Cancer Cell Metabolism: The Warburg Effect

Cancer cells alter their metabolism to encourage growth, proliferation, and long-term survival. A common feature of this altered metabolism is an increased uptake of glucose and fermentation of glucose to lactate, even in the presence of oxygen and functioning mitochondria. This phenomenon is called the Warburg Effect. Research on the Warburg Effect has advanced knowledge of the conditions for oncogenesis (the development and growth of tumours), but the function of the effect is unknown.

What is the Warburg Effect?

Cancerous cells have a higher demand for glucose and glutamine (an amino acid). In normal cells, pyruvate, which is formed from glucose in glycolysis, is converted to acetyl CoA and then enters the Krebs cycle in mitochondria. This then undergoes oxidative phosphorylation under aerobic conditions, resulting in the production of 32 ATP molecules. It is only in anaerobic conditions that normal cells will produce large amounts of lactate instead of acetyl-CoA. Cancer cells, despite having fully functioning mitochondria and a sufficient supply of oxygen, convert pyruvate to lactate, hence their metabolism often being referred to as “aerobic glycolysis.” This is a specific hallmark of tumour cells. As a result, to meet the increased requirement for rapid tumour growth, an increased rate of glucose uptake is required. However, this is a less efficient method of energy production, and scientists aren't sure why tumour cells use it. Otto Warburg originally hypothesized that cancer cells develop a mitochondrial defect that leads to a subsequent reliance on

glycolytic metabolism. However, later work has showed that mitochondrial function is not impaired in most cancer cells, suggesting an alternative explanation for aerobic glycolysis in cancer cells. We now know that cancer cells exhibit aerobic glycolysis because of activation of oncogenes and loss of tumour suppressors.

Furthermore, the metabolism of cancer cells is altered from being catabolic (breaking down molecules) to anabolic (building molecules) to generate the extra protein, nucleic acids, and lipids required to maintain their increasing rate of proliferation. They absorb amino acids as well, with glutamine being especially significant. It is an essential source of nitrogen for the synthesis of amino acids, as well as a source of carbon for replenishing Krebs cycle intermediates and producing more pyruvate. Some tumours are so dependent on glutamine that if they are deprived of it, they stop growing and die.

Possible functions of The Warburg Effect

The Warburg Effect and Rapid ATP Synthesis. Aerobic glycolysis in cancer cells is an inefficient method of producing ATP per unit of glucose when compared to mitochondrial respiration. However, the rate of glucose uptake via aerobic glycolysis is faster, with lactate produced 10-100 times faster than full oxidation of glucose in the mitochondria in normal cells. As a result, a reasonable explanation for why cancer uses aerobic glycolysis should account for this inherent difference in the rate of glucose uptake. Although oxidative phosphorylation produces more ATP per mole of glucose, proliferative cells primarily rely on aerobic glycolysis as it generates ATP faster and provides substances to support cell proliferation and metastasis (the spreading of cancers). However, certain elements of this theory do not fully make sense as empirical calculations show that the amount of ATP a cancer cell releases is not even close to a tumour’s demand for ATP.

Warburg Effect and the tumour microenvironment. The Warburg Effect may provide an advantage for cellular metabolism in a multicellular environment as the acidification of the microenvironment and other metabolic features may enhance oncogenesis. Due to lactate secretion, increased glucose uptake lowers the pH in the microenvironment. Acidosis has a variety of potential advantages for cancer cells as one theory suggests that an acidic microenvironment would cause H+ ions to be secreted from cancer cells. These ions would then diffuse into the surrounding environment, altering the tumorstroma (the structural components holding tumour tissues together) and causing penetration and spreading of cancer cells into neighbouring tissues. The availability of glucose is the result of direct competition between tumour and tumour infiltrating lymphocytes (immune cells that recognise and penetrate tumours). The high rates of glycolysis reduce the availability of glucose for tumour infiltrating lymphocytes and they require a high amount of glucose to perform their functions. Research shows that tageting aerobic glycolysis in proliferated cells will increase the amount of glucose for tumour infiltrating lymphocytes, thereby enhancing their main function, which is to eradicate tumour cells. The Warburg Effect is likely to provide an overall advantage that promotes a favourable microenvironment for tumours that leads to proliferation and long-term survival.

Warburg Effect and biosynthesis. The Warburg Effect could potentially promote a metabolic environment that allows for rapid biosynthesis to support growth and proliferation. Increased glucose consumption is utilized as a source of carbon for anabolic (promoting metabolism) processes. This extra carbon is used to create lipids, nucleotides and protein from scratch which would help the tumour grow and proliferate. However, more research is needed to determine whether the Warburg Effect supports biosynthesis.

Conclusion

Research on the Warburg effect has been vital in helping scientists

understand the requirements of cancer cells to proliferate and survive. However, many elements of the Warburg Effect and its function are still unclear but nonetheless this concept is highly significant for therapeutic advances to be made in treating cancer. This can be done through intervention in a cancer cell’s metabolism through the immune system, especially in terms of glucose and glutamine.

-Tharunya

Adaptive Growth

We humans, and other organisms, grow at an astonishing rate while still embryos and foetuses in the mother’s womb. Which means there should be a lot of opportunity for things to go wrong, yet most organisms leave the womb looking okay, in the sense that they are symmetrical. Why is this the case?

Alberto Roselló-Díez, along with a few other scientists, carried out research to see what would happen when a mouse foetus’ growth in one leg was restricted. It was known that in fly larvae, injury to individual tissues would kickstart mechanisms that acted both in the local tissue, and across the whole body to compensate for the injury. Ultimately, this allows the injured tissue to grow to become of a normal proportion compared to other tissues. However, catch-up growth in vertebrates, which have a more complicated route of development, was still a foggy area. Roselló-Díez and his team used foetal mice for their experiments and carried out experiments in which they triggered insult to the left limb during the mouse’s last gestational week. This was done through the manipulation of a cell cycle suppressor p21, which they introduced exclusively to the cartilage that was driving the growth of the left hindlimb. During cell division, the cells monitor and regulate the process, for which they require cell cycle checkpoints (CPs). One example is tumour suppressor genes, which inhibit cell division and thus, tumour development. At times, they can even trigger apoptosis, or programmed cell death. By introducing p21 to cartilage cells (chondrocytes), the chondrocytes were unable to divide, preventing the growth of the left limb. The right limb would serve as an internal control.

What Roselló-Díez and his team found was that left-right symmetry remained normal in the mouse, which meant that some type of compensatory mechanism must have taken place during its development. Through further research they found that there were two main such mechanisms, one local and one systemic. Locally, they found a hyperproliferation - an abnormally high rate of cell division leading to a rapid increase in number - of the unaffected left limb chondrocytes. This indicated that these cells must be responding to a signal, probably coming from the targeted cells. Firstly, extracellular matrix production is increased which results in a decrease in cell density. This means that the cartilage scaffolding is still being laid down as usual, and endochondral