Back from Scotland and Gatenby's talk

I am back from sunny Scotland in sunny Saxony. Of the remaining speakers in Dundee, the one whose talk I was looking for the most was the one from Robert Gatenby, Arizona University (as with Vito Quaranta, a life scientist).

I know the work of Gatenby because he is one of the few researchers involved in using evolutionary game theory (although not of the most conventional, fitness-and-payoff-table kind) to study cancer evolution. Specifically he is working on how acidity due to glycolysis (the anaerobic metabolism that constitutes and advantage for tumour cells that lack oxygen due to the distance to a blood vessel) is a necessary step in the evolution towards cancer. The so called Warburg effect is the result of a well known biochemical mechanism but, what is the evolutionary advantage?

As he has shown in other papers, the advantage for glycolytic cells is that the poison the environment of other cells so they face less competition. They also degrade the connective tissue and thus increase the motility of cells, which is a required step for a tumour to become invasive. From my point of view it is interesting that he seemed to imply that this acidification of the microenvironment is not only a facilitator for cancer but a necessary step. I guess that Hanahan and Weinberg could include this in the section for mechanisms for invasion and metastasis.

From the therapeutic point of view, his research suggests that either alkalising the microenvironment (to counteract the progressive acidification resulting from the glycolytic metabolism) or making it even more acidic by reducing the pH in the blood (and thus contributing to self poisoning of glycolytic cells) would be something worth trying.

Mitochondria and glycolysis

As mentioned in a previous post the acquisition of the glycolytic metabolism is regarded by many researchers as a necessary step on the carcinogenic path (this is known as Warburg effect). Compared to healthy cells, glycolytic cells do no need oxygen for their metabolism and although this is very inefficient it has advantages such as the capability of surviving in environments that do not have vasculature in the vicinity and the capability of acidifying the environment (which makes other cells go to programmed death and leaves glycolytic cells room to grow). The reason that healthy cells have a more efficient metabolism is due to the mitochondria, the cellular organelles that oxidises sugar molecules to produce energy. Mitochondrias are what remains of symbiotic bacteria that in the last couple of thousands of millions of years have became integral parts of the cells of many living beings. Glycolytic cells seem to revert to a premitochondrial state thus forfeiting the need of oxygen.

Researchers at the university of Harvard Medical School have created a method based on RNAi (RNA interference, the revolutionary method to knock out genes using double stranded RNA which was the work that has rewarded its authors the Nobel prize in medicine in 2006) in order to put the mitochondria back to work not with the purpose of normalising the metabolism of tumour cells but for the role they play in programmed cell death. The result of applying this therapy on animals resulted in a surge of tumour cells performing apoptosis and a significant increase in the survival rate.