Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer.
Impact of tumor microenvironment and epithelial phenotypes on metabolism in breast cancer.
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DOI：
10.1158/1078-0432.ccr-12-2123
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发表时间：
2013-02-01
期刊：
影响因子：
--
通讯作者：
Troester MA
中科院分区：
文献类型：
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作者：
Brauer HA;Makowski L;Hoadley KA;Casbas-Hernandez P;Lang LJ;Romàn-Pèrez E;D'Arcy M;Freemerman AJ;Perou CM;Troester MA
癌细胞改变了代谢，增加了葡萄糖摄取、糖酵解和生物质生产。本研究进行了基因组学和代谢组学分析，以阐明肿瘤和间质基因组学特征如何影响肿瘤代谢。33例乳腺肿瘤和6例正常乳腺组织通过基因表达微阵列和质谱分析代谢产物。与代谢表型相关的基因表达数据和临床特征进行了评价。为了评估基质相互作用在代谢改变中的作用，使用乳腺癌细胞和原发性癌症相关成纤维细胞（CAF）进行共培养。在所有代谢物中，无监督聚类产生两个主要样品聚类。正常乳腺组织和具有较低侵袭性临床特征的肿瘤子集具有较低水平的核酸和氨基酸以及糖酵解副产物，而更具侵袭性的肿瘤具有较高水平的这些Warburg相关代谢物。虽然肿瘤内在亚型不能预测代谢表型，但代谢簇与伤口反应特征的表达显著相关。在共培养物中，CAFs从基底样乳腺癌增加葡萄糖摄取和基底样上皮细胞增加葡萄糖氧化和糖原合成，表明代谢的基质和上皮表型的相互作用。细胞因子阵列鉴定肝细胞生长因子（HGF）作为基质-上皮相互作用的潜在介质，HGF的抗体中和导致葡萄糖转运蛋白1（GLUT 1）表达减少和上皮细胞葡萄糖摄取减少。肿瘤/上皮和间质特征在代谢中起重要作用。Warburg样代谢受基质-上皮相互作用变化的影响，包括HGF/Met途径和GLUT 1表达的改变。
Cancer cells have altered metabolism, with increased glucose uptake, glycolysis, and biomass production. This study performed genomic and metabolomic analyses to elucidate how tumor and stromal genomic characteristics influence tumor metabolism. Thirty-three breast tumors and six normal breast tissues were analyzed by gene expression microarray and by mass spectrometry for metabolites. Gene expression data and clinical characteristics were evaluated in association with metabolic phenotype. To evaluate the role of stromal interactions in altered metabolism, cocultures were performed using breast cancer cells and primary cancer-associated fibroblasts (CAFs). Across all metabolites, unsupervised clustering resulted in two main sample clusters. Normal breast tissue and a subset of tumors with less aggressive clinical characteristics had lower levels of nucleic and amino acids and glycolysis byproducts, while more aggressive tumors had higher levels of these Warburg-associated metabolites. While tumor intrinsic subtype did not predict metabolic phenotype, metabolic cluster was significantly associated with expression of a wound response signature. In cocultures, CAFs from basal-like breast cancers increased glucose up take and basal-like epithelial cells increased glucose oxidation and glycogen synthesis, suggesting interplay of stromal and epithelial phenotypes on metabolism. Cytokine arrays identified hepatocyte growth factor (HGF) as a potential mediator of stromal-epithelial interaction, and antibody neutralization of HGF resulted in reduced expression of glucose transporter 1 (GLUT1) and decreased glucose uptake by epithelium. Both tumor/epithelial and stromal characteristics play important roles in metabolism. Warburg-like metabolism is influenced by changes in stromal-epithelial interactions, including altered expression of HGF/Met pathway and GLUT1 expression.