Sunday, January 22, 2012

Cancer and Stem Cells

Ever wondered why a cancer treatment can so successfully reduce tumor size only to see it come back stronger than ever some months later? If you're prepared to investigate the mathematical model put forward in this paper then you'll have an interesting perspective on the challenge of cancer treatment and the realisation that modern cancer treatments are still missing a vital component in strategy.

The paper I am referring to is ...
Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells
Caterina A. M. La Porta1, Stefano Zapperi2,3*, James P. Sethna
PLoS Computational Biology | 1 January 2012 | Volume 8 | Issue 1 | e1002316
Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted.

Link to full paper

A few weeks ago I sent an email off to some friends wherein I referenced an abstract which indicated that in any given tumour there can be a highly heterogenous population of cells. There was even the suggestion that this distribution was regionally specific, an idea which intrigues me because it suggests that local microenvironment can have a fundamental bearing on cell developmental outcomes and maturation. For example, some stem cells will differentiate into markedly different types of cells depending on the shape of the matrix they are placed in. Thus ...
Extending this mechanism to stem cells, a number of studies have shown that stem cell fate can be influenced artificially through control of their shape by artificial extracellular matrices.
I only found that article while writing this up but browsing through it ... fascinating! It is and can be downloaded from the above or below links:

Control of Stem Cell Fate by Physical Interactions with the Extracellular Matrix
Cell Stem Cell,  Volume 5, Issue 1, 2 July 2009, Pages 17–26

That paper is very important because it demonstrates that the limitations of the gene centric perspective. There are just molecular events, there is no need to presume that genes are instruction sets because instruction sets presume an observer. There is no observer.

Because a tumour is undifferentiated growth it is conceivable that within the tumour there is sufficient variation in structures to promote slightly differing cell types through stem cells.

That is where this paper becomes very interesting because it is all about cancer stem cells which they argue originate from stem cells. This is not a new idea, it has been around for several years and as the authors argue raises some fundamental questions about cancer treatments. As they write:

Simulations of cancer treatments
It is illuminating to use the CSC model to simulate the effect of a treatment on the progression of a tumor. ... Our model quantifies the common-sense statement that if the cancer stem cells are the only parties that double forever, then a treatment that does not remove them will be fruitless in the long term.
The above claim, however, has the problem that obviously some cancer treatments are successful and these are not specifically targeted at stem cells. It might perhaps be instructive to examine the more successful treatments and see if those treatments do have impacts on normal stem cells and if possible cancer stem cells.

To learn more about cancer stem cells, the NIH, as it so often does, provides this useful information.

It is important to note that stem cells are not found in all tumours. That may represent a failure to find the same or that some cancers are not being driven by stem cell populations, though the paper above leans very much towards that hypothesis and their modelling is given in some support of the same. Perhaps it is even the case that stem cells driving tumour expansion do not lie within the tumour but the surrounding tissues. There are a lot of interesting questions here.

The above paper claims that many cancer cells become senescent after a period of time but stem cells avoid this fate. Cell senescence is a state of repair, it raises the question that given the abnormal metabolism of cancer cells, these cell are already stressed and vulnerable to attack whereas stem cells appear remarkably resistant to similiar types of stress. It suggests that we by targeting the senescent cells in a tumour we may simply be paving the way for a new tumour to form which will be less resistant to the treatment.

My suspicion is that the vulnerable cancer stem cells are also killed by the treatment but the stem cells themselves do not represent a homogenous mass of cells but rather a diverse population which under somatic evolution pressures some will be able to not only survive the insult but create other stem cells and tumour cells with similiar ability. Additionally, the changed environment of the tumour may facilitate the emergence of new cells lines not through somatic evolution but because the micro-environment has changed and this will influence the types of cells stem cells will produce.

Accordingly cancer stem cells should be the first therapeutic target as this will prevent somatic evolution of the tumour and the possibility of adaptation. It may even be the case that the demise of cancer stem cells in a tumour will initiate the death of the tumour. Not sure, just being hopeful ... .

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