A 3D model of human breast cancer

This has been covered in a few places like the BBC and ScienceDaily. It seems that some researchers at Queen Mary College in London have recently come with a non animal 3D human breast cancer model.

This is interesting at more than one level. Their research was funded by a research charity (Dr Hadwen Trust) that supports the development of methods that avoid animal experiments. Working with rats is not that satisfactory for ethical reasons and also because there are many cases in which the results of rat experiments cannot be extrapolated to humans (seems we are not so similar in some respects after all). It is also much more realistic than just taking some human cancer cells and studying them on a petri dish.

Being capable of performing experiments using realistic 3D models quickly and efficiently is one of the holy grails of theoreticians since it would make experimental validation of our models much easier (confusingly enough what theoreticians call model, eg, equations or computer rules, is not what experimentalists understand as a model, eg. rat, arabidopsis or drosophila). This validation is quite complicated as I have already mentioned in another post. Making this validation easier and more convenient will go a long way in terms of making our work more reliable and quantitative.

Autophagy and cancer

This is a new cellular mechanism I did not know about: autophagy. Nature's issue of April 12th (I am bit behind I know) has an interesting article in the section Q&A on autophagy and its role in cancer.

Autophagy is the process by which cells degrade faulty or redundant components. It is used by cells when they need to reuse molecules for other uses and also it plays an important role in complementing apoptosis. Both apoptosis and autophagy are connected to cell death but in the case of autophagy cell death is not always the outcome although it can be a substitute when the apoptotic mechanism is crippled. In that case the cell literally eats itself to death.

The image bellow comes from the article. Autophagy has the potential of being useful for cancer supression but also for cancer promotion. The balance is important, too little and you get cell death when the cell cannot produce things it needs by reusing parts of itself. Too much of it and you also get cell death since the cell can eat itself. Altering this balance in a tumour cell could be the source of a new therapy although as usual it is important to remember that cells might evolve mechanisms to avoid the trouble of autophagy, maybe by inactivating the atophagy mechanism all together. Even in that case the tumour cell would be less capable of surviving in situations of stress since it would not be able to recycle material.

Autophagy seems to be a mechanism whose precise role in cancer has not been fully studied yet but could be a promising extra target for a multi target therapy that could hinder cancer evolution and growth.

cancer genes

The information can be found tailored for all types of users. For those who want an easy take here is the BBC version. Nature has a nice overview and the article proper.

Here is my take: a (fairly large) group of researchers mainly at the Sanger, in UK have studied hundreds of genes that are mutated in about 200 types of cancers. The trick here is to find what genes DO drive cancer as opposed to 'just happen to be mutated' in a cancer. At the end of the day your average tumour cell in an advanced stage tumour is likely to contain several mutations and many of them will probably be hitchhikers not necessarily contributing to the overall fitness of the cell. Unfortunately the result of the research is that the number of genes mutated in many cancers is higher than expected and telling apart driving genes from others will be a challenging task. One thing of working with so many types of cancers (200) is that genes that might not play any significant role in one type of cancer might turn to be important in the next.

World cancer day

I guess I missed it. It seems that yesterday, 4th of February, was the world day of cancer. As many other "World day of...", this WOC was one of these events designed to raise awareness of the problem of cancer in the world, although given that cancer is in the top two of the diseases that are responsible for more deaths in the developed world I guess that many people are more than aware of it.

The headlines I am reading sound actually quite optimistic. Death rates are decreasing due to early detection and improved therapies. Of course nobody is suggesting that cancer will be eradicated but that it will become a chronic disease. I am not sure of how much impact has mathematical oncology had on all these successes but I suspect that it has been limited. For one, mathematical oncology is a fairly relative newcomer in the world of oncology and oncology is a discipline in which cutting edge discoveries take many years (or decades) to reach the public. For another one, I think it is highly unlikely that there will ever be headlines of the kind "theoretician cures cancer". Theoreticians deduce rules or laws that try to describe things like, for instance, cancer growth. These can be used by experimentalists to focus on the more promising areas of research and design the therapies with more likelihood of success faster.

Another added advantage of theoreticians is that they can connect research in different areas. Things that apply to cancer evolution can also be used to study the evolutionary dynamics of other diseases. Many diseases are dangerous due to their capability of evolving and being able to tell what (phenotypes) to expect in the near future from what is there now (genome) would be crucial to deal with them. This week's issue of science carries a paper (http://www.sciencemag.org/cgi/content/abstract/315/5812/655) about how the H5N1 virus (infamous for the avian flu) suggest that only two mutations stand between the current problem and one in which the virus could affect and spread in humans causing a global pandemic. Is there anything that we know about how a tumour evolves that could be used here? I would not be surprised if the answer turns to be positive.

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.

Edge of existance

Researchers of the Zoological Society of London have started a new campaign (called EDGE) to promote the protection of certain species that might not be so close to extinction as some other more famous ones (say, whales?) but whose impact on the survival of other species might be significant. The news can be found in BBC or for those of you that can read Spanish in El Pais.

Now, this is probably not something that many people might find relevant to cancer research but I think that there might be a connection. In ecological systems (and here I assume that a tumour is one of those) species depend on other species for their survival. This dependency does not need to come in terms of food webs (a species needs other to prey on) but also in the way that one species can change the environment for the benefit (or not) of the other ones. The idea then would be to identify 'agents' in a tumour whose role in principle might not look so relevant but that might provide support to other more important but less vulnerable targets. Given the current emphasis on the role of the microenvironment in cancer research I would be surprised if there was not already some work pointing in this direction.

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.

Cancer and stem cells

Canadian and Italian scientists have just came with research that adds further strength to the idea that mutations to stem cells are the main driving force driving tumour growth and ultimately cancer. Stem cells are non differentiated cells that can replicate indefinitely. When a stem cell duplicates this can lead to two stems cells or to a stem cells and a differentiated cell. These differentiated cells can perform useful things such as become muscle cells, breast cells, epithelial cells, etc. As opposed to stem cells, these differentiated cells lose the capability of limitless replication. Every time a differentiated cell divides, the telomerase needed at the ends of the chromosomes gets shorter. Eventually there is not enough for replication and the cell undergoes apoptosis. That is one reason why many tissues have a pool of stem cells that keep producing differentiated while needed.

The researchers tried to find out how relevant stem cells are for cancer growth. They show than when performing animal experiments (much more convincing than in vitro), animals with injected colon stem cancer cells are more likely to develop cancer than those in which non-stem cancer cells are used.

It all sounds reasonable to me: one of the capabilities that tumour cells have to acquire for the tumour to become a cancer is limitless replicative potential. If you inject into an animal cells that already have that capability, that should make it easier for the cancer to appear. Also, it is known that some tumour cells, as they mutate, might revert to an undifferentiated state with stem-like behaviour. Therapies that specifically target stem-cell cancer cells should be the next step since stem cells amount to a small proportion of the cells in the body but seem to have such a great potential in cancer initiation.

Evolution on a chip

Via Nature research highlights I found an intersting article in PNAS about how a group of researchers in Princeton are studying evolution in silico...for real!

Normally, when theoretical biologists talk about biology in silico they are thinking of computer models of biology, but this time the in silico referes to silicon chips that have been used to create patched environments, each one representing a different microenvironment (the main difference between the patches being the availability of nutrients). In these patches they placed colonies of E. coli and let them grow. The bacteria were allowed to move from one patch to the next using narrow corridors.

Interestingly but maybe not surprisingly, the bacteria move towards more promising neighbouring patches and some times, adapt, genetically and physiologically to the environment. Asides from some interesting experiments, the guys have been kind enough to produce some mathematical model to study the evolution in silico as well as analysis of what is the evolution of bacterial density in a patch as nutrient availability gets depleted and competition gets tougher.

It is really interesting stuff but it seems that they need to complicate a little bit more the patches in order to get more adaptation to the environment and less motility to the greener grass.

Interview with mathematical biologist Luigi Preziosi

I guess it will be irrelevant for those of you that don't speak Spanish but the Spanish news paper El Pais has interviewed the mathematical biologist Luigi Preziosi. Luigi happens to be one of the coordinators of the EU Marie Curie Network in which I am involved.

In the interview he argues that biology is geting more mathematical, explains how mathematicians and life scientists and physicians collaborate, how the mathematical models can help to explain medical phenomena and hint to innovative therapies. He also says that traditional biologists are still necessary (as if that was not obvious: theoretical physicists still need experimentalist to work with so they can validate their theories, it should not be different in the life sciences, there would not be biology without people that know how to perform experiments).

Tumour supressor gene involved in virus protection

Got this from mainstream media but the paper itself has been published in the EMBO journal in September. Researchers at the Madrid based Centre for Oncological Research have found a gene (for those interested in the gene itself: ARF) that is implicated in both tumour supression and protection from viral infection.

I guess this amounts to another cellular mechanism that has been successfully evolved to adopt an extra new function. The results of evolution can be messy but I'm still impressed.

Turning on genes again

I confess to read The Economist newspaper more than occasionally and I find the Science and Technology section readable but rigorous.In this week's issue there is an article about a new class of drugs that has recently gained approval in the US.

One of the things I have learned reading this article is about how mutations might occur that could lead to tumour formation. Up to now, as far as I was concerned, a mutation is a mutation is a mutation, that is, something that just happens and, ooops, one more ticket for the lottery of cancer. Well, it seems that a curious way to turn off large parts of the DNA is by increasing the packing density of the DNA so it becomes effectively unreadable. It seems that cancer cells can use this mechanism to avoid expressing genes so they can proliferate faster as well as avoid apoptosis and senescence. Given that the drug that has just been granted regulatory approval works best with leukemia it seems that the mechanisms employed by tumour cells to deactivate certain cell mechanisms varies from cancer to cancer. Still, having cancer cells with the capability of turning off significant parts of the DNA is such an evolutionary advantage that it should not be surprising if equivalent mechanisms are found in other types of cancer.

Genes and cancer

I start the week with a post about something really exciting that I read in Science. Unfortunately my institution does not have access to articles in Science published online before they have been printed on paper so I had to be satisfied for the time being with the reports pusblished by conventional media like the Washington Post.

It seems that researchers have screened for and found 189 genes that are altered in colon and breast cancers. Although we are talking about only two types of cancer, breast and colon cancer are two of the most diagnosed cancers in the western hemisphere. It is remarkable that both types of cancer share very few cancer-related genes and that most of the genes discovered to have a role in these cancers have not been known to be so before.

Tumour supressor gene and aging

Read at the NYT: Researchers at the universities of North Carolina, Michigan and Harvard have found that p16 gradually inhibits the proliferation capabilities of stem cells when they reach certain age. The mechanism is useful to prevent the proliferation of cells that, due to their age, have a significantly increased probability of creating tumours.

The paper reporting the research will be published in Nature. One interesting comment by one of the authors is that in his opinion aging is not random but an anticancer mechanism. I find this observation plausible but having an interest in evolution I cannot help thinking that the reason for aging could also be that once an organism has fulfilled its replication duties, its evolutionary-shaped genetic program does not care much for the long term survival of the individual. In other words, evolution does not favour individuals who are good at surviving for ever but that are good at surviving for long enough as to have lots of equally successful offspring.

Scientists find molecule that tricks cancer cells into dying

Taken from The Guardian, 28th August. It's molecular biology but still interesting: Scientists at the University of Illinois at Urbana-Champaign have found the way to restore apoptotic capabilities to tumour cells. It is known that tumour cells tend to have a defective apoptotic mechanism so they do not die when they should (eg. when the DNA repair mechanism is rendered useless).

One way to give back apoptotic capabilities to tumour cells is to provide the cell with a synthetic molecule that reactivates the production of enzymes involved in apoptosis. This is what Paul Hergenrother and fellow researchers seem to have acomplished.