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Multi-omics analysis reveals adipose-tumor crosstalk in colorectal cancer patients
Cancer Prevention Research ( IF 2.9 ) Pub Date : 2020-07-12 , DOI: 10.1158/1940-6207.capr-19-0538
Andreana N Holowatyj 1, 2, 3, 4 , Mariam Haffa 5, 6 , Tengda Lin 1, 2 , Dominique Scherer 7 , Biljana Gigic 7 , Jennifer Ose 1, 2 , Christy A Warby 1, 2 , Caroline Himbert 1, 2 , Clare Abbenhardt-Martin 5, 6 , David Achaintre 8 , Juergen Boehm 1, 2 , Kenneth M Boucher 1 , Audrey Gicquiau 8 , Andrea Gsur 9 , Nina Habermann 10 , Esther Herpel 6, 11 , Hans-Ulrich Kauczor 7 , Pekka Keski-Rahkonen 8 , Matthias Kloor 10 , Magnus von Knebel-Doeberitz 10 , Dieuwertje E Kok 12 , Johanna Nattenmüller 7 , Peter Schirmacher 6, 10 , Martin Schneider 7 , Petra Schrotz-King 5, 6 , Thomas Simon 13 , Per M Ueland 14 , Richard Viskochil 1, 2 , Matty P Weijenberg 15 , Augustin Scalbert 8 , Alexis Ulrich 7 , Laura W Bowers 16, 17, 18 , Stephen D Hursting 17, 18 , Cornelia M Ulrich 1, 2
Affiliation  

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte–colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling—the major signaling receptor for collagen—as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition—as in fibrosis and metastasis—and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose–tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose–tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted. See related spotlight by Colacino et al., p. 803

中文翻译:


多组学分析揭示结直肠癌患者的脂肪-肿瘤串扰



全球范围内,肥胖和肥胖导致的癌症发病率持续上升。我们假设脂肪细胞与结肠细胞的相互作用是肥胖相关癌症的关键驱动因素。为了了解内脏脂肪组织在促进肿瘤生长中的临床相关性,我们分析了配对的肿瘤邻近内脏脂肪、正常粘膜和结直肠肿瘤组织以及散发性结直肠癌患者的术前血液样本。我们报告过氧化物酶体增殖物激活受体γ(PPARG)内脏脂肪组织的高表达与糖蛋白VI(GPVI)信号传导(胶原蛋白的主要信号传导受体)以及结直肠肿瘤中的纤维化和脂肪生成途径信号传导相关。这些关联得到 PPARG 内脏脂肪组织表达与血浆 4-羟脯氨酸和血清细胞间粘附分子 1 (ICAM1) 循环水平之间的相关性以及基因集富集分析和联合基因代谢途径结果整合的支持,这些结果产生了显着富集的定义上皮间质转变(如纤维化和转移)的基因以及参与糖酵解代谢的基因证实了这种关联。我们还发现前列腺素内过氧化物合酶 2 (PTGS2) 结直肠肿瘤表达升高与通过 GPVI 信号传导和内脏脂肪组织中树突状细胞成熟的脂肪-肿瘤串扰中的纤维化特征相关。全身代谢物和生物标志物分析证实,结直肠肿瘤中 PTGS2 的高表达与结直肠癌患者血清淀粉样蛋白 A 和甘氨酸浓度较高以及鞘磷脂浓度较低显着相关。 这项多组学研究表明,结直肠癌患者的脂肪-肿瘤串扰是一种关键的微环境相互作用,可以作为治疗目标。请参阅 Colacino 等人的相关聚焦,第 17 页。 803
更新日期:2020-07-12
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