Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
Eur Urol Focus. 2019 Jul;5(4):608-618. doi: 10.1016/j.euf.2018.01.016. Epub 2018 Feb 13.
Renal cell carcinoma (RCC) consists of prognostic distinct subtypes derived from different cells of origin (eg, clear cell RCC [ccRCC], papillary RCC [papRCC], and chromophobe RCC [chRCC]). ccRCC is characterized by lipid accumulation and metabolic alterations, whereas data on metabolic alterations in non-ccRCC are limited.
We assessed metabolic alterations and the lipid composition of RCC subtypes and ccRCC-derived metastases. Moreover, we elucidated the potential of metabolites/lipids for subtype classification and identification of therapeutic targets.
DESIGN, SETTING, AND PARTICIPANTS: Metabolomic/lipidomic profiles were quantified in ccRCC (n=58), chRCC (n=19), papRCC (n=14), corresponding nontumor tissues, and metastases (n=9) through a targeted metabolomic approach. Transcriptome profiling was performed in corresponding samples and compared with expression data of The Cancer Genome Atlas cohorts (patients with ccRCC, n=452; patients with papRCC, n=260; and patients with chRCC, n=59).
In addition to cluster analyses, metabolomic/transcriptomic data were analyzed to evaluate metabolic differences of ccRCC and chRCC using Welch's t test or paired t test as appropriate. Where indicated, p values were adjusted for multiple testing using Bonferroni or Benjamini-Hochberg correction.
Based on their metabolic profiles, RCC subtypes clustered into two groups separating ccRCC and papRCC from chRCC, which mainly reflected the different cells of origin. ccRCC-derived metastases clustered with primary ccRCCs. In addition to differences in certain lipids (lysophosphatidylcholines and sphingomyelins), the coregulation network of lipids differed between ccRCC and chRCC. Consideration of metabolic gene expression indicated, for example, alterations of the polyamine pathway at metabolite and transcript levels. In vitro treatment of RCC cells with the ornithine-decarboxylase inhibitor difluoromethylornithine resulted in reduced cell viability and mitochondrial activity. Further evaluation of clinical utility was limited by the retrospective study design and cohort size.
In summary, we provide novel insight into the metabolic profiles of ccRCC and non-ccRCC, thereby confirming the different ontogeny of RCC subtypes. Quantification of differentially regulated metabolites/lipids improves classification of RCC with an impact on the identification of novel therapeutic targets.
Several subtypes of renal cell carcinoma (RCC) with different metastatic potentials and prognoses exist. In the present study, we provide novel insight into the metabolism of these different subtypes, which improves classification of subtypes and helps identify novel targets for RCC therapy.
肾细胞癌（RCC）由不同起源细胞衍生的预后不同的亚型组成（例如，透明细胞 RCC [ccRCC]、乳头状 RCC [papRCC]和嫌色细胞 RCC [chRCC]）。ccRCC 的特征是脂质积累和代谢改变，而关于非 ccRCC 的代谢改变的数据有限。
我们评估了 RCC 亚型和 ccRCC 衍生转移瘤的代谢改变和脂质组成。此外，我们还阐明了代谢物/脂质在亚型分类和鉴定治疗靶点方面的潜力。
设计、设置和参与者：通过靶向代谢组学方法，定量测定 ccRCC（n=58）、chRCC（n=19）、papRCC（n=14）、相应非肿瘤组织和转移瘤（n=9）的代谢组学/脂质组学图谱。在相应的样本中进行转录组谱分析，并与癌症基因组图谱队列的表达数据进行比较（ccRCC 患者，n=452；papRCC 患者，n=260；chRCC 患者，n=59）。
除了聚类分析外，还使用 Welch's t 检验或适当的配对 t 检验分析代谢组学/转录组学数据，以评估 ccRCC 和 chRCC 的代谢差异。在需要的情况下，使用 Bonferroni 或 Benjamini-Hochberg 校正对 p 值进行了多次测试校正。
总之，我们提供了关于 ccRCC 和非 ccRCC 代谢谱的新见解，从而证实了 RCC 亚型的不同发生机制。定量测定差异调节的代谢物/脂质可提高 RCC 的分类，有助于鉴定新的治疗靶点。
存在几种具有不同转移潜能和预后的肾细胞癌（RCC）亚型。在本研究中，我们对这些不同亚型的代谢情况提供了新的见解，这提高了亚型的分类，并有助于鉴定 RCC 治疗的新靶点。
