Tuesday, December 26, 2006

Gatenby and Smallbone: Glycolysis and tumour invasion. Two papers

Why do cancers have high aerobic glycolysis? R Gatenby, R. Gillies. Nature reviews cancer, Vol. 4, November 2004, pp 891-899.

The role of acidity in solid tumour growth and invasion. K. Smallbone, D. Gavaghan, R. Gatenby and P. Maini. Journal of Theoretical Biology 235 (2005) pp 476-484.

Gatenby and Gillies present a review paper in which they explain that the glycolytic metabolism is a requirement for a tumour to progress into a cancer. Cancer cells tend, at least by the time they become invasive, to have an altered glucose metabolism. This metabolism has drawbacks when compared with the conventional glucose metabolism in at least two senses. First of all the glycolytic metabolism is less efficient since it produces 2 ATP (the cell's energy currency) compared with 38 ATP that result from normal metabolism. Second of all, as a by product of this metabolism lactic acid is produced. Lactic acid increases the pH of the microenvironment of the cell and when it reaches a given threshold results in apoptosis or necrosis. As a consequence of this the switch from conventional to glycolytic metabolism does not happen under normal circumstances but under hypoxia, that is, when there is insufficient access to oxygen. In those circumstances the inefficient glycolytic metabolism, which does not need oxygen, represents a significant advantage. Hypoxia is a normal event in a growing tumour since there will always come a point in which the tumour cells are far from blood vessels carrying the needed oxygen. Periodic moments of hypoxia select for cells with the glycolytic metabolism that have adapted to acid environments by, for instance, resistance to apoptosis or by reducing intracellular acidity by pumping it out. The end result of this selection is that a tumour will have a group of cells that, despite having a less efficient metabolism, are capable of harming other cells and also of degrading the ECM (Extra Cellular Matrix, that hold tissue cells together) so the next thing you know is that your tumour cells are capable of invasion and metastasis.

In the second paper, Smallbone and colleagues introduce a mathematical model to study the possibility that tumour invasion and growth could be the result, not of genetic changes, but of changes in the tumour environment. This is, of course, a mathematical formalisation of the hypothesis presented in the other paper. They decided to take multicellular spheroids and produce an ODE model that describes tumour growth and progression as travelling waves: the one for the increased microenvironmental acidity and the second one with the tumour cells invading normal tissue. This is a clearly a quantitative model that, unfortunately, has not yet been validated by in vitro experiments although it looks to me that its design has been done with care so it would be feasible to do so. The model predicts among other things that avascular tumours will have higher acidity than vascular ones (which makes sense since blood vessels can be used to take part of this acidity out of the microenvironment) and that tumour necrosis could potentially be explained without the need to talk about cell starvation or overcrowding but by the acidification of the environment. They make a good case for antiangiogenic therapies since blood vessels can contribute to a decrease of microenvironment acidity that could be sufficient for tumour cells to survive but not for healthy cells that have a lower threshold of acidity resistance. They also suggest a treatment in which the membrane pumps that transport the acidity from within the cell to the outside environment, would be somehow blocked so glycolytic cells would literally poison themselves to death without changing the microenvironment for the healthy tissue cells.

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