During the course of tumor initiation and progression, cancer cells need to reprogram their metabolic pathways in order to respond to the demanding requirements for their own growth. This re-programming is accomplished by both genetic and epigenetic alterations of various metabolic genes, and the dysregulations of some of these genes are directly involved in the initial step of transformation while others contribute to maintenance and acceleration of malignant phenotypes. However it is still not clear how and when these changes occur in normal cells. For example, the dysregulation of the FAS gene is often observed at very early stages of cancer and in benign tumors, suggesting the direct role of this gene in tumor initiation. However, how and what causes this dysregulation remains unknown, and understanding the mechanism and identifying the factors contributing to these changes is of paramount interest. It is suspected that not only carcinogens, but also dietary factors, hormonal balance, inflammatory conditions and tumor microenvironment such as stroma and ECM are all likely to be involved in the re-programming process of metabolic pathways. In this context, it is worth noting that some metabolic abnormalities such as diabetes and even ageing are linked with higher incidence of cancers. However, whether these abnormalities are directly involved in tumorigenesis remains to be determined.
It is well established that HIF1, AMPK and LKB play central roles in keeping the balance of cell metabolism for survival and growth under various stressful environments such as hypoxic, acidic and low nutrient conditions. Furthermore, recent findings indicate that the sensitivity of tumor cells to dietary restriction is closely associated with activation of PI3K pathway, suggesting a key role of this pathway in balancing metabolic homeostasis. It is also noted that the PI3K/AKT pathway directly controls lipogenesis by up-regulating SREBP1 which is considered to be a master control gene of various lipogenic genes (177
). Oncogenes that encode transcription factors are also actively involved in regulation of cellular metabolism. For example, Myc is known to regulate Glut1 and other genes in glycolysis. Myc can directly bind the promoters of these genes with other co-factors (eg. E2F1 for nucleotide metabolism and HIF1 for glucose metabolism) and significantly up-regulate the target genes. Therefore, metabolic changes in tumor cell are also modulated by activation of these oncogenes; however, dissecting the exact molecular mechanism of this process is critically important in order to identify a specific target for both preventive and therapeutic intervention.
Another key question is homeostasis and crosstalk of each pathway after the re-programming in cancer cells. For example, dysregulation of the Glut1 gene affects not only glycolytic pathway but also lipogenesis because glycolysis generates substrate for TCA cycle which ultimately provides a precursor for lipogenesis. In addition, glycolysis and lipogenesis are closely linked through the redox pathway. Despite ill-functioning mitochondria and the Warburg effect, the balance of these pathways is still well maintained in the cancer cells during their survival and aggressive growth, suggesting that an alternative balancing mechanism needs to be in place, although how this compensatory mechanism works is yet to be defined.
The higher glucose uptake is indeed observed in the majority of tumor cells as originally found by Otto Warburg. However, impairment of mitochondrial function in cancer cells is still a controversial issue. These conflicting observations are perhaps due to the different experimental approaches including different tumor cell lines, culture methods (mostly monolayers) and assay procedures of mitochondrial functions. Rodríguez-Enríquez et al. recently addressed this question using spheroid tumor model (178
). The authors showed that mitochondrial activities markedly decreased in a late stage of spheroid, whereas activity of glycolysis significantly increased with concomitant over-expression of HIF1. Therefore, the level of mitochondrial function appears to be dependent on the stage of tumor growth and location of each cell in tumor mass. The central region of tumor mass is often necrotic and hence under hypoxic condition which profoundly affects the balance between mitochondrial function and glycolytic flux. It is also known that stabilization of HIF1α is induced by oncogenes such as Ras, Src and Myc followed by stimulation of aerobic glycolysis. In addition, expression level of H+-ATP synthase, a key enzyme of oxidative phosphorylation, was shown to be significantly decreased in lung cancer cells, and blocking the enzymatic activity promoted glycolytic flux (179
). Furthermore, the inhibition of the same enzyme enhanced cell survival by attenuating ROS which is known to control apoptosis (180
), while augmentation of mitochondrial metabolism induced suppression of tumor growth (181
). Fantin et al. also showed that enhancement of mitochondrial metabolism by inhibiting LDHA diminished tumorigenecity of cancer cells (182
). These results suggest that mitochondrial function is likely to be intact in tumor cells; however, the level of their activities is heavily dependent on their microenvironment, mainly on availability of oxygen in the tumor mass, and that different tumor cells adapt different survival strategies and energy metabolism even in the same tumor mass by changing the balance between glycolysis and oxidative phosphorylation.
Re-programming of metabolic pathways in cancer stem cell is another important aspect of recent tumor biology and has critical therapeutic implication. Are the metabolic genes already mutated in cancer stem cells? If so, when and how does it occur? How do they affect the abilities of self-renewal and differentiation of the cancer stem cell? What are the roles of niche or microenvironment in the metabolism of the tumor stem cell at both primary and metastatic sites? Answers to these questions are virtually unknown at present; however, understanding the underlining mechanism of metabolic re-programming in cancer stem cell may provide important clues for novel therapeutic targets. It should be noted that cancer stem cell is likely to be responsible for chemo-resistance according to the recent stem cell theory. Therefore, elucidating these questions may also provide us with a tool to overcome the problem of chemoresistant cancers.
Identifying small chemicals to specifically intervene in metabolic pathways and inhibit the function of metabolic genes is considered to be a promising approach to develop a novel type of anti-cancer drug, and it is under active investigation. Some of these compounds, such as 2-DG for glycolysis and CALAA-01 for nucleotide metabolism, are already in clinical trials. For lipogenesis, FAS is particularly an attractive target because of its specific expression in various types of cancers and blocking this enzymatic function is known to induce tumor cell apoptosis. However, considering the balancing and compensatory mechanism of each pathway in cancer cells, simultaneous blocking of multiple pathways instead of targeting a single gene is likely to be a more effective approach. Because the metabolic genes are mostly up-regulated at an early stage of cancer, they are also considered to be ideal targets for chemo-prevention which is by far the most cost effective way to fight cancer. Some of the metabolic genes and their products are also likely to serve as useful diagnostic tools, and FAS and PGI are promising examples. Perhaps more aggressive proteomics approach using serum and urine from a cohort of patients with various cancers may identify better diagnostic markers of metabolic pathways.