Turning Stem Cells Into Cancer

An interesting new paper (Open Access, click away!!!) exploring the cancer stem cell hypothesis, describing to my knowledge the first transgenic cancer model to be derived by specifically targeting a normal stem cell population. The Spanish group of Maria Perez-Caro et al. show that they can induce chronic myeloid leukemia (CML) in mice by introducing the infamous bcr-abl oncogene (a gene encoding an aberrent fusion protein known to drive the human disease), specifically into Sca1+ normal hematopoietic stem cells.

They go on to use the model to investigate an important corollary of the cancer stem cell hypothesis, which postulates that residual CSCs are responsible for disease remission during/following therapy. They show that their CML mice cannot be cured with the bcr-abl targeted inhibitor STI571/Gleevec, whereas ablation of the Sca1+ stem cell compartment is sufficient to eliminate the disease. Therapeutically speaking they cheated a bit here by simply engineering a suicide gene into the oncogene cassette, but it's a start. It would be nice to see whether a therapeutically relevant approach to CSC depletion (ie anti-Sca-1 MAb) would also be able to eliminate the disease in their model.

Doubts on the Cancer Stem Cell Hypothesis

The cancer stem cell hypothesis states that a tumour consists of a subpopulation of cells that give rise to all the heterogeneity found in the cancerous tissue. These cells have some common markers and characteristics of normal stem cells. These, the hypothesis suggests, give rise to the tumour and are therefore the best target for cancer therapeutics.
A recent paper in Nature seems to have caused a bit of a stir in the cancer stem cell field. (first born child or expensive subscription required). Part of the evidence for the cancer stem cell hypothesis is that when human tumour cells are implanted into an immunocompromised host mouse only a small percentage of these cells are capable of reproducing a tumour. This new paper demonstrates that if the host is more immunocompromised then a larger number of cells are capable of reproducing a tumour, instead of only as low as one in a million cells to as many as one in four.
A wired artcle on the work really tries to stir the pot:(free)
"The controversial idea that all tumors are created by cancer stem cells received a setback Wednesday."
There are also some great summaries of what the impact of this paper may be in this field of research in Nature. News and Views. Nature News. Again you will have to sell organs or have an institutional subscription.

I can't say that I know much about cancer stem cells, only that I find the hypothesis interesting. As the summaries suggest, I would not find it surprising that some cancers do indeed consist of a subpopulation of cancer stem cells wereas others do not. I also don't know if specifically targetting cancer stem cells is going to cure a patient since these cells, while capable of causing a recurrance don't cause the symptoms of cancer.
I also don't follow the logic that the cancer stem cells are the reason that chemoresistance occurs, and other hypothesis that have come out of the cancer stem cell hypothesis.
That being said I certainly don't find this study to be blow to the cancer stem cell hypothesis.

Urban dictionary for science?

Nature this week has a news feature concerning the erosion of the definitions of certain terms. It is a pet peeve of mine to hear epigenetic (it has to be heritable!) and de-differentiation (hint: if you're talking mammalian cell, you're probably wrong) misused. And I find stem cell is being used so loosely that it has sort of lost its meaning as we've discussed before.

The article tackles (excerpts to follow):

-paradigm shift:
"Unless a Nobel prize is in the offing, it might be wise for scientists to adopt the caution of contemporary historians of science and think twice before using a phrase with a complex meaning and a whiff of self promotion."

-epigenetic:
"The NIH is careful to define the epigenetics it is paying for as including both heritable and non-heritable changes in gene activity, something that Ptashne describes as "a complete joke".) Bird says he remains in favour of a relaxed usage. "Epigenetics is a useful word if you don't know what's going on — if you do, you use something else," he says."

-complexity
"Even within the precise world of binary code and bit strings, there was computational complexity, which describes how much memory and processing is required to carry out a calculation; algorithmic complexity, which is related to how much a digital description of something can be compressed; and any number of combinations and variations. "So my bottom line is, add an adjective to 'complexity'," Crutchfield says."

-race
"Race was long used to imply a shared, distinct ancestry [...] But in other contexts researchers are abandoning the term in favour of other ways to group humans, by 'population,' genetic ancestry' or 'geographic ancestry'"

-tipping point
"The term was originally coined in 1958 by sociologist Morton Grodzins in the context of studies on the racial makeup of US neighbourhoods. He found that when the migration of African-Americans into traditionally white neighbourhoods had reached a certain level, whites began to move out."

""There is no convincing theoretical argument or model that at some point the planet as a whole will snap into a second state of system," says Timothy Lenton, an Earth scientist at the University of East Anglia, UK."

-stem cell
"Alleged 'stem cells' can fail to meet the definition on many counts. Stem cells should persist long term, yet many 'stem cells' exist only in the fetus. Multipotency — the ability to generate multiple cell types — is a criterion for a haematopoietic, or blood-forming, stem cell, but spermatagonial stem cells only produce sperm. Stem cells specific to tissue such as cartilage, the kidney and the cornea have been reported, with varying degrees of acceptance. The quest for a 'stemness signature', a collection of markers common to all stem cells, has been met with frustration."

-significant
"Most statisticians resign themselves to abuse of the term's strict definition. But more grievous trespasses abound. "Statistical significance is neither a necessary nor a sufficient condition for proving a scientific result," says Stephen Ziliak, an economist at Roosevelt University in Chicago, Illinois, and co-author of The Cult of Statistical Significance. P-values are often used to emphasize the certainty of data, but they are only a passive read-out of a statistical test and do not take into account how well an experiment was designed."

-consciousness
"Many definitions of consciousness include the ability to sort through the relentless onslaught of incoming data to create and respond to an internal model of the external world. And some believe that simply gathering data about neurons and behaviours will not be enough."

The Stem Cell Delusion: Are They Still Stem Cells If They're Bacteria?

On a previous episode of the bayblab podcast, I argued (rather poorly) that so-called mammalian "stem" cells are not so magical and deterministic as we think (ie they do not "exist"). Rather, I attempted to argue, the stem cell illusion is an emergent property of fundamental cell population dynamics and is even exhibited by the lowly unicellular prokaryotes, as exemplified by the phenomenon of bacterial persistence. A new PLOSone paper explores the theoretical basis of bacterial persistence as population bet-hedging:

"Within a population of bacteria there exists a subgroup of cells that do not grow at the normal rate but exists in a quiescent, non-growing or slow-growing state. These cells are sometimes called persister cells [1], because they are able to persist in the face of catastrophic events such as antibiotic treatment...A key aspect of persister cells is that their resistance to antibiotic treatment is not genetically determined. Consequently, following antibiotic treatment, persisters give rise to new populations that have the same vulnerability to antibiotic treatment as the ancestral population [9]."

Sound familiar stem-cell believers? Slow growth, resistance to insult, and capable of repopulating diverse cell types. OK, so maybe bacteria have stem cells too. Maybe we should even think of them as multicellular organisms. But wait, now for the challenge to faith:

"The resistance of persister cells is therefore determined phenotypically, with cells switching between the alternative phenotypic states of persistence and normal growth [7], [11]."

What the !@#$& ?? Cells shape-shifting back and forth? Stem cell one minute, non-stem cell the next? Clearly mammalian cells are different. Once a stem cell always a stem cell. Right? Wrong. The stochastic outcome of asymetric stem cell division was one of the first properties described by McCulloch and Till soon after they discovered mammalian stem cells waaaaay back in the day.

Obviously then, "stem" cells do not exist....then they do....then they don't, then they do....

Wave....particle.....wave....no, particle....no it's a wave....

Maybe it's not that bad. At least one might say there's a certain probability that a given cell will be "stem" at a certain point in space-time?

Creating cancer stem cells

Ok maybe I'm thick, but this latest paper still doesn't make it clear to me that static cancer stem cells exist. A team at MIT has developed a kind of media that promotes the growth of cancer stem cells. When growing identical breast tissue samples in normal or "special" media and then transforming them with the same oncogene, two types of cells are formed. Each line produced different tumours when xenografted, with the cells growing in the "special" media forming more agressive, metastasis prone cancers. Furthermore those special cells were 4 orders of magnitude more likely to form tumours (i.e. it took 10^4 less cells). The researchers concluded that they had a found a way to make cancer stem cells.

Lets get back to the definition of cancer stem cell: it's a cell which has the ability to initiate a tumour. So it should really be called a tumour initiating cell. It this respect it is more akin to an ES cell. ES cells are destroyed in the process of forming a human being. Conversely adult stem cells cannot form an organ, but they are needed for tissue homeostasis. These properties are, I think, what most people imagine a cancer stem cell has. It's the replicative compartment of the tumor.

This leads to an ambiguity: is the tumour initiating cell the same as the tumour homeostasis cell?

Take these facts into consideration:

-Many tumours only grow in the periphery and have a necrotic core, does it mean tumour homeostasis cells always migrate to the periphery, or are self-renewing at a high rate on the exterior. Would the explanation that any cancer cell in the periphery has a probabilistic ability to act as a homeostatic cell be more parsimonious?

-The authors suggest that normal cell lines have much lower abilities to form tumours than their "super" cells. They say it usually takes a million cells in a xenograft versus as little as 100 of their cells. So they argue that only about a cell in a million can hold the proliferative potential of a cell line. We know that's not true, all the cells are dividing, and you can easily start a new culture flask with 100 cells, I've done it countless times. The limiting factor here, I think, is the ability to implant and survive in the hypoxic and growth factor poor environment of a mouse, after having lived in the easy condition of growth media.

-Finally the authors argue that their media selects stem cells. Obviously that's not true, otherwise both culture conditions would create the same tumours but at different rates depending on the selection stringency. Here they get 2 types of tumour. More likely they've either selected for two types of cells or changed the phenotype of the cell with their media. They do acknowledge they have two cell types, but they argue that they have enhanced stemmness, when all they show is they have a different cell with a different probabilistic ability to initiate a totally different cancer type.