I have been neglecting this blog for the last few weeks due to work (why do I have the feeling that this might be one of the most common excuses in the blogsphere??). Part of that work involved hypothethising whether cells in a tumour cooperate, and if they do, how does that happen and what are the implications (from the therapeutical point of view and otherwise).
Although discussed in this blog before (here, here,here, here and here), I know that cooperation is not an entirely uncontroversial topic. The idea of cells competing or cooperating is, admittedly, a problematic one if it results in anthropomorphism. What is the meaning of cells in a tumour cooperating? Does it mean that they sit down and discuss possible alliances? do they sign contracts to make sure that the cooperation can be legally enforced? Obviously we are not talking about that type of cooperation: cells (tumorous or not) have no will or mind, they do not decide to cooperate.
We can also try to think differently about cooperation and competition. Tumours are made of various types of cells, some of them normal (in a healthy tissue) some of them not. This diversity is dynamic and new types appear and disappear as the tumour progresses. In this context, each new cell type interacts with the remaining ones in ways that can contribute or be detrimental to the fitness of each of them. Fitness being, as usual, the capability of having a large progeny in the long term. For instance, if two cells are after the same nutrient we can say that they compete for it, which has a detrimental effect on both of them. On the other hand if during progression a mutation appears that allows a cell to produce a growth factor that could be shared with other neighbouring cells, then that cell is cooperating. In general (and this is, unashamedly taken from wikipedia), depending on the fitness that each of cells (with phenotypes A and B in the example) obtain, the types of interactions are:
It seems reasonable to think that when two cellular species compete for a resource they will evolve to become more efficient at either competing for the resource or finding it through different means. It seems equally reasonable that when two cellular species cooperate (basically mutualistic but to certain extent, comensalistic interactions) there is an evolutionary pressure to make this cooperation more effective (e.g., trait specialisation).
In a recent article in Science (perspective and the article itself) shows that the fact that cells in a tumour can cooperate (the cooperation being not necessarily among tumour cells but includes stromal cells like fibroblasts) could be used against cancer. Olive and colleagues studied, using animal models, how fibroblasts in pancreatic tissues are responsible for poor vasculature. This could seem to be bad news for the tumour as that would limit the amount of oxygen and other resources but it also means that drug delivery becomes less efficient. Furthermore, not all tumour phenotypes suffer equally from poor oxygenation. Cells with a glycolytic metabolism fare better in hypoxic environments which means that these cancer associated fibroblasts in effect cooperate with the more aggressive tumour phenotypes. This cooperation can be (crudely) formulated as “Fibroblast, if you make sure that us, aggressive cancer cells, are sheltered from drugs and allowed to have an upper hand on our competition with other tumour cells, then we will produce Hedgehog factors which you relay on”. What Olive and his colleagues did was to target the Hedgehog, thus reducing the population of fibroblasts, helping to renormalise the vasculature and help drug (gemcitabine) delivery.
This is a very interesting piece of research that, in my opinion, highlights that if cooperation can explain certain aspects of tumour progression, then therapies that target the weaker elements of that cooperation could be very helpful.
Olive, K., Jacobetz, M., Davidson, C., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M., Caldwell, M., Allard, D., Frese, K., DeNicola, G., Feig, C., Combs, C., Winter, S., Ireland-Zecchini, H., Reichelt, S., Howat, W., Chang, A., Dhara, M., Wang, L., Ruckert, F., Grutzmann, R., Pilarsky, C., Izeradjene, K., Hingorani, S., Huang, P., Davies, S., Plunkett, W., Egorin, M., Hruban, R., Whitebread, N., McGovern, K., Adams, J., Iacobuzio-Donahue, C., Griffiths, J., & Tuveson, D. (2009). Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer Science, 324 (5933), 1457-1461 DOI: 10.1126/science.1171362
David,
Fascinating paper, thanks for pointing it out. We normally think of tumor cells and endothelial cells as having a mutualistic relationship. Thus the tumor cells react to hypoxia by activating HIF/VEGF to induce angiogenesis and thus increase their nutrient/oxygen supply. This puts a different spin on things, that I hadn’t really considered. Very cool. Cancer, as always, is more complicated than we think.
Hi Simon, thanks for the comment. I am glad you liked it. Also thanks for pointing out that endothelial cells need to be considered. From what you say I guess that endothelial cells help certain tumour phenotypes (the ones that are more susceptible to hypoxia). So one could think of endothelial, certain fibroblasts, tumour cells that are less sensitive to hypoxia and those that are more. Hypoxia sensitive cells would then compete against hypoxia insensitive ones, and each one would count on their allies (antropomorphic as this might sound) in a struggle to produce (or prevent) a functional vasculature for the tumour. Is that a more complete/accurate picture?
Thanks David. I also ended up reading both the perspective and (part of) the paper. And blogged about it, but on my Italian blog.
The picture is possibly getting more complicated. Hypoxia & genomic instability, Worburg, blood perfusion and access for chemo agents, paracrine factors and molecular chatter.
Hi Massimo, thanks for your comment, don’t heasitate to put the link to your italian blog, some of us can somewhat understand some italian :)
The picture is indeed getting more complex, but it seems to me that a more simplified (reductionist?) approach has not yielded a lot of results so far…
I agree, it looks like going for the bigger picture is becoming promising.
Here’s my Italian blog, and since you may be proficient in Spanish, as it seems, you are invited to guess what I wrote about you…
Hi Massimo, thanks a lot. Nice entry, thanks. Would be definitely nice to meet, I guess I just have to attend more cancer biology conferences (and not just those involving mathematical oncologists too!).