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How to separate cancer cells from normal stem cells?


I was thinking about it for a long time. Especially after that discussion [1] about our satisfaction with hematopoietic stem cell transplantation that we had. The question I’ve been asked [2] was whether it’s possible at all? I was almost sure it is, as referred to in Irving Weissman’s talk [3] (slide on 11 – 13 min). He basically said that we can “remove contaminating cancer cells from stem cells grafts”, based on sorting different populations by surface markers.

But recently I realize that he didn’t say anything about cancer stem cells (CSC). If leukemic stem cell (LSC) share surface markers with normal hematopoietic stem cell (HSC), how can we separate them? By that time (2007) Weissman hadn’t noticed. Modern blood separators that are used in bone marrow transplant clinics for autologous grafts cannot give us CSC-free apheresis product.

I started to search more information about it. What I found was that there are a few experimental approaches, which could give us a hope for possibile separation of CSC from HSC in mobilized peripheral blood of leukemic patients. All of these approaches are once again based on elimination of CSC by surface markers. Even though they share expression with normal HSC the level of signal is so much higher that all activity of eliminating antibody will be directed to CSC without significant depletion of HSC.

The identification of cell-surface molecules that can distinguish between leukemic and normal stem cells is essential for flow cytometry-based assessment of minimal residual disease (MRD) and for the development of prospective separation strategies for use in cellular therapies.

Here are some markers that are proposed to discriminate normal HSC from leukemic stem cells:

marker
reference
CD123 Jordan et al, 2000 [4]; Jin et al, 2009 [5]
CD44 Jin et al, 2006 [6]
CD96 Hosen et al, 2007 [7]
CLL-1 van Rhenen et al, 2007 [8]
CD47 Majeti et al, 2009 [9]

As you can see some markers were described a while ago. I was trying to track their following development in terms of clinical trials and didn’t find any information. I assume, for now, all of them are stuck in “xenogeneic assays stage”. CD47 is the latest “new hope” for clinical trials, and it could have some advantages:

We demonstrate not only that CD47 is more highly expressed on AML LSC compared to normal HSC and MPP but also that this differential expression can be used to separate normal HSC/MPP from leukemia cells. This demonstration of the prospective separation of normal HSC from leukemia cells in the same patient sample offers the possibility of leukemia-depleted autologous HSC transplantation therapies.

If you know any other approaches which got very close to clinical trials and that I didn’t mention here, please discuss in comments. For now, I can’t wait when we will get a “magic blood separator”: up right – T-cells, up left – cancer stem cells, low right – HSC, low left – myeloid progenitors. Jut hit a “start” button!

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citations: Majeti R, et al. Cell 2009;138:286 [10]