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Chasing Cancer Stem Cells

Why does chemotherapy not work very well? That is, why do the cancers we treat tend to come back, and in a more difficult to treat form? The standard answer is that the drugs kill off all the cells that are susceptible, but that most tumors, being derived from genetically unstable cell lines, are a mixture of many similar (but genetically distinct) cell populations. Killing off half or more of the tumor with chemotherapy buys some time, but also leaves the field open for the resistant cells, which stage a comeback.

This seems clearly to be just what’s going on in many cases. But there are other possible answers, and over the last few years, another theory has gotten a lot of attention: cancer stem cells (CSCs). It could be that there are fast-dividing progenitor cells driving some kinds of cancer, and unless you target these, you’ll always be fighting uphill. You can see the appeal of this idea, because it has the potential to reduce things down to a more manageable target: a much smaller population of cells that are causing most (or all) of the trouble. And there’s evidence for this in some forms of leukemia, and possibly other tumor types as well.

The problem is, though, that you could be setting yourself up for a long chase. Somewhere in that mass of badly acting cells are the few that you need to stamp out, but where are they? And how do you know if you’re targeting them? No one can be sure if this idea is correct, or if it’s a reasonable therapeutic avenue, unless these questions can be answered definitively, and (so far) that’s been elusive. This article at Technology Review will serve to illustrate why. It’s about Stemcentrx, a well-funded (but rather quiet) startup founded on just this idea, and they’re finding that they’re really having to do it the hard way:

One aspect of that design was a methodical—and expensive—way of zeroing in on what cell type in a tumor is the ultimate culprit. At Stemcentrx it’s done by inserting bits of freshly obtained human cancers under the skin of a mouse with no immune system, a so-called xenograft. The cancer that grows is collected and divided into different cell types. Then each fraction is implanted into other mice. The process, called “limiting dilution,” gets repeated as long as it takes to find the one type of rare cell that never fails to regenerate a tumor just like the original. That’s the cancer stem cell.

Ay, multiple generations of xenograft dilution – what a way to make a living. The company says that they’re doing 150 xenografts a day (!) But their rationale is that trying to culture CSCs in vitro runs the risk of having them change character too much, making any assays using them unreliable. My guess is that they’re right about that, but my worry is that xenograft tumors themselves are already unreliable enough to cause trouble (and I have no idea of what happens to them after you “passage” them through multiple animals). Xenograft models are, of course, well known in oncology drug discovery, but one of the things that’s well known about them is that they’re the pure example of “necessary but nowhere near sufficient”. If your drug fails in a xenograft, it will probably fail in the clinic. But if your drug works in a xenograft, it will probably fail in the clinic, too. The odds get better, but they go from “extremely likely not to work” to “pretty likely not to work”, and you take what you can get in this business.

So how’s Stemcentrx doing in their cell hunt? They’re not going to tell Technology Review, naturally, but as the article mentions, the entire CSC hypothesis has been taking some hits recently. It’s still very much an open question. How many tumor types are driven by stem cells, whether they can be targeted (and how), how to tell when such an approach is indicated at all – there are a lot of open questions. It seems very likely that there are cell types inside a given tumor population that are more aggressive and likely to spread, but whether that narrows down to a particular stem cell group, I don’t know. What if there are 234 cell types in some particular tumor, and (say) fourteen of them are the ones to really worry about? What then? Will there be a common mechanism to target these, or not?

These are fundamental questions in clinical oncology that we just don’t quite have the answers for yet. You can hope that Stemcentrx is on to something, but we’ll see how things go in the clinic – which is, as usual, where it really matters. They’re not the only people trying to get this to work, either: Verastem, Oncomed, and others are all in there pitching, too. Even the clinical trials, though, are not going to be straightforward – as that last link has it:

. . .it may be difficult to draw definitive conclusions from these trials. Unlike traditional chemotherapy, the drugs undergoing testing are not expected to quickly shrink tumors, because they are designed to kill just the tiny subset of cells that seed and resupply the main tumor. So detecting whether the drugs are working in the intended way is not straightforward. Indeed, for solid tumors, researchers lack simple, rigorous assays for measuring the number of cancer stem cells.

The efforts also face some fundamental skepticism: Many still don’t believe cancer stem cells exist as a cell type distinct from other tumor cells, and some suggest that companies are hyping or at least oversimplifying the premise. A win in the clinic could resolve some of the controversy. . .

It could indeed, as long as we’re all working from the same meaning of “win”. The last few years have been lively ones for the CSC field, but that’s going to be nothing compared to the next few. . .

22 comments on “Chasing Cancer Stem Cells”

  1. RenHoeg says:

    I share your worries regarding the xenograft. The approach is surely superior to cell culture as cells have to establish 3D structures and vascular supply in situ and will encounter hypoxia, limited nutrient supply etc. However, the very reason this is possible in the first place is the mice being immunodeficient. Therefore, the one thing that the cells are not exposed to is a functioning immune system – while they owe their survival in humans to their ability to constantly trick and escape this very system. So the xenograft approach removes one of they key selection criteria for cancer stem cells in humans and it will remain to be seen whether this won’t actual lead to expansion/biased survival and thus ID of cells that are of limited relevance in humans. However, I also clearly fail to see what they could do instead…

  2. Witold Witkowski says:

    This comment will be a bit self-serving, but I’d like to mention that my employer is .

    It is also public information that we have clinical trials on going.

    1. Witold W says:

      Replying to myself because there is not -edit comment- ability. The commenting system ate some of my comment, but the gist of it is that at BBI, we’re working on cancer stem cells as well. Follow the link for more information. Its very exciting work.

  3. Me says:

    #2 & 3 probably censored due to using trademarks?

    This xeongraft work looks a tough sell to me…

  4. johnnyboy says:

    If the CSC hypothesis is true, then taking a biopsy of a patient tumor right after a course of chemotherapy should yield tissue that is replete with them. Hasn’t anyone tried that ? It would be a hell of a lot simpler than the multiple passages and filtrations that Stemcentrx does, and yield cells that are likely much less altered by the multiple steps of their method.

  5. shanedorf says:

    Taking a biopsy post- treatement is being tried, but there are limits. Its not like serial sampling in a PK study- a biopsy involves a lot more and there’s a limit to how many a patient can handle
    When should they take the biopsy ? 1 hr, 8 hrs, 1 day post treatment ? That’s why there are several companies working on liquid biopsies- trying to find and characterize circulating tumor cells in the blood and DNA fragments in the urine. Several companies are taking this approach
    See this article from The Scientist for more info
    http://www.the-scientist.com/?articles.view/articleNo/39503/title/Capturing-Cancer-Cells-on-the-Move/

  6. Chemjobber says:

    Stemcentrx was hiring bench chemists not too long ago, fwiw.

  7. DrSnowboard says:

    So at risk of being naive, the selection process you’re describing in re-emerging tumours is very similar to viral escape, except that it is the ‘mutated’ host cells that are ‘resistant’ . The parallels are similar in treatment too, antivirals since rapid escape variants seen in HepB, are now routinely given in combination.
    As Domestos used to disingenuously promote ‘kills 99.9% of known germs’ , neglecting to say its the 0.1% that are your real problem.

  8. Barry says:

    “Cancer Stem Cells” sounded like a new idea to those who never understood what–thirty years ago–we called “the multifactorial etiology of cancer” and what more recently we describe as the five (sometimes six) “Hallmarks of Cancer”. Solid tumors are judged to be “cancer”(and worthy of treating) when they manifest all the hallmarks. By that time, they’re necessarily heterogeneous and genetically unstable.
    It’s different with leukemias which are routinely treated when the first pathology is diagnosed. And it’s different in dermatology in which “pre-cancerous lesions” (i.e. less than all five Hallmarks) are routinely snipped/frozen off.

  9. Ty says:

    Call it what you want, but it’s only natural and obvious (to me) that cancer cells respond to insults (drugs, radiation, immune, etc) by stopping proliferation and re-inventing themselves for survival. First they senesce, then some escape senescence through tetraploidy followed by (pseudo)meiosis. ‘Virgin birth’ of a new life form. That’s how ‘stemness’ and developmental genes are activated. Anti-CSC should not be about ‘accounting for and killing the CSC types’. It should be about stopping the process of ‘evolution’. IMHO

  10. Ran Friedman says:

    The CSC hypothesis is supported by a large body of evidence, see e.g., http://www.cell.com/cell-stem-cell/abstract/S1934-5909(12)00240-8 . However, it is indeed not clear what sorts of cancer follow the hypothesis. There are some markers associated with CSCs, although again this is not bulletproof.

    Given that both cytotoxic and targeted treatment are liable for resistance, there may be an evolutionary benefit in maintaining the solid tumour rather than shrinking it, so I’d say the attack on CSCs is certainly worth a try.

    @Ty – interesting conjunction. Do you have references to support this behaviour of cells?

    1. Ty says:

      Admittedly, I am hooked on these theories…

      “Three steps to the immortality of cancer cells: senescence, polyploidy, and self-renewal” Cancer Cell Int. 2013

      “Size does matter: why polyploid tumor cells are critical drug targets in the war on cancer” Frontiers in Oncology 2014

      “The “virgin birth”, polyploidy, and the origin of cancer” Oncoscience 2014

      References cited therein.

  11. interested reader says:

    The usefulness of the cancer stem cells paradigm depends on cancer stem cells behaving as true stem cells, i.e., they give rise to more differentiated cells (in this case ordinary cancer cells that can’t initiate tumors) and also self renew by replication. However, if ordinary cancer cells can dedifferentiate into cancer stem cells at an appreciable rate, then any therapy directed only at cancer stem cells is doomed to fail. So far as I can tell, the concept of cancer stem cells is a repackaging of the concept of tumor heterogeneity, in which a clonally derived tumor can exhibit large differences in gene expression from cell to cells. This has been known for decades.

  12. Stemmy says:

    The CSC field is a mess. I know – I’m in it.

    It’s an odd field to work in. For a long time there were more CSC review articles than primary publications. I fear this has done the field a disservice and has prejudiced investigators assumptions of what exactly a CSC might look like.

    The field is full of confusion and misinformation. Just about every second paper pollutes the literature with grandiose claims to have defined another CSC population in another tumour type, but when you dig beneath the hype and really look at the data.. concrete evidence is severely lacking.

    Most papers don’t even know what they’re measuring. Some measure tumour initiating cells (TICs) and confuse these as CSCs – these are not the same thing. TICs are the cells that establish the tumour upon transplantation into a new host, or metastasis to a new site, whereas (as mentioned in the article) CSCs are a cell type that is able to evade chemo, self-renew and drive bulk tumour growth. The Limiting Dilution (LD) assay referred to in the above article for example is measuring TICs. Scientists have prejudiced ideas that the CSC fraction must be small, slowly dividing, chemo resistant, exhibit self-renewal, and feed the tumour bulk – where is the direct evidence for this? Most of these beliefs are simply borrowed other paradigms (from development; ‘normal’ adult stem cell biology; bacterial biofilm formation; etc).

    There is clear evidence in blood cancers to support the CSC hypothesis, however this is still lacking in solid cancers. Perhaps the best evidence is seen in lineage tracing experiments (eg http://www.nature.com/nrc/journal/v14/n7/full/nrc3744.html), however this still isn’t ‘cancer’.

    The current thinking is that CSC is a ‘state’ and that this state is plastic (again another borrowed paradigm – this time from normal blood stem cell biology with ‘stemness’ being conferred to a non-stem cell by a specific supporting structure (niche)). The worry with this latest hypothesis is that any therapies will now be targeting a moving and constantly evolving target. How does one do that?

    Can’t we just target a CSC-specific activity? Well.. what exactly might that be and how would you test it?

    It amazes me that anyone could launch a company on such ‘woolly’ science.

  13. Kelvin says:

    Why not treat the cancer cells with the initial chemotherapy drug(s) in vitro to narrow down the field and look at what remains? Maybe also use FACS with the right probe to identify any stem cells? Just a thought, though this is not my field…

  14. tangent says:

    If the CSC hypothesis is true, then taking a biopsy of a patient tumor right after a course of chemotherapy should yield tissue that is replete with them. Hasn’t anyone tried that ?

    I’d naively expect you’d get all kinds of chemo-resistant subtypes, “stemmy” and not, and why not mostly not?

    I mean, yes, it *would* work assuming the strong hypothesis is true that there’s this one subpopulation that holds both the chemo resistance and the progenitor capability. Just seems likely to me if that combination occurs, it occurs as the intersection of the two traits and they show up separately too. If they’re independent then chemo wouldn’t even concentrate the progenitors at all.

  15. Steve says:

    So, as usual, it’s a bit more complicated than has been portrayed. Sean Morrison did an interesting experiment a while back where he showed that the number of “cancer stem cells” in a xenograft was dependent on the mouse system used – the more immunosuppressed the mouse (i.e., using NOG mice instead of NOD) the more cells in the population read out as CSCs. In fact, if the mice were sufficiently immunosuppressed, every cell in the melanoma could act as a cancer stem cell (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597380/?tool=pubmed).

    What constitutes a stem cell isn’t that well defined even for hematopoietic stem cells, the best understood system. Work by Connie Eaves and others have shown that there are actually multiple types of HSC, not just a single stem cell that gives rise to the whole hierarchy as previously thought.

    There are also data that cancers can recapitulate their stem cell hierarchy, with cells that didn’t have stem cell characteristics developing them if the original stem cell population is depleted.

    It’s better not to think of CSC as a discrete population but rather a physiological state that can be influenced by epithelial-mesenchymal transitions (EMT) and other mechanisms. Attack the mechanisms, not the population if you want effective drugs.

  16. steve says:

    Sorry, should have said that in Morrison’s experiment a quarter of the cells could act as CSC and one might suspect that, given the right conditions, all the cells could act like that.

  17. ADC chemist says:

    Stemcentrx focus on CSC makes for a nice PR optic and good funding but the success of their drug is more dependent on the quality of their ADCs than whether or not they are CSC targeted.

    Their targets like DLL3 are located on tumors and for what it’s worth let’s say on CSC. But that’s not much different than a whole host of antigen targets, HER2, CD30 and CD33 which all may have a CSC component to them. And the presence of CSC marker (if there is even such a thing) may be irrelevant if the payload being delivered has good bystandard effect.

  18. Jim Hartley says:

    For Bob Weinberg’s view of the role of stem cells in cancer, see Cancer Discov; 5(1); 22–4, 2015.

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