Zhang Yue, Udayakumar Durga, Cai Ling, Hu Zeping, Kapur Payal, Kho Eun-Young, Pavía-Jiménez Andrea, Fulkerson Michael, de Leon Alberto Diaz, Yuan Qing, Dimitrov Ivan E, Yokoo Takeshi, Ye Jin, Mitsche Matthew A, Kim Hyeonwoo, McDonald Jeffrey G, Xi Yin, Madhuranthakam Ananth J, Dwivedi Durgesh K, Lenkinski Robert E, Cadeddu Jeffrey A, Margulis Vitaly, Brugarolas James, DeBerardinis Ralph J, Pedrosa Ivan
Radiology.
Advanced Imaging Research Center.
JCI Insight. 2017 Aug 3;2(15). doi: 10.1172/jci.insight.94278.
Dysregulated lipid and glucose metabolism in clear cell renal cell carcinoma (ccRCC) has been implicated in disease progression, and whole tumor tissue-based assessment of these changes is challenged by the tumor heterogeneity. We studied a noninvasive quantitative MRI method that predicts metabolic alterations in the whole tumor.
We applied Dixon-based MRI for in vivo quantification of lipid accumulation (fat fraction [FF]) in targeted regions of interest of 45 primary ccRCCs and correlated these MRI measures to mass spectrometry-based lipidomics and metabolomics of anatomically colocalized tissue samples isolated from the same tumor after surgery.
In vivo tumor FF showed statistically significant (P < 0.0001) positive correlation with histologic fat content (Spearman correlation coefficient, ρ = 0.79), spectrometric triglycerides (ρ = 0.56) and cholesterol (ρ = 0.47); it showed negative correlation with free fatty acids (ρ = -0.44) and phospholipids (ρ = -0.65). We observed both inter- and intratumoral heterogeneity in lipid accumulation within the same tumor grade, whereas most aggressive tumors (International Society of Urological Pathology [ISUP] grade 4) exhibited reduced lipid accumulation. Cellular metabolites in tumors were altered compared with adjacent renal parenchyma.
Our results support the use of noninvasive quantitative Dixon-based MRI as a biomarker of reprogrammed lipid metabolism in ccRCC, which may serve as a predictor of tumor aggressiveness before surgical intervention.
NIH R01CA154475 (YZ, MF, PK, IP), NIH P50CA196516 (IP, JB, RJD, JAC, PK), Welch Foundation I-1832 (JY), and NIH P01HL020948 (JGM).
透明细胞肾细胞癌（ccRCC）中脂质和葡萄糖代谢失调与疾病进展有关，而基于全肿瘤组织的这些变化评估受到肿瘤异质性的挑战。我们研究了一种非侵入性定量MRI方法，该方法可预测整个肿瘤中的代谢改变。
我们应用基于 Dixon 的 MRI 对 45 例原发性 ccRCC 的感兴趣靶区域内的脂质蓄积（脂肪分数[FF]）进行体内定量，并将这些 MRI 测量结果与基于质谱的脂质组学和代谢组学相关联，这些脂质组学和代谢组学来自于手术后从同一肿瘤中分离出的解剖学上共定位的组织样本。
体内肿瘤 FF 与组织学脂肪含量（Spearman 相关系数，ρ = 0.79）、光谱测定的甘油三酯（ρ = 0.56）和胆固醇（ρ = 0.47）呈统计学显著（P < 0.0001）正相关；与游离脂肪酸（ρ = -0.44）和磷脂（ρ = -0.65）呈负相关。我们在同一肿瘤分级内观察到脂质蓄积的瘤间和瘤内异质性，而大多数侵袭性肿瘤（国际泌尿病理学会[ISUP]4 级）表现出脂质蓄积减少。与相邻肾实质相比，肿瘤中的细胞代谢物发生了改变。
我们的结果支持使用基于 Dixon 的非侵入性定量 MRI 作为 ccRCC 中脂质代谢重编程的生物标志物，这可能作为手术干预前肿瘤侵袭性的预测指标。
美国国立卫生研究院 R01CA154475（YZ、MF、PK、IP）、美国国立卫生研究院 P50CA196516（IP、JB、RJD、JAC、PK）、韦尔奇基金会 I-1832（JY）和美国国立卫生研究院 P01HL020948（JGM）。
