Метаболизм опухолей: особенности и роль в развитии рака.

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine. Although the link between the cancer and metabolism was observed in the early days of cancer research by Otto Heinrich Warburg, which is also known as Warburg hypothesis, not much substantial research was carried out until the late 1990s because of the lack of in vitro tumor models and the difficulty in creating environments that lack oxygen. Recent research has revealed that metabolic reprogramming occurs as a consequence of mutations in cancer genes and alterations in cellular signaling. Therefore, the alteration of cellular and energy metabolism has been suggested as one of The Hallmarks of Cancer.

High amount of aerobic glycolysis (also known as the Warburg effect) distinguishes cancer cells from normal cells. The conversion of glucose to lactate rather than metabolizing it in the mitochondria through oxidative phosphorylation, (which can also occur in hypoxic normal cells) persists in malignant tumor despite the presence of oxygen. This process normally inhibits glycolysis which is also known as Pasteur effect. One of the reasons it is observed is because of the malfunction of mitochondria. Although ATP production by glycolysis can be more rapid than by oxidative phosphorylation, it is far less efficient in terms of ATP generated per unit of glucose consumed. Rather than oxidizing glucose for ATP production, glucose in cancer cells tends to be used for anabolic processes, such as ribose production, protein glycosylation and serine synthesis. This shift therefore demands that tumor cells implement an abnormally high rate of glucose uptake to meet their increased needs. In this regard, cancer cells and stromal cells can symbiotically recycle and maximize the use of nutrients. Hypoxic adaptation by cancer cells is essential for survival and progression of a tumor. In addition to cell autonomous changes that drive a cancer cell to proliferate and contribute to tumorigenesis, it has also been observed that alterations in whole organism metabolism such as obesity are associated with heightened risks for a variety of cancers.

The protein AKT1 (also known as Protein Kinase B or PKB) in the PI3K/AKT/mTOR pathway is an important driver of the tumor glycolytic phenotype and stimulates ATP generation. AKT1 stimulates glycolysis by increasing the expression and membrane translocation of glucose transporters and by phosphorylating key glycolytic enzymes, such as hexokinase and phosphofructokinase 2. This leads to inhibition of forkhead box subfamily O transcription factors, leading to the increase of glycolytic capacity. Activated mTOR stimulates protein and lipid biosynthesis and cell growth in response to sufficient nutrient and energy conditions and is often constitutively activated during tumorigenesis.

Apart from being as a general tumor suppressor gene, p53 also plays an important part in regulating of metabolism. p53 activates hexokinase 2 (HK2) that converts glucose to glucose 6 phosphate (G6P) which enters glycolysis to produce ATP, or enters the pentose phosphate pathway (PPP). It therefore, supports macromolecular biosynthesis by producing reducing potential in the form of reduced Nicotinamide adenine dinucleotide phosphate (NADPH) and/or ribose that are used for nucleotide synthesis. p53 inhibits the glycolytic pathway by upregulating the expression of TP53 induced glycolysis and apoptosis regulator. Wild type p53 supports the expression of PTEN (gene), which inhibits the PI3K pathway, thereby suppressing glycolysis. POU2F1 also cooperate with p53 in regulating the balance between oxidative and glycolytic metabolism. It provides resistance to oxidative stress that would regulates a set of genes that increase glucose metabolism and reduce mitochondrial respiration. This will provide additive force when the p53 is lost.

Pyruvate kinase type M2 or PKM2 is present in embryonic, adult stem cells. It is also expressed by many tumor cells. The alterations to metabolism by PKM2 increases ATP resources, stimulates macromolecular biosynthesis and redox control. Pyruvate kinase catalyses the ATP generating step of glycolysis in which phosphoenolpyruvate (PEP) is converted to pyruvate. This is a rate limiting step. It decreases the glycolysis activity and allows carbohydrate metabolites to enter other pathways, like hexosamine pathway, Uridine diphosphate glucose–glucose synthesis, glycerol synthesis and Pentose phosphate pathway or PPP. It helps in generating macromolecule precursors, that are necessary to support cell proliferation, and reducing equivalents such as NADPH. It has been observed in some studies that MYC promotes expression of PKM2 over PKM1 by modulating exon splicing. They are also found to interact with arginine residues required for isocitrate binding in the active site of the proteins of IDH1 and IDH2. Some of the fatty acids have been linked to acquire resistance against some of the cancer drugs. Fatty acid synthase (FASN), a key complex catalyzing fatty acid synthesis has been found to be linked to acquired docetaxel, trastuzumab and adriamycin resistance in breast cancer. Similar resistance have been found with intrinsic gemcitabine and radiation resistance in pancreatic cancer. Glutaminolysis is linked to cisplatin resistance via the activation of mTORC1 signaling in gastric cancer.

NADPH plays an important role as an antioxidant by decreasing the reactive oxygen produced during rapid cell proliferation. It has been shown that attenuation of the PPP would dampen NADPH production in cancer cells, leading to the decrease in macromolecular biosynthesis and rendering the transformed cells that are vulnerable free radical mediated damage. In this way, the advantage conferred by PKM2 expression would be eliminated. In preclinical studies, drugs such as 6 amino nicotinamide (6 AN), which inhibits G6P dehydrogenase, the enzyme that initiates the PPP have shown anti tumorigenic effects in leukemia, glioblastoma and lung cancer cell lines. Cyclosporine inhibits TOR and is used as an effective immunosuppressant. Mycophenolic acid inhibits of IMPDH and pyrimidine biosynthesis and is clinically used as immunosuppressant. Both agents also display anti tumor effects in animal studies.

The use of the amino acid glutamine as an energy source is facilitated by the multistep catabolism of glutamine called glutaminolysis. This energy pathway is upregulated in cancer, which may represent a therapeutic target as cancer cells are thought to be more dependent on glutamine than healthy cells. This especially holds true for specific tumor types that are metabolically dysregulated, such as malignant brain tumors (i. e. glioblastoma) that carry mutations in the IDH1 gene. These tumors use glutamine or the structurally related amino acid glutamate as an energy source and a chemotactic sensor in the brain, which increases their malignancy and may explain why these tumors grow so invasive. [9][10]