Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small-cell lung cancer study.
Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small-cell lung cancer study.
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DOI：
10.1101/mcs.a000893
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发表时间：
2016-07
影响因子：
1.8
通讯作者：
Lane AN
中科院分区：
文献类型：
--
作者：
Fan TW;Warmoes MO;Sun Q;Song H;Turchan-Cholewo J;Martin JT;Mahan A;Higashi RM;Lane AN
肿瘤和基质细胞代谢对于理解高度依赖于肿瘤微环境（TME）的肿瘤发展是重要的。细胞或动物模型不能概括人类TME。我们已经开发了一种离体配对的癌性（CA）和非癌性（NC）人肺组织方法来探索天然人TME中的癌症和基质细胞代谢。这种方法能够完全控制实验参数和采集个体患者的靶组织对治疗剂的反应，同时消除遗传和生理变异的干扰。在这两个非小细胞肺癌病例研究中，我们对用巨噬细胞活化剂β-葡聚糖和13 C6-葡萄糖处理的配对CA和NC肺组织进行了稳定同位素分辨代谢组学（SIRM）实验，然后对代谢物的13 C标记模式进行了离子色谱-傅立叶变换质谱（IC-FTMS）和核磁共振（NMR）分析。我们证明，CA肺组织切片比其NC对应物代谢更活跃，这概括了在体内观察到的CA肺组织中的代谢重编程。我们在患有慢性阻塞性肺疾病（COPD）和大量肿瘤相关巨噬细胞（TAM）的患者UK 021中发现了β-葡聚糖增强的糖酵解、克雷布斯循环、磷酸戊糖途径、抗氧化剂产生和衣康酸盐积聚，但在没有COPD和巨噬细胞浸润少得多的患者UK 049中没有发现。UK 021组织的这种代谢反应伴随有丝分裂指数降低、坏死增加和诱导型一氧化氮合酶（iNOS）表达增强。我们推测重编程网络可以反映人巨噬细胞β-葡聚糖M1的极化。本病例研究提供了一个独特的机会，研究人类巨噬细胞在其原生微环境中对免疫调节剂的代谢反应，以个体患者为基础。
Cancer and stromal cell metabolism is important for understanding tumor development, which highly depends on the tumor microenvironment (TME). Cell or animal models cannot recapitulate the human TME. We have developed an ex vivo paired cancerous (CA) and noncancerous (NC) human lung tissue approach to explore cancer and stromal cell metabolism in the native human TME. This approach enabled full control of experimental parameters and acquisition of individual patient's target tissue response to therapeutic agents while eliminating interferences from genetic and physiological variations. In this two-case study of non-small-cell lung cancer, we performed stable isotope-resolved metabolomic (SIRM) experiments on paired CA and NC lung tissues treated with a macrophage activator β-glucan and 13C6-glucose, followed by ion chromatography–Fourier transform mass spectrometry (IC-FTMS) and nuclear magnetic resonance (NMR) analyses of 13C-labeling patterns of metabolites. We demonstrated that CA lung tissue slices were metabolically more active than their NC counterparts, which recapitulated the metabolic reprogramming in CA lung tissues observed in vivo. We showed β-glucan-enhanced glycolysis, Krebs cycle, pentose phosphate pathway, antioxidant production, and itaconate buildup in patient UK021 with chronic obstructive pulmonary disease (COPD) and an abundance of tumor-associated macrophages (TAMs) but not in UK049 with no COPD and much less macrophage infiltration. This metabolic response of UK021 tissues was accompanied by reduced mitotic index, increased necrosis, and enhaced inducible nitric oxide synthase (iNOS) expression. We surmise that the reprogrammed networks could reflect β-glucan M1 polarization of human macrophages. This case study presents a unique opportunity for investigating metabolic responses of human macrophages to immune modulators in their native microenvironment on an individual patient basis.