I am eagerly waiting the responses of specialists in this domain but I emit more than serious doubts about the fact that "one of the makor hallmark" of CSCs is asymmetrical division.

And without assymetrical division, reading the recent literature on the subject, I am confident that several researchers will selectively target (hopefully soon) CSCs in tumors.

Best regards

Robert

Hello

This very interesting question , and i hope help you these references

Good Luck

http://www.bostonbiomedical.com/research-and-development/publications/

http://www.nature.com/ng/journal/v37/n10/full/ng1005-1027.html

Thank you Dr Alkarim, I will have a look at some of these articles.

HI Gustav,

My lab is focusing on this question.  Let me start by saying a cancer stem cell or tumor initiating cell does possess the ability to carry out asymmetric division, just as any other normal stem cell.  We isolate CSC from fresh tumor and when they are put into culture they differentiate within several passages to what we call the bulk tumor phenotype (non-stem), but always maintain a low level steady state of CSC in the population (3-15%) and this always corresponds to what the original CSC level was in the tumor.  There seems to be "memory" within the population and this is controlled through asymmetric division.  We hope to have a paper out soon!

Kind regards,

Steve

Dear Steve,

Is assymetric cell division an actual hallmark of CSCs?

Or have they the "capacity" of performing assymetric(al) division?

Which is in my opinion two quite distinct processes.

Thank you for your attention.

Robert

HI Robert,

I guess it depends on your definition of"hallmark".  But all stem cells have this unique ability.  We only define CSC as cells that express classic embryonic markers of stemness such as Nanog, Sox-2 Klf-4 Oct3/4.  Our work indicates that asymmetric division is critical in tumor growth as the CSC are able to maintain a steady state low level population within the bulk tumor population.  So I guess I WOULD call it a hallmark of CSCs!

Steve

Thank you very much Steve for your prompt response.

Are the rates of assymetric cell division the same in normal versus cancer stem cells?

Do you have any ideas (or articles) indicating whether a differential effects would exist for anti-tubulin and/or anti-actin agents in assymetric divisions in normal versus cancer stem cells?

Kind regards

Robert

Hi Steve

Apologies for my belated response. I am glad to hear that others also think that asymmetric cell division is a key characteristic of CSC!

Your reason for believing so is ‘empirical’- you guys observe CSC to divide asymmetrically. My motivation for arguing asymmetric cell division of CSC must be a ‘hallmark’ is more based on the fact that if CSC don’t divide asymmetrically, there would be no point in calling dividing cancer cells CSC. (If all cells divided symmetrically, were would the tumour heterogeneity come from? What dividing cancer cell would then NOT be considered a CSC?)

Here is the thing though: If a sub-clone would immerge that do not divide asymmetrically (i.e. a CSC that consistently divide symmetrically), that clone would dominate. (I.e. over time, the tumour should tend to consist of a bunch of CSC that divide symmetrically). Also, a tumour consist of various cancer cells, some would divide symmetrically, with a grater or lower propensity. That is, cancer cells don’t always divide symmetrically, but do so with a statistical propensity. (I.e. cancer cells exhibit degrees of ‘stemness’). This would suggest that, over time, the tumour would end up being saturated with cancer cells that dividing symmetrically.  See figure: symmetric cells populations grow exponentially- asymmetrically dividing cell populations grow linearly.

So, we should not observe CSC in ‘mature’ tumours?

Dear Gustav,

Even if:

1) I am a "has been" guy due to my great age as compared to yours,

2) I already wrote on the RG web community Q&A facilities that you are already a "master in your field",

I will never buy your story according to which

"My motivation for arguing asymmetric cell division of CSC must be a ‘hallmark’ is more based on the fact that if CSC don’t divide asymmetrically, there would be no point in calling dividing cancer cells CSC. (If all cells divided symmetrically, were would the tumour heterogeneity come from?" ...

Tumor heterogeneity can be issued indeed from CSCs ... but also from genetic mutations (nothing to do with CSCs), to microenvironment selection (some of them are related to CSCs, but other not at all ...), etc..., etc...

Best regards

Robert

Robert, your impact points are higher than my entire department combined! I think it obvious (even to a newbie as myself) that it is in my own best interest to heed what you have to say!

First off, I completely agree about the role of cancer heterogeneity immerging trough evolutionary mechanism- that is exactly what I wanted to hear! In fact, this is where I am heading: the clonal evolution model of cancer is far superior to the CSC model in explaining the origin of tumour heterogeneity, at least in advanced tumours. As argued, eventually a sub-clone will emerge that divide symmetrically ant this clone would dominate the population. The clonal evolution model can also explain why only a fraction of the population of tumour cells are capable of initiating tumour growth: Each cancer cell is an ‘evolutionary experiment’ and many of the tumour cells are on an ‘evolutionary death trajectory’ (i.e. unable to sustain tumour growth). Thus, the clonal evolution model are just as capable in explaining why only a small population of cells manage to maintain (or initiate) tumour grafts.

I am also very suspicious of the essays used to ID CSC, as well as the ‘mythical’ attributes that are ascribed to CSC, and the implications of the fact that ‘stemness’ is often observed to a transient state, with cells fluxing into and out of a stem-like state (what is then a marker of a non-CSC?). I'm also suspect that cancer cells co-opt normal stem cell ‘genomic protocols’ not because cancer cells what to be CSC, but because these pro-survival strategies of normal stem cells are also useful to cancer cells. (I.e. cancer cells 'figure out' [by evolutionary 'trail and error'] how to use the best parts of our genome and delete the ‘bad parts’ and in so doing end up activating a bunch of genes that are also active in stem cells- but without completely taking on a stem cell phenotype).

Of note, it is not that CSC don’t exist, but ‘the way' in which they exists that leave me sceptical regarding the actual untidily of the CSC model: They are prominent in the initial tumour phase, but become progressively less relevant later. As an example, Lineage tracking (LT) experiments provide excellent evidence for CSC. But note, LT studies performed by , [1] , [2]  and [3]  were conducted on adenomas and papillomas –growths that are often benign and in the very early phase of tumour genesis (i.e. not advanced tumours).

I posted this question as a result of the response I received from a specialist editor on a manuscript I recently submitted (under review). In the manuscript, I point out these and a number of additional issues I have with the CSC model. I know the CSC model is currently very fashionable, so I did not want to voice my concerns directly. Instead, I was using a bit of ‘Socratic irony’ to see if I could inspire scepticism of the CSC mode. This is a summary of my argument: (a) asymmetric cell division is necessary attribute for the CSC model; (b) clonal evolutional play an active role in generating tumour heterogeneity (e.g. as a necessary explanation for cancer). From (b) it appears that cancer cells with ‘devolve’ asymmetric division (i.e. develop symmetric cell division) as this would enhance their fitness. And, since (b) will undo (a), it cast doubt on the utility of the CSC in advanced tumours. Currently, asymmetric cell division is not a defining feature of the CSC model (as the specialist editor pointed out to me). However, people do recognise that “utility of the CSC model is based on the assumption that most cells in the malignant population do not have tumour-initiating activity” [4]. In fact, some people (such as Steve) would also argue that it seem to be an important feature of CSC. If a person also agree that cancer cells that divide symmetrically would have a fitness advantage, it follows that, in mature tumours, very few cells would divide asymmetrically and the very thing that makes the CSC model ‘useful’ (asymmetric cell division) also guarantee its irrelevance in advanced tumours (because evolution favours cells that don't divide asymmetrically, i.e., cells that divide symmetrically should make mor copies of them selves).

So I, prefer an ‘eco-oncological’ approach to cancer, focusing on the 'evolvability' of cancer. This approach is not mutually exclusive with a CSC model (e.g. CSCs could be the ‘evolutionary units of analysis’), but for various reasons, I am not completely convinced that CSC deserve the attention they currently enjoy.

Refs

[1] A Zomer, SIJ Ellenbroek, L Ritsma, E Beerling, N Vrisekoop, J Van Rheenen: Brief report: intravital imaging of cancer stem cell plasticity in mammary tumors. Stem Cells 31(3), 602-606 (2013).

[2] G Driessens, B Beck, A Caauwe, BD Simons, C Blanpain: Defining the mode of tumour growth by clonal analysis. Nature 488(7412), 527-530 (2012).

[3] AG Schepers, HJ Snippert, DE Stange, et al.: Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337(6095), 730-735 (2012).

[4] LV Nguyen, R Vanner, P Dirks, CJ Eaves: Cancer stem cells: an evolving concept. Nature Reviews Cancer 12(2), 133-143 (2012).

Dear Gustav,

"Now" I am sharing at 100% your views!

Take care

Robert

PS: the impact points relating to one person (say a researcher) essentially relate to her/his collaborators and to the friends in the scientific community!!

I know some exceptions, but these persons are "exceptions"!