Discussion: Markers of circulating cancer stem cells – validity and prognostic value

by Alexey Bersenev on August 4, 2011 · 1 comment

in cancer

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I’d like to start open discussion on the markers of circulating cancer stem cells (CCSC). The necessity of this discussion was triggered by series of recent articles and rapidly increasing uncertainty in the field.

If CTSCs are the cells that are responsible for the generation of metastatic disease, then one would predict that assessment of these cells for biologically important markers, such as those that confer cell stemness, would provide more clinically relevant prognostic and predictive information than simple enumeration—in other words, biologic specificity.

This discussion will be submitted in professional LinkedIn group: Circulating Tumor Cell (CTC) and Cancer Stem Cell Group. This group is open, so everyone can read it, irrespective of LinkedIn account.

Questions for discussion (BIG picture):

  • Are circulating tumor cells (CTC) represent cancer stem cell (CSC) fraction of the tumor?
  • Are surface markers of CCSC valid? Should we look for other (better) markers?
  • What are the best assays for CCSC detection?
  • Are CTC and CCSC markers stage-dependent or stable and representative in course of tumor progression?
  • What is prognostic value of CCSC detected by markers?

The concept that circulating tumor stem cells can be identified and targeted is attractive and has major diagnostic, prognostic, and therapeutic implications for patients with metastatic cancer. However, the identification of authentic CTSCs continues to be a challenge because of the lack of a clear understanding of the biologic heterogeneity of tumor stem-cell populations and also because of the lack of characterization of surface markers that predict clinically important subsets of CTSCs, such as those with aggressive malignant potential or drug resistance.

Some clinical oncologists think that circulating cancer stem cells are detectable have a prognostic value. For example, recent large clinical study, published in Journal of Clinical Oncology, showed the prognostic value of few CTC and CCSC markers (CEA/CK/CD133) in colon cancer patients at some stages of disease. This study triggers interesting discussion in the journal. The responders challenged the significance of using circulating CSC for clinical prognosis. You can read correspondence for free:
Editorial
Response 1
Author’s reply to Response 1
Response 2 (.pdf)

Significant part of discussion was dedicated to CD133 as potential CCSC marker. You can find a lot of papers about CD133+ tumor-initiating cells, but validity of this marker still under the question:

CD133 has been proposed as a CSC marker in many tumors, including CRC. As the authors themselves specify, CD133 is also expressed by circulating endothelial cells. Thus, CD133 mRNA detected by this study is not entirely tumor derived. Besides, it has recently been shown that CD133 mRNA and protein are expressed by both differentiated cancer cells and CSCs in CRC specimens. Only one CD133 epitope (AC133) is specifically expressed by CSCs as a result of differential glycosylation of the protein. Thus, only antibodies directed against AC133 epitope may discriminate between CSCs and the bulk tumor mass.

Please, feel free to discuss here or in LinkedIn group. Let me know if you would like to write a guest post about it.

PS: Excerpts from Editorial, Response 1 and 2.

{ 1 comment… read it below or add one }

Anthony Williams August 5, 2011 at 12:41 pm

These issues that you raise are certainly interesting and provacative. I think the answer to many of these questions will be dependent on the method you use to enrich CTC. If you use an affinity-based platform, you’ve gotta be sure that the disease system you are looking in will have majority CSC that are also EpCAM positive. Some diseases, this is the case (i.e. pancreatic, HCC). Some diseases, this may not be the case. Also, the numbers of CTC you might capture may be on the low side, you may not have enough critical mass of cells to figure out if the CCSC fraction is majority/minority (i.e. If you get 4 total CTC, and 2 of the express CCSC markers, does that really mean that 50% of CTC fraction are CCSC?).

You raise a very interesting issue, and one that I have considered before. One would have to be clever about generating experiments to test this.

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