ccRCC is fundamentally a metabolic disorder

Clear cell renal-cell carcinoma (ccRCC) represents the most common RCC subtype, being exceptionally resistant to therapy and responding poorly to radiotherapy, hormonal therapy and chemotherapy¹; thus urging the development of early diagnostic markers for this particular RCC subtype. Hypoxic, rapidly proliferating tumor cells predominantly exhibit a metabolic switch toward aerobic glycolysis (the Warburg effect), which is characterized by an increase in glucose catabolism to lactate at the expense of mitochondrial oxidation.² In fact, glutamine is able of contributing to citrate and lipid metabolism by reversing the tricarboxylic acid (TCA) cycle or through the reductive carboxylation of α-ketoglutarate or even through forward cycling of glutamine carbons (Fig. 1).

Figure 1.

In aerobic proliferating cells glucose and glutamine are used to produce the necessary biomass through the tricarboxylic acid (TCA) cycle (left). In hypoxic cells, glucose is shunt to lactate resulting in rewiring of the glutamine metabolism (right). Glutamine can be used to drive the TCA cycle independently of glucose or contribute to lipid synthesis via isocitrate dehydrogenase (IDH)-mediated reductive carboxylation of α-ketoglutarate that is generated from glutamine.

Lately, great interest in tumor metabolism has come again into the surface, as a growing number of reports expose the molecular link between cellular transformation and metabolism. We recently performed a meta-analysis of various publicly available gene expression datasets in order to identify the deregulated genes in ccRCC and to measure their discriminatory capability from the normal kidney. We focused our study on the top co-deregulated genes among 5 microarray data sets and investigated the canonical pathways in which they are implicated, the networks that they form and their associated functions. The deregulated expression pattern of these genes was further validated in 2 ccRCC cell lines and a patient cohort.³ Our data highlight that kidney cancer cells manipulate more than one molecular mechanisms and a number of biological pathways to achieve their aggressive phenotype. The top co-deregulated genes were found to participate in the antigen presentation pathway and cytotoxic T lymphocyte (CTL)-mediated apoptosis of target cells, thus highlighting the importance of autoantibodies produced against tumor-associated antigens.³ However, since the majority of the top co-deregulated genes were found to participate in inositol metabolism, the pentose phosphate pathway (PPP), glycolysis/gluconeogenesis, and metabolism of fructose and mannose, emphasis was put on the notion that ccRCC is fundamentally a metabolic disorder.³ All these pathways account for higher rates of nucleic acid and protein biosynthesis and higher energy demands that aggressive tumors have.

In order to synthesize new nucleotides, cells require more ribose 5-phosphates, which they produce by diverting carbon from glycolysis into either the oxidative or non-oxidative strand of the PPP. An increased glycolysis in ccRCC, as measured by high levels of lactate, was recently reported by others.^4,5 Increased glycolysis has been noted among other tumor types, as well. In metastasis, the glycolytic phenotype has been hypothesized to arise as a result of transient hypoxic episodes that occur while cells travel to distant sites through the bloodstream.⁶ Ultimately, cells that are able to perform glycolysis and are resistant to hypoxia, are selectively favored for survival and growth and result in successful metastasis.⁶ Highly expressed reactions in the metabolism of fructose and mannose principally include the conversion of D-fructose, D-fructose-1P and D-mannose into glyceraldehyde-3P (GA3P), which is a substrate of glycolysis that leads to augmented production of ATP.

Most researchers studying tumor metabolism are driven by one of two general notions regarding how cellular metabolism is regulated. The first idea is that tumor metabolism is principally the result of stress imposed on cells during tumor growth. Ample evidence shows that hypoxia in the tumor microenvironment dramatically affects cellular metabolism.⁶ Nevertheless, glycolytic change can still appear even in the abundance of oxygen (hyperoxia) in tumors; thus leading to specific deficiencies in the biosynthesis of proteins and lipids and resulting in inefficient cellular growth and proliferation. Therefore, the cellular responses to hypoxia in tumors, together with enhanced glycolysis, assist tumor cell survival, not growth.

On the other hand, tumor cell metabolic activities are considered to function primarily in order to support the abnormally elevated rates of cellular growth and proliferation, both characteristics of tumor cells. Since the required number of proteins, lipids and nucleic acids is the double in each round of cellular division, the tumor cell metabolism needs to provide for all the necessary energy and biosynthesis. Rapidly growing tumor cells need to seize nutrients and to be able to process them in the appropriate metabolic pathways, in order to convert their carbon and nitrogen to macromolecules. The Warburg effect, synthesis of fatty acids and metabolism of glutamine in the mitochondria, all happen along with cellular growth, and there's now enough evidence to show that these pathways work together in order to produce as many macromolecules as possible, in those rapidly multiplying cells.⁷

The reversal of the Warburg effect could be a promising novel treatment for ccRCC. However, a deeper understanding of the mechanisms driving altered metabolic pathways is the key for the development of novel targeted therapies in this kidney tumor.