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.
2 comments:
David,
Does the acid degrade the microenvironment? Or do the same hypoxic tumor cells also secrete MMPs that contribute to proteolytic degradation of the ECM? (Or do the necrosing non-cancerous cells in the surrounding microenvironment contribute to degradation? For instance, the contents of lysed cells are known to be oxygen-reactive. See information on oxygen reperfusion injuries in heart attack patients, for instance.)
I was just curious if you had more information on the actual agent at play here. Thanks! -- Paul Macklin
Hi Paul,
That is a very good question. Most of the things I know about the role of acidity in tumour invasion comes from the papers of Gatenby and his collaborators in Arizona and Oxford.
If the microenvironment of a tumour cell includes other neighbouring healthy cells then it is reasonable to think that cells that can outlive other cells in acid environments would degrade the microenvironment to their benefit. That I think is the main contribution of acidity to microenvironmental degradation. If glycolytic cells do have an increased production of MMPs that could contribute to a degradation of the ECM is something I do not know although from what I read I assume it would not be a phenomenon exclusive to this type of cells.
At any rate I am sure that there are several biochemical mechanism that have a degrading effect on the ECM and that some of them can be leveraged by tumour cells. I definitely did not know about the impact of necrosis on the microenvironment and find the hypothesis you hinted, that some tumour cells might have a fitness advantage by increasing the probability of neighbouring cells of dying from necrosis, quite intriguing.
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