Monday, June 13, 2016

Cancer Stem Cells: A Philosophical Look

The recent book by LaPlane on Cancer Stem Cells is a brilliantly well-crafted introduction to the field from is a philosophical perspective. Such an approach is significant since it was Galen who promoted the use of logic, and in fact the full trivium, as an integral part of the practice of medicine. Words do mean something and the term "cancer stem cell", the CSC, has been used by many over the last decade and a half oftentimes for multiple and possibly conflicting purposes.

As LaPlane initially notes the somewhat accepted definition of a CSC is (p. 2):

"Cancer stem cells are, as their name suggests, cells that combine two identities; they are both cancer cells and stem cells."

Thus starts the debate. For one must then ask what is a cancer cell and what is a stem cell. There is also a somewhat adjunct issue of the Cancer Cell of Origin. This construct is one that states that the initial change occurs in some cell. Then the CSC states that there may very well be another cell which carries on the proliferation. The questions then are: what are the characteristics of that cell, how can it be identified, how can it be targeted, and what are the therapeutic strategic that should be pursued? This is what the author examines.

The author's approach is philosophical in that she is concerned about definitions and the words that are applied. It is a bit of a return to the Trivium and even to Boethius. Words have meaning and what do we really mean by them. Furthermore, the author examines the meanings in terms of the phenomenological basis of each. As such this is a unique and frankly brilliant approach to a complex area.

It is not clear is this an exclusive coverage but it logically appears to be. It does assume that the CSCness is defined and immutable. On p. 4 the author raises the concern:

"Stem cells and CSCs raise philosophical questions regarding their identity because we still do not know exactly what they are."

Thus we are beginning to read an analysis of things for which we have a great deal of uncertainty as to their very nature.

On pp 28-31 the author starts to provide some structure to the definition of a CSC. She initially uses the definition by Reya from 2001 and she appears to give a definition (p. 29) as follows:

"If a cell is capable of self-renewal (a) and differentiation (b) then it is a stem cell."

The above describes stemness. Yet there are two other requirements. One requires that it is a CSC is a tiny amount of the total cancer growth and that, this is critical, that (p. 30):

"…cancers are initiated and maintained by cancer stem cells."

Just what and how the terms initiated and maintained are to be interpreted is yet to be determined. Now this word study albeit being philosophical is essential. Somehow to study something we must be able to define it in a universally accepted manner so that phenomenologically it is consistent. The author keeps driving this critical point.

The author, in summary, thus divides CSC into several categories. First is:

1. Intrinsic: CSCs are CSCs and that is all. Once a CSC always a CSC. Once a cell has CSCness it always retains that character, and thus is intrinsic to the cell.

2. Extrinsic: CSCness may be dependent on where and when the cell resides. A CSC may become a CSC and then change back to something else depending on some yet to be defined extrinsic factors.

Then for Intrinsic we have (Chapter 7):

1.1 Categorical: It is in its very essence. It is what it is.

1.2 Dispositional: It depends on some extrinsic factor. It has a potentiality but it must be activated by some externality.

and for Extrinsic we have (Chapter 8):

2.1 Systemic: It can be determined from any niche. As the author states on p. 169:

"…at least two kinds of processes can induce stemness: stochastic events affecting gene expression and cell population level regulations. In both cases stemness appears to be regulated at the population/system level suggesting stemness would be a "systemic property""

2.2 Relational: This is purportedly analogous to Dispositional but it is for the extrinsic mode. Namely some extrinsic niche element.

Thus there are four models of the CSC and each has some element of plausibility. Frankly perhaps all exist. The author then proceeds to examine each with both phrenological analyses as well as logical. She further posits possible therapeutic mechanisms for each. This is exceptionally well done and understandable.

Overall this is a unique and highly valuable contribution to the literature as well as to the discussions on the field of CSCs. Phenomenologically we seem to be obtaining new insights each day and having a framework to consider them is essential.

There are several areas where the author should have explored more. Let me name a few.

Mitosis: We know that cells divide by a process of mitosis. Generally, the cell divides and the resultant two cells are identical to the parent. Unless of course if some aberrant change occurs in copying the DNA as it splits.  Thus it would be useful to demonstrate phenomenologically how this process would work so smoothly in CSCs. How does mitosis occur with a CSC so as to enable this bifurcation into a duplicate and an aberrant albeit non-CSC cell? What is the phenomenological steps that allows this? Thus far it appears to be some magical process which is just skipped over.

Dynamics of CSCs: In the classic CSC model each CSC divides creating a single copy of itself and a copy of some type of non-CSC cancer cell. Then somehow this collection of non-CSC cancer cells increases. If they do not divide, then growth rates are dominated by the CSC. For example, in the simplistic clonal theory where a single cell mutates and thence this cell just multiples the resultant populations grows exponentially. This may be modified by some form of apoptosis or lack of cell progression but it states that it is just a clonal explosion. We now know however that cancer cells as they go through he body are highly heterogeneous. Thus cancer is not purely clonal.

Epigenetics: We now understand that epigenetics plays a key role. However, their cellular dynamics is relatively little understood. Certain cancers such as MDS are really methylation disorders, that is epigenetic, and yet they often progress to AML.  

Ensemble Models: In physics such as in statistical dynamics and in engineering in large scale stochastic adaptive control systems one develops ensemble models. Namely one could consider cancer as ensemble of cell states with transitions occurring between these states. A cell state would be the expression state of the genes, namely what genes are functioning and which are not. This of course is suggestive. Then one could consider a model for a space time spread of this new organism, the cancer states, and instead of looking for a CSC one could look to identify the "control elements" of this new quasi organism. This would be an adaptive system approach based upon a totally different view of the cancer. Thus is the CSC a transient artifact or a fundamental target for cancer?

Coverage: Are the epistemological models posited by the author complete? Do they cover all possible options in which a putative CSC can take? The four seem to be so: internal with internal control, internal with external control, external with internal control, and external with external control. It appears that these cover all options. Yet is it too all encompassing? Or as an Ockhamist is each CSC just another representation of how cancer can develop. Is the attempt by the author to categorize to be defeated by nominalism?

Overall this is a superb book and should be read and consumed by those in the field. The debates still continue but having such an approach brings new insight and discipline that is of great value.