Metabolism represents the set of life-sustaining chemical reactions in cells and is essential for cancer progression. We evaluated metabolite profiles in advanced EOC tissues using metabolome analysis and analyzed alteration in energy metabolism.
Urea concentration was significantly decreased in the OMC group than in the PC group and alterations of the urea cycle were observed. The urea cycle is an essential pathway for the disposal of ammonia, and enzymes of this cycle in non-hepatic cells are regulated by a variety of pro- and anti-inflammatory cytokines . Thus, the relationship between the alteration of the urea cycle and cancer progression has been presented . Our results indicated that the citrulline/ornithine ratio was increased in OMC and considered to reflect decreased arginase activity and increased NOS activity. As a result, NO was also considered to be increased. The function of NO is somewhat ambivalent, but NO primarily promotes cancer-related events, such as angiogenesis, apoptosis, and cell cycle . Unfortunately, in this analysis, NO was not a target compound and further studies are needed to evaluate urea cycle dysfunction and NO during EOC progression.
Next, we focused on glycometabolism that is essential for cell survival and unique to cancer tissues according to Warburg [12-15]. In addition to glycolysis, the PPP is also a major pathway for glucose catabolism and plays an important role in cancer cell survival and growth [15, 28-30]. The PPP is classified into two biochemical branches known as the oxidative and non-oxidative PPP. In the former, the chemical reaction is irreversible and two molecules of NADPH are generated from one molecule of glucose, whereas, in the latter phase, the five-carbon sugar, R5P, is generated from a six-carbon glucose molecule. However, this phase is reversible (Fig. 3B). Therefore, depending on which phase of the PPP is activated, the production of NADPH and R5P is regulated [28-30]. Our results indicate that the OMC exhibited a low G6P/R5P ratio. Therefore, the PPP was dominant in the OMC and the demand for R5P and NADPH was increased. However, NADPH concentrations were similar in all of the samples. The consumption of NAPDH may have been increased in the OMC due to oxidative stress. Otherwise, the OMC cells may produce more R5P than NAPDH by activating the non-oxidative phase of the PPP. In addition, the proportion of cancer stem cells (CSCs) exhibiting enhanced PPP metabolism may be increased in the OMC tissues [28, 31]. Hence, the significance of the PPP in cancer progression should be reconsidered. Next, we evaluated glycolysis as the Warburg effect predicts that cancer cells use glycolysis even under aerobic conditions [12, 15]. We discovered that the lactate/pyruvate ratio was decreased in the OMC. This suggests that the oxygen environment is different at metastatic sites and cancer cells may change energy metabolism process based on their environment. Alteration of glycolysis between PC and OMC was also previously reported, although the detailed metabolic changes were not consistent with our results . Therefore, the heterogeneity of cancer cells and individual differences may be significant and further larger-scale studies are needed.
We demonstrated that HGSOCs contained significantly more glutamine and other amino acids than non-serous carcinomas. Glutamine was the prominent amino acid and it has been reported that proliferating cells require glutamine since the 1950s [15, 33]. In addition, highly proliferative cells produce high levels of reactive oxygen species (ROS) . To maintain the intracellular redox balance, NADPH and GSH play an important role and elevated GSH levels are observed in various tumor types [24, 35]. We observed high glutamine and GSH levels in HGSOC, which may reflect a high proliferative potential. Moreover, GSH is known to mediate resistance to platinum analogs through several mechanisms including increased DNA repair and the inhibition of apoptosis [35, 36]. Thus, GSH represents a potent therapeutic target and several inhibitors have been evaluated [35, 36]. Based on our results, the efficacy of GSH-targeted therapy should be separately evaluated for various histological subtypes.
Finally, we observed differences in polyamine concentrations among the histological subtypes. Polyamines are involved in many fundamental processes of cell growth and survival and polyamine metabolism is associated with cancer-driving pathways including the PTEN–PI3K–mTOR complex 1, WNT signaling, and RAS pathways . In addition, a previous study reported that cycline E1-driven EOC was associated with activated polyamine synthesis and decreased cancer immunity . Therefore, several polyamine-targeted drugs might exhibit efficacy in EOC, especially EGSOC .
This metabolome-based study has several limitations. First, detailed molecular biological changes such as genetic mutations, mRNA and protein expression, and enzyme activities were not evaluated. Second, lipidomics was not done, although it is an interesting approach because the omentum is characterized by an adipose-rich microenvironment. However, lipid metabolites were not measurable with of C-SCOPE. Therefore, these metabolomic changes related to those molecules are worth evaluating in the future.