Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression

Abstract

Purpose: Clear cell renal cell carcinoma (ccRCC) has recently been redefined as a highly heterogeneous disease. In addition to genetic heterogeneity, the tumor displays risk variability for developing metastatic disease, therefore underscoring the urgent need for tissue-based prognostic strategies applicable to the clinical setting. We have recently employed the novel PET/magnetic resonance (MR) image modality to enrich our understanding of how tumor heterogeneity can relate to gene expression and tumor biology to assist in defining individualized treatment plans.Experimental Design: ccRCC patients underwent PET/MR imaging, and these images subsequently used to identify areas of varied intensity for sampling. Samples from 8 patients were subjected to histologic, immunohistochemical, and microarray analysis.Results: Tumor subsamples displayed a range of heterogeneity for common features of hypoxia-inducible factor expression and microvessel density, as well as for features closely linked to metabolic processes, such as GLUT1 and FBP1. In addition, gene signatures linked with disease risk (ccA and ccB) also demonstrated variable heterogeneity, with most tumors displaying a dominant panel of features across the sampled regions. Intriguingly, the ccA-and ccB-classified samples corresponded with metabolic features and functional imaging levels. These correlations further linked a variety of metabolic pathways (i.e., the pentose phosphate and mTOR pathways) with the more aggressive, and glucose avid ccB subtype.Conclusions: Higher tumor dependency on exogenous glucose accompanies the development of features associated with the poor risk ccB subgroup. Linking these panels of features may provide the opportunity to create functional maps to enable enhanced visualization of the heterogeneous biologic processes of an individual's disease.

Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas

“…These findings suggest that there are either inherent metabolic differences that may influence the progression of ccRCC tumors, or that a metabolic switch occurs favoring HIF targeted glycolytic gene expression and higher rates of glycolysis during tumor progression, the latter of which has been suggested by studies showing fructose bisphosphatase 1 downregulation, and commensurate increase in glucose uptake in tumor samples displaying loss of this enzyme and patterns of poor risk gene expression (31, 32). Although the mechanisms by which these metabolic differences contribute to tumor progression have not yet been elucidated, these findings may help to explain some of the heterogeneity that is observed between ccRCC cases.…”

Renal cancer subtypes: Should we be lumping or splitting for therapeutic decision making?

“…16,39,40 In addition, these molecular subtypes feature distinct metabolic patterns, with the aggressive ccB tumors demonstrating increased glucose uptake on imaging. 41 However, the other clear finding from that study was that individual tumors can harbor both ccA and ccB components, making this classification strategy difficult for informing therapeutic selec-tion, although it has emerged as a strong prognostic indicator in numerous studies. 40,42 Other investigators have successfully merged gene expression data with metabolomics profiling to parse clear cell RCC into multiple molecular subtypes, including an aggressive cohort with increased glutathione metabolism.…”

Development and verification of a nomogram for prediction of recurrence‐free survival in clear cell renal cell carcinoma

“…6 Analysing gene expression profiles of different cancer tissues or cells, with different tumour stages, may be helpful for identification of characteristic risk gene signature in cancer. 6 Analysing gene expression profiles of different cancer tissues or cells, with different tumour stages, may be helpful for identification of characteristic risk gene signature in cancer.…”