim: To analyze the MMPs, TIMP1, and HSPs on CD9-positive (CD9+) exosomes, as well as on exosomes of adipocytic origin (FABP4+) in rectal cancer patients with overweight/obesity under thermoradiochemotherapy (TRCT) and their association with the immediate treatment efficacy. \nMethods: Since 2021, 20 patients (of those 8 men; median age 59.0 [52.0; 63.0] years, median body mass index 29.6 [28.5; 33.1] kg/m2) with morphologically verified rectal cancer (T3-4N0M0 and T3-4N1M0, differentiation grade G1–G3) have been participating in the study. 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引用次数: 0

摘要

背景:超重尤其是肥胖与结直肠癌的发生和发展风险有关。可以认为,在抗肿瘤治疗过程中,肿瘤与脂肪组织之间存在着多方面的相互作用。癌细胞会分泌外泌体,这种细胞外囊泡会影响肿瘤的微环境,促进肿瘤的发展或消退。辐照细胞和暴露于高热的细胞分泌的外泌体中存在转录/翻译/折叠因子(热休克蛋白(HSPs)、基质金属蛋白酶(MMPs)及其组织抑制剂(TIMPs)),表明细胞对热和辐射应激的适应。目的:分析接受热放射化学治疗(TRCT)的超重/肥胖直肠癌患者 CD9 阳性(CD9+)外泌体以及脂肪细胞来源(FABP4+)外泌体上的 MMPs、TIMP1 和 HSPs 及其与即时疗效的关系。研究方法自 2021 年以来,共有 20 名形态学确诊为直肠癌(T3-4N0M0 和 T3-4N1M0,分化等级 G1-G3)的患者(其中 8 名男性,中位年龄 59.0 [52.0; 63.0] 岁,中位体重指数 29.6 [28.5; 33.1] kg/m2)参与了研究。他们接受了TRCT治疗:体外伽马治疗(2 Gy,1次/天,5天/周,病灶总剂量54 Gy)、卡培他滨化疗(825 mg/m2,每天2次)和局部热疗(42-44 °C,60分钟,3次/周,10次疗程)。TRCT 疗效根据 RECIST 1.1 和 ESGAR 标准进行评估。分别在基线(第1点)、疗程中期(第2点)、TRCT结束后6至10周(第3点)和第1点后6个月(第4点)抽取患者血液样本检测外泌体。通过超滤和双重超速离心从血浆中分离出小细胞外囊泡。通过透射电子显微镜、流式细胞术和纳米粒子轨迹分析(NTA)对分离出的外泌体进行表征。结果显示13/20的直肠癌患者通过TRCT治疗后肿瘤完全消退,7/20的患者肿瘤部分消退或稳定。发现了与 TRCT 疗效相关的 CD9+ 和 FABP4+ 外泌体的四个亚群(CD9+MMP2+、СD9+MMP2+9+TIMP1+、СD9+MMP2+9+TIMP1- 和 FABP4+MMP2+9-TIMP1+)。与 CD9+ 外泌体相比,脂肪细胞囊泡的 MMP2 表达更高(p = 0.026);然而,脂肪细胞囊泡亚群中几乎不存在同时表达 MMP2 和 MMP9 明胶酶的囊泡。循环外泌体在不同 TRCT 阶段的 HSPs 表达既与直接治疗效果无关,也与囊泡类型无关。结论CD9+和FABP4+外泌体上MMPs和TIMP1的表达与TRCT疗效有关。未来,囊泡标记物可用于建立预后模型,识别预后不良的患者群体,并进行个性化治疗和随访。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The association between exosomal proteins and the efficacy of thermoradiochemotherapy in overweight/obese rectal cancer patients: a pilot prospective cohort study
Background: Overweight and especially obesity are associated with the risk of the development and progression of colorectal cancer. It can be assumed that there are multifaceted interactions between the tumor and adipose tissue during anti-tumor treatment. Cancer cells secrete exosomes, extracellular vesicles affecting the microenvironment of the tumor and promoting its progression or regression. The presence of transcription/translation/folding factors (heat shock proteins (HSPs), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in exosomes secreted by irradiated cells and cells exposed to hyperthermia, indicates the cell adaptation to the thermal and radiation stress. Aim: To analyze the MMPs, TIMP1, and HSPs on CD9-positive (CD9+) exosomes, as well as on exosomes of adipocytic origin (FABP4+) in rectal cancer patients with overweight/obesity under thermoradiochemotherapy (TRCT) and their association with the immediate treatment efficacy. Methods: Since 2021, 20 patients (of those 8 men; median age 59.0 [52.0; 63.0] years, median body mass index 29.6 [28.5; 33.1] kg/m2) with morphologically verified rectal cancer (T3-4N0M0 and T3-4N1M0, differentiation grade G1–G3) have been participating in the study. They were treated with TRCT: external gamma therapy (2 Gy, 1 fraction/day, 5 days/week, total focal dose 54 Gy), chemotherapy with capecitabine (825 mg/m2 twice daily) combined with local hyperthermia (42–44 °C, 60 min, 3 times/week, 10 sessions). The TRCT efficacy was assessed by RECIST 1.1 and ESGAR criteria. Blood samples for exosomes were taken from the patients at baseline (point 1), in the middle of the treatment course (point 2), at 6 to 10 weeks after the end of TRCT (point 3), and at 6 months after point 1 (point 4). Small extracellular vesicles were isolated from plasma by ultrafiltration with double ultracentrifugation. The isolated exosomes were characterized by transmission electronic microscopy, flow cytometry and nanoparticle trajectory analysis (NTA). Results: TRCT resulted in complete tumor regression in 13/20 of the rectal cancer patients and partial regression or stabilization in 7/20. Four subpopulations of CD9+ and FABP4+ exosomes associated with the TRCT efficacy were identified (CD9+MMP2+, СD9+MMP2+9+TIMP1+, СD9+MMP2+9+TIMP1-, and FABP4+MMP2+9-TIMP1+). Compared to the CD9+ exosomes, the adipocytic vesicles had higher MMP2 expression (p = 0.026); however, the adipocyte vesicles subpopulation were virtually free of vesicles with combined MMP2 and MMP9 gelatinase expression. The HSPs expression by circulating exosomes at various TRCT steps was associated neither with direct treatment efficacy nor with the vesicle type. Conclusion: The expression of MMPs and TIMP1 on CD9+ and FABP4+ exosomes is associated with TRCT efficacy. In the future, vesicular markers could be used to build prognostic models, to identify patient groups with an unfavorable prognosis, and to personalize treatment and follow-up.
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