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.


Quote of the week

Maybe this will start a new trend in this blog: quotes. I was recently rereading some old issues of Nature and found this article in the careers section. It is a nice article in which the authors give an alternative view to that of this other article of how long and hard should a PhD student work. According to the original view a researcher should work all the time. According to this other alternative view some scientists have many of the weaknesses commonly associated with humans and thus this approach is likely to be useless.

They cite this anecdote from Ernest Rutherford. It seems that he found a student working late on an evening and asked him if he also worked in the mornings. The student answered that that is what he usually did and Rutherford then asked “But, when do you think?”. Some times I think to myself that my best ideas usually come in the most unexpected places and circumstances. Now I think that I never had any good idea while in the office in front of the computer. Since now I am off for Xmas holidays there is a chance I will have time for some good ideas.

Evolution and creationism in Europe

Many people in the European academic community have a condescending view on the lack of scientific knowledge of the American population in general and also of their political class. While probably these concerns are fair, it would be useful to redirect part of it towards our own citizens and politicians here in Europe.

The Nature issue of a couple of weeks ago reports about how creationism is on the increase in Europe (at least the public awareness of what used to be a dormant line of ‘thought’). They also have an interview with the leader of a European creationist group (who has a PhD in astrophysics and whose photo in the article seems to be taken by one of his enemies). Nature has also recently published the letter of Maciej Giertych, an MEP and scientist, with a PhD in population genetics, of the Polish Academy of Sciences in which he criticises evolution. The publication of this letter in a journal with the reputation of Nature has generated a considerable amount of controversy as can be seen in the letters send to the editor and published in the last issue.

Anderson et al: Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment

A. Anderson, A. Weaver, P. Cummings and V. Quaranta. Tumor morphology and phenotypics evolution driven by selective pressure from the microenvironment. Cell 127, 905-915, December 2006.

This is the paper I mentioned in my previous post. It is not that usual to find a mathematical model in a journal like Cell so I hope that this is part of a growing trend.

The paper investigates how the microenvironments helps to drive cancer evolution. To do so they use a hybrid cellular automata model in which cells live in the discrete lattice and the microenvironment (oxygen concentration, extra cellular matrix macromolecule concentration and matrix degrading enzyme) is modeled using continuous variables. The cells are characterised by a number of parameters that determine their behaviour with respect to proliferation, cell-cell adhesion, oxygen consumption, haptotaxis or production of matrix degradation enzymes. Cells follow a life cycle and only proliferate when they reach a certain age. That age depends on the cell’s phenotype. During mitosis a cell might alter its phenotype and change the values of proliferation, adhesion, oxygen consumption, etc.

With heterogeneous microenvironment and cell behaviour you get different patterns of tumour growth, some of them favouring agressive invading phenotypes and some of them favouring the coexistance of all sorts of phenotypes. Having the model they described it is possible to study who different microenvironmental factors determine evolution. The results show that harsh environments (little oxygen) select for aggressive phenotypes whereas in milder environments allow for the coexistance of a much bigger range of phenotypes and that these tumours are unlikely to be invasive.

The model is very interesting and the conclusions seem pretty reasonable: Tough microenvironments lead to aggressive tumours. My intuition tells me that on the other hand, heterogeneous populations are more likely to be able to cope with an external aggression which would imply that a less aggressive but more diverse tumour would not respond well to therapies that target any specific kind of behaviour. The main problem with the paper is that the model is fairly complicated for clinical validation.

We are big news!

We are big news. Ok, I am personally not included but it seems that the theorical medicine community starts to be noticed.

I browse a tech-news website, called slashdot, very often. One of the entries today is the following: “Computer simulations of cancer growth“. There they talk about research performed by Sandy Anderson (Dundee, part of the Marie Curie Network in which I am involved), Vito Quaranta (Vanderbilt, I talked about him in my post on the Lyon workshop in late September) and colleagues. They have just got a paper published in Cell of which I will talk about it in a later post.

At any rate, it looks impressive than sites such as Slashdot report on mathematical and computational models of cancer research. The audience of Slashdot is reputed to be very competent in matters of IT but I could see that some of them are medically competent too (I mean, enough to convince a computer scientist like myself, not necessarily more than that), even if, as in many news in Slashdot, people tend to concentrate on what they want to say regardless of the news they are supposed to comment on.

Cancer and development

Reading a just outdated issue of The Economist, I find this article in the science section about how HIV treatments could be used to treat cancer.

One of the things many people interested in biology but without a background in biology believe (I hope I am not just describing myself here) is that information goes only in one direction: genes – mRNA – proteins. Actually the opposite is true. Enzymes such as reverse transcriptase can copy can include fragments of RNA into DNA. This is of course a technique used by viruses in order to alter the genetic programme of a cell to produce more copies of the virus. This system is also used to change the genetic programme of a cell during development so if the work of the enzyme is hindered so is development (at least in some crucial steps).

It seems that cancer cells have a lot of reverse transcriptase (this is, unfortunately, not explained in the article) and thus treatments used to prevent viral diseases could be used to hinder tumour growth. In vivo experiments with mice transplanted with human cancer cells show that there is a correlation between tumour growth and the use of HIV treatments that hinder the reverse transcriptase enzymes.

It is one more example of how development and cancer are connected (my take, and I don’t claim to be the first one with this insight) is that we would not have cancer if we were not the result of developmental processes.