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Complexity of cancer stem cells

With such a diversity of opinion, one might imagine that some hugely controversial or complex data sets have led investigators to propose widely varying interpretations.
Craig Jordan

Lately I was reading a few reviews and commentaries about the validity of cancer stem cell concept and possibility of targeting these cells for therapeutic purposes. I realize that all of controversies and scientific debate caused not only by misunderstanding the concept [1] or difference in assays [2] but also high natural complexity of cancer stem cells (SCS). The more we learn about them the more complex it seems.

Like all good things in science, I suspect that the rigid version of the cancer stem cell model is going to need some tweaking
John Dick (U of Toronto)

Earlier, I divided people who discuss about the validity of the CSC concept into 2 categories:
A. believers (CSC exist and concept is correct)

There is no doubt that there are cancer stem cells… This has tremendous clinical importance; the therapies we currently use don’t target them.
Max Wicha (U of Michigan)

B. non-believers (all points of the concept are questioned and challenged)

It now appears likely that the remainder of the cancer stem cell hypothesis may also fall by the wayside
Joseph Lipsick (Stanford University School of Medicine)

Now, due to the apparent complexity 2 more categories appeared in the list:

C. partial believers – basic scientists:

some cancers follow cancer stem cell concept, some are not. We have to distinguish them
Sean Morrison (U of Michigan)

D. partial believers – clinicians (CSC model is true for some cancers, but there is no point in attempts to target them therapeutically)

Trying to find ways to treat cancer stem cells is like trying to close the barn door after the horse is out
Isaiah Fidler (MD Anderson Cancer Center)

Ok, now I’d like to share some thoughts about what makes CSC so complex.

1. Let’s look at cell-of-origin: Most of us thought before that CSC should arise from normal adult stem cell due to mutations because they are so similar. Now we know that CSC could arise from normal adult stem cell or progenitor or even mature differentiated cells due to mutations. So, mutations happening on any level could create the cancer cells sharing characteristics of normal tissue stem cells.

2. The rarity of CSC was one of the first characteristics that was questioned [3].
In different kinds of tumors in different kinds of detection assays it appear to be now something between from 0.01% to 50% of tumor mass. Big variation, isn’t it?

3. Detection problem is number one in developing the CSC concept. It’s becoming clear that identification of CSC by surface markers could not work for many cancers that was proposed before.

example 1: acute myelogenous leukemia CSC: proposed detection phenotype Lin-/CD34+/CD38- is not valid today, because leukemia-initiating cells were detected in CD34+/CD38+ and even outside of Lin- progenitor cells (unpublished data).

example 2: Recently validity of bona fide cancer stem cell marker – CD133 was put under question for lung cancer [4], colon cancer [5] and glioblastoma [6].

Some doubts about validity of CD24 and CD44 for breast cancer in disease progression context you can find in this review [7].

In the search of cancer stem cells, the approach of identifying subpopulations of cells from surface marker expression is flawed. It’s much more complicated than taking out a cell with a marker and asking if you can form a tumor.
Kornelia Polyak (Dana Faber Cancer Institute)

4. CSC dynamically change with cancer progression.

Cancer stem cells themselves aren’t a homogeneous entity and they can evolve
John Dick (U of Toronto)

We are just coming to the realization of this point. It was nicely shown in Kornelia Polyak’s group 2007 work [8].
Can you imagine the situation: you are working in the lab and isolating CSC from the patients biopsy samples by defined phenotype, you inject them into NOG mice and get a tumor. Half of year later you take sample from the same patients with progression of the same cancer, sort CSC out by the same markers, inject them into the mice and… don’t get any tumors!

So CSC are continually evolving, changing genetically and epigenetically, turning off and turning on a different number of different signaling pathways during cancer progression! Moreover, CSC progeny could acquire new genetic mutations and become a new drug-resistant stem-cell-like “tumor seeds” different from the parental population. So how can we catch this moving target?

I summarized some positions of evolution of the cancer stem cell concept in the table:

cancer stem cell concept statement was before is now
nomenclature cancer stem cell same
validity (universality) for all tumors for some tumors
cell-of-origin tissue adult stem cell tissue adult stem cell or progenitor or mature differentiated cell
frequency rare (<1%)
of tumor mass
of tumor mass
hierarchical organization yes most not following
detection by surface markers yes frequently not
therapeutic targeting yes, based on unique markers flawed and illusive
CSC defined by markers and function by function
development with cancer progression stable and detectable evolve, unstable, detection is blurry and nearly impossible
what question CSC study addresses? tumorogeneity, ability to proliferate extensively potential to determine disease fate in particular patient

5. Nearly impossible to target?

Finally, as CSC evolve as cancers progress, their unique characteristics become so blurry that it’s almost impossible to target them precisely. In an attempt to target signaling pathways, which are selectively activated in CSC but not in normal stem cells, we should give to a patient cocktail of drugs in addition to conventional therapy, destroying tumor mass. With this toxicity one might imagine number and scale of side effects that could affect a patient.

But not everything about CSC is so pessimistic. We know many good examples of successful targeting and eradication in tumors where the CSC model could be applied. We still have a lot of ways, other than surface molecules and signaling pathways, to target them. We are still developing a models to validate the concept. We can see clinical relevance and significance of CSC. Field is developing tremendously right now and a model is in the making.

… debating the existence of CSCs or their frequency is not a particularly useful exercise, and the scientific community would be well served to move beyond these issues. Rather, the more pertinent question is whether studying and targeting CSC is important for developing better forms of therapy. The answer to that query seems somewhat less clear.
Craig Jordan (U of Rochester)


Craig Jordan. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 2009;4:203 [1]
Karen Rowan. Are cancer stem cells real? After four decades, debate still simmers. J Natl Cancer Inst. 2009;doi:10.1093/jnci/djp083 [9]

read more for free:
Breast cancer’s genetic profile calls the cancer stem cell hypothesis into question [10]. (The Scientist)
The cancer stem cell hypothesis: in search of definitions, markers, and relevance [7]. (Lab Invest)
Cancer stem cells: controversies and misconceptions [11]. (The Niche)
Cancer stem cell sightings and slightings [3]. (Nature Reports Stem Cells)
John Dick: careful assays for cancer stem cells. [12] (Nature Reports Stem Cells)
Validity of the cancer stem cell concept under discussion [13] (Hematopoiesis)
Cancer stem cells – how mouse model can change the concept [2] (Hematopoiesis)
Cancer stem cells and CD133 controversies [5] (Hematopoiesis)

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