Metastasis, the spread of a tumour from a primary site to secondary ones, is the reason cancers become life threatening. Metastasis requires tumour cells to acquire a number of capabilities, mainly the capacity to get into the bloodstream (or any other system that would allow the cells to reach other parts of the organism like the lymphatic system, or the bones), the capacity to get out of it and finally the capacity to grow and prosper in the new location.

Interestingly, not all these capabilities are beneficial from the evolutionary view point. A tumour cell in a primary site that gets in a blood vessel is unlikely to be able to contribute to the metastatic potential of the primary tumour. Metastasis is also an extremely wasteful process in which only a tiny minority of cells in the bloodstream manage to extravasate (leave the circulatory system) and colonise a new site successfully.

So the question of how tumours evolve to become metastatic is both intriguing and very relevant from the clinical point of view.

Recently, researchers like Larry Norton at Sloan Kettering and colleagues have been advocating the role of self-metastases to explain tumour growth. This would imply that the metastatic cells traverse the body and end back in the same organ from where they came from. If that were to be true that would explain metastasis: cells capable of self-seeding would have a (probably better) chance of increasing their share in a growing tumour population.

But whether this hypothesis is true remains still unclear and so far, controversial. A different view is that metastasis does not represent an advantageous trait for a tumour cell but is a side effect; the consequence of tumour cells acquiring other traits that contribute positively to the fitness of a phenotype that possesses them. In March last year this blog discussed that increased cell motility (a clear advantage for tumour cells) could also correlate with an increase in metastatic potential as some of these motile cells could stumble into the circulatory system. For similar reasons, angiogenic capabilities could also help tumours become metastatic: even if some cells end in the blood stream , it is still advantageous for tumour cells to be able to co-opt endothelial cells and produce blood vessels providing them with oxygen and nutrients.

Cells with certain traits will thus be in position to progress on the path of becoming successfully metastatic so a proper understanding of the selection forces that let these. Still, getting inside the circulatory system (intravasation) is only the first step as the vast majority of those cells will never manage to extravasate and colonise another organ.

The chosing of a site for colonisation is not random: physical constraints and Paget’s seed and soil hypothesis can help explain why certain cancers (the seed, e.g. prostate cancer cells) have a preference to metastise in organs that resemble to some extent their original soil (e.g. bone). This does not require a deep understanding of the genetic mechanisms of metastasis, only to understand that metastatic cells end up in sites where it’s easier to get in (extravasate) and are either similar to where they come from or represent rich soils (nutrients, space, other growth factors, a co-optable stroma…).

The topic of metastasis remains poorly understood but evolution plays a role in selecting for cells that get into the bloodstream and it also plays a role in explaining how the tumour changes and adapts to a new secondary site as it attempts to colonise it. An understanding of how the environment of the primary site acts on that selection could go a long way in helping to minimise the chances of cells that get into the bloodstream having the right type of traits for metastasis.

The year of Darwin is over and I decided to go over some posts in this blog that I felt were particularly Darwinian (not a small feat as the main topic of this blog is evolution in the context of cancer).

The posts highlight (or at least that would be my hope) the importance of understanding that tumours evolve, that evolutionary dynamics make cancer a very difficult disease to treat, that ignoring these dynamics is one of the reasons for the limited success in the fight against cancer and that evolutionary enlightened (as a colleague at Moffitt likes to refer to them) treatments are our best hope for a cure. Some of these topics were treated in my post about the paper Darwinian medicine: a case of cancer in February.

A darwinian enlightened therapy should then exploit the limitations of evolution as was discussed on the post about Jerry Coyne’s book Why evolution is true in March. This subject was discussed again in August in the post about another masterpiece about evolution, nothing less than Dawkins’s The Extended Phenotype. Both books discuss Darwinian evolution at the level of traditional ecosystems but the lessons drawn should be also applied in cancer research.

One of the most clinically relevant aspects of cancer progression is metastasis. Metastasis represents, in my view, a paradox in evolutionary terms as it is a rather wasteful process in which only a tiny minority of metastatic cells manage to survive to start a secondary site. The fact that metastatic potential could be a byproduct (and not a feature selected for) of evolution is discussed in this post from March.

Finally in November the topic of the evolutionary origins of religion was discussed. This topic is not about medicine but was part of Science magazine special coverage of the year of Darwin, a reminder that evolution can work at many different levels.

Happy 2010!

This challenges one of my fundamental assumptions in biology: that of all somatic cells sharing the same genome. In an article entitled BAK1 Gene Variation and Abdominal Aortic Aneurysms the authors show that the BAK1 gene, associated with apoptosis, exists in multiple variants in our bodies. Specifically the authors found differences between the gene found in the blood cells and other tissues. The authors also hypothesise that multiple variants of genes may exist within nondiseased tissues.

Until now the assumption was that only tumour cells had a different DNA than the other eukaryotic cells in our organism. These results represent a challenge for a multitude of genetic studies based on the assumption that the genetics of blood cells (which are comparatively easy to obtain for those studies) and other somatic cells is the same. While it remains to be seen whether these genetic differences are small or not, the fact that the one studied happens to encode a gene involved in apoptosis suggests that the differences could be significant enough to have an effect on diseases like cancer.

This is very intriguing research and opens a lot of questions: How do cells with different genes appear in a developmental process that starts from a single fertilised egg (the article mentions RNA editing)? how would this affect personalised treatments (i.e. based on doing a genomic analysis of the patient)? Does that mean that finding genetic differences in a cell (when compared with cells in other tissues) does not necessarily constitute cause for alarm (as it does not have to be the result of somatic mutations)?

Gottlieb, B., Chalifour, L., Mitmaker, B., Sheiner, N., Obrand, D., Abraham, C., Meilleur, M., Sugahara, T., Bkaily, G., & Schweitzer, M. (2009). BAK1 gene variation and abdominal aortic aneurysms Human Mutation, 30 (7), 1043-1047 DOI: 10.1002/humu.21046

Science continues with a series of essays commemorating the year of Darwin. This week (and by this week I mean the one I got this week, actually dated 6th of November) the topic is the evolutionary origins of religion.

This is quite an interesting topic to which I was first introduced with Daniel Dennett’s Breaking the spell: religion as a natural phenomenom. The central premise is that there could be evolutionary advantages to communities in which individuals follow ways of thinking that can lead to religion. Specifically, it is thought that the thought processes that could lead to religion could also lead towards more cooperation. Recent research has shown that, under very special circumstances, group selection could explain the emergence of features that are somewhat detrimental to an individual that would display them in isolation but that would benefit the community at large [ link ].

Compounded with this is our tendency, as a species, to see agents in every action. When something happens (a noise in the middle of the night) we tend to attribute it to the actions of another being. Evolution could have selected for a way of thinking that, although presents many false positives, tends to be safer. If you hear a strange sound, it is better to think that somebody is around and that you should be careful than to think that the noise you heard was just the wind blowing. This teleological view means that we are predisposed to look for thinking beings in living and nonliving things. Studies with kids or adults in stressful situations seem to confirm this view.

A recent NYT article mentions that the presence of divine beings could be a way to enforce cooperation in small and egalitarian societies of hunter-gatherers. When societies became more complex, with the introduction of agriculture, and religious beliefs were well entrenched in the human neural circuitry, religious beliefs could be co-opted as a source of authority by the ruling classes.

The article also points out that, if religion is an evolved behaviour, it would not be good news to either religious people nor to atheists. Religious people should find that religious beliefs emerging from evolution make God less likely. Atheists might not be so willing to criticise religion if it has evolved as a framework in which cooperation is encouraged. I am not personally convinced that either group will be too discouraged by this. Religious people will probably argue that our religious compass was part of God’s design and that it is precisely that what sets us aside from the rest of the creation. Atheist can argue that the religious instinct, even if the side-effect of other mental processes that could lead to cooperation, is surely not necessary to maintain a complex modern society as it is clear that some of the most cooperative societies in the world today are remarkable secular. Furthermore, this would not address the central premise of atheism which is about the unsuitability of religion to explain truth and nature.

Culotta, E. (2009). On the Origin of Religion Science, 326 (5954), 784-787 DOI: 10.1126/science.326_784

I haven’t updated this blog for a while, the reason being the usual for many researchers working in the US: grant writing. Part of this grant writing involved producing diagrams to illustrate various processes occurring at different scales in prostate tissue. These diagrams describe rather sophisticated intra and extra cellular interactions in the simplest possible manner. Yet these diagrams can be complicated and selecting the right symbols and colours to describe these interactions in a visually appealing but consistent manner can be far from trivial.

As someone with a background in computer science I appreciate the advantage of having a standard notation to describe processes. Software engineers use tools such as UML to describe software modules and how they interact to form complex software systems. This allows other software engineers to understand complex systems with little ambiguity. Now systems biologist will be able to do the same thanks to SBGN, recently discussed in Seed magazine (article that came to my attention thanks to Simon Hayward).

Standarising on a formal graphical notation will allow computational, mathematical and system biologists to better communicate with biologists but only if both communities learn how to speak this language. This will be tricky but if funding bodies and journals start requesting diagrams in this notation, that could ease its introduction. I hope that this (or an alternative formal graphical notation) will eventually emerge successfully. Formal graph notations are easier to read by non experts than mathematical equations or software algorithms but being more precise than informal non-standard ones they represent a more solid foundation in which to build integrative work, combining theoretical and experimental research, and exchanging models between different groups.

Evolution of coperation is one of my main interests and I think it is a topic that could be very relevant to cancer researchers as I discussed a while ago.

Rand DG, Dreber A, Ellingsen T, Fudenberg D, & Nowak MA (2009). Positive interactions promote public cooperation. Science (New York, N.Y.), 325 (5945), 1272-5 PMID: 19729661

Cooperation in nature occurs mostly between individuals that are closely related from a genetic point of view. In most other instances cooperation happens when all the interacting individuals benefit to some extent from their cooperation. Still, in some situations altruism happens if the benefactor expects to get rewarded at some point in the future, potentially by another individual. This is problematic as it was thought that a mechanism of punishment would be necessary: those that cooperate should be rewarded but those that cheat should be punished. And punishing is not simple: cooperators should stick together to punish the cheaters as punishing itself is rarely cost free. That means that some individuals might be cooperators when it comes to the game but cheaters when it comes to punish. And that would require an extra layer of punishing, one that would deal with those that cheat at the punishing level. This, of course, has no end as one cooperator at one level might be a cheater at the next.

What Rand and colleagues have proven is that punishment might not be necessary for this type of cooperation, at least in the public goods game. Remarkably, in a population that is expected to interact together a number of times. Sometimes just the carrot (when other players reward the best cooperators) can be a better alternative than the stick (punishing the cheaters). Even when both options are available, those groups that leaned on rewarding more than on punishing were more likely to obtain higher payoffs.

Can biologists and mathematicians accomplish more together than working separately? My answer to that question has always been a resounding yes but today I am backing up that statement with a piece of research: the result of a collaboration involving mathematicians and biologists (and a pathologist) in Tampa, Nashville and Houston.

Basanta, D., Strand, D., Lukner, R., Franco, O., Cliffel, D., Ayala, G., Hayward, S., & Anderson, A. (2009). The Role of Transforming Growth Factor- -Mediated Tumor-Stroma Interactions in Prostate Cancer Progression: An Integrative Approach Cancer Research, 69 (17), 7111-7120 DOI: 10.1158/0008-5472.CAN-08-3957

The paper, of which I am one of the authors, studies the role of stromal-tumour interactions in prostate cancer progression. It introduces a computational model, developed as a result of extensive conversations with Vanderbilt’s Hayward Lab and the results have led to interesting biological experiments and observations of relevance in pathology. Hope you guys will find it an interesting read.

Spending so much time on planes and airports (as I am doing lately) means that I have more time to read books, some of which were in my reading list for way too long. The book I am reading now is Dawkins’s The Extended Phenotype. I am a big fan of Dawkins so there’s no easy explanation for why it took me so long to start reading the book that Dawkins himself consider’s his most important.

In one of the earlier chapters (chapter 3), Dawkins mentions some constraints that put limits to commonly held view that evolution optimises the phenotypes of individuals in a species. These are:

1. Time lags: your usual living being has a genetic material that makes him very well adapted to an environment that, in many cases, has changed. Given enough time there are good chances that the species will evolve to adapt to the current situation but by then there might be new changes to adapt to. An example from the book: the hedgehog strategy of rolling up into a ball to escape predators doesn’t work too well when crossing a motorway. The fact that cancer phenotypes represent an adaptation to an environment that might have changed significantly means that tumour cells are more vulnerable when there is sudden change but using this fact therapeutically is dangerous as this will select for those cancer cells more able to cope with change, making tumours more difficult to treat in the long term.

2. Historical constraints: What you do today will limit and bias what you will do in the future. Same goes in evolution. Flatfish share a lot of their developmental programme with other fish but given their lifestyle (laying flat on the surface of the ocean) they are better off having both eyes on the same side of their head. Evolution has to work around the fact that both eyes are developed in different sides of the head by adding an extra step in which one of the eyes slowly shifts in the direction of the other. With the right knowledge of how a cell genotype maps into a phenotype, we could select for phenotypes that require genetic or molecular mutations that would make difficult or impossible to acquire, later on, more aggressive features. Although initially these phenotypes would be more fit than other tumour cells, in the long term their genotypes would make them evolutionary dead ends.

3. Available genetic variation: That one is pretty straightforward, evolution requires that individuals are different in a manner that can be passed on from parents to offspring. A population with little genetic diversity will always take longer to adapt (sometimes for all practical purposes will never succesfully adapt) to changes in the environment. We know that very selective microenvironments (those that exact a high toll on phenotypes that are not well adapted) will reduce the phenotypic (and hopefully the genotypic) diversity of the tumour. This could slow down the pace of tumour evolution but the selection should be such that does not select for more malignant phenotypes.

4. Costs: Even if time was not a constraint, some adaptations are more costly than others. An individual that devotes its time and resources doing something might not have enough to do something else even if that turned out to be beneficial. Like in engineering, evolution has to deal with costs and tradeoffs in which perfection is the enemy of good. We know that some adaptations are more costly than others. Gatenby and colleagues idea of double bind therapies, by which a treatment selects for phenotypes that have to pay a high fitness cost to survive, could be considered a tool based on the cost of adaptation evolutionary constraint.

5. Mistakes due to environmental unpredictability or malevolence: The environment of any given individual is extremely complex and dynamic. It would be rather difficult (and costly!) for evolution to produce individuals capable of coping optimally with every conceivable situation. What evolution does then is to evolve individuals that are good at coping with most situations, especially if they happen often enough and the consequence of mismanaging them would be too high. Providing a tumour with a stable microenvironment will select for phenotypes that could overadapt to this environment (and select against more generalistic tumour phenotypes as this generality comes at a fitness cost and provides little advantage in a stable environment). Such tumour would then be more sensitive to small (and big) alterations to the microenvironment.

While Dawkins places all these constraints in terms of classical ecological species (ants, wasps, fish…) there’s no reason to believe that this same constraints apply to the evolution in tissues where cancer has been initiated. Here I just put a few examples off the top of my head (very likely not very good ones) of ways in which these constraints could be exploited therapeutically but the point is that evolution, which makes cancer such a difficult disease, can also be used to fight it. Knowledge of these constraints could be a powerful tool to hinder tumour progression towards malignancy if we could have some degree of control over the selection pressure.

Some time ago I learnt that a significant proportion of cancers are started as a result of virus activity (I believe that the figure was something around 20% of them). That left me thinking how neat (intellectually, that is) would be if viruses and tumour cells became mutualistic cooperators. A virus that alters the behaviour of a cell making it proliferate when in other circumstances wouldn’t (as tumour cells do) does provide a fitness benefit to tumour cells. The payback that would make this interaction mutualistic would be something that increases the reproductive rate of the virus.

Virus (even those associated with tumourigenesis) are not normally too concerned about boosting the replicative capabilities of the cells they infect. If they do initiate a tumour that is more likely than not a side effect of the virus taking over the replicative machinery of the host cell. As soon as enough copies of the virus have been produced, the host cell will burst making the virus free to infect new cells.

I am currently reading One renegade cell, a pop science book by the well known cancer biologist Robert Weinberg. The book is not exactly new (first published more than 10 years ago) and, despite mentioning somatic evolution, it is (unsurprisingly) heavily biased towards a genetic interpretation of cancer. Still, Weinberg does a superb job of explaining a complex disease to a non specialist readership without dumbing the topic down and while keeping the book readable and entertaining.

In chapter 3 (The elusive quarry), Weinberg shows that I was not the first one to think that viruses and tumour cells could interact cooperatively (although I doubt that a lot of people framed this idea in terms of cooperation). Apparently a now forgotten school of thought about tumour initiation a few decades ago thought that virus were the prime cause of tumourigenesis. Those viruses would trigger uncontrolled cellular growth as that would allow the viruses to grow a large population without having to expose themselves (as they are particularly vulnerable out of a host cell). This way the virus drives tumour growth and the tumour growth translates into more viruses. A perfect example of mutualism. Still no evidence for this though, but a neat idea.

I don’t watch telly so although I imagine that this programme was meant to be watched in the comfort of your living room I only found about it on the PBS website. The programme I am referring to is called Animals behaving worse: America’s least wanted and shows some species that have (relatively) recently arrived to America and, in many cases, displaced the local populations.

People have already found parallelisms between species invading new ecosystems and tumour cells metastasing to different sites so this show will appeal to those of us that see tumour cells as constituents of a tissue ecosystem. For instance, the africanised honeybee has displaced the european kind from the south of the USA as they outcompete other pollinators. Other invading species might not have clear local competitors to displace but by consuming resources more aggressively they alter the ecosystem in significant ways, thus affecting the viability of other species. The reasons by which the invaders reach the new ecosystem are varied (and oftentimes due to us, careless humans) but all cases presented in the programme show them as quite capable to take advantage of the resources of their new home as well as free from predators (although in some cases, humans have introduced predators to gain control on their growth, sometimes successfully).