Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution
Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009 Sep 4;138(5):822-9. doi: 10.1016/j.cell.2009.08.017. PMID: 19737509.
The cancer stem cell model postulates that there are a few tumorigenic stem cells that give rise to the majority of the tumor cell population and these cells are the ones that can self-renew and grow the tumor. This means therapies for cancers driven by these stem cells need only target the stem cells to remove the tumor.
There is quite a lot of evidence for the cancer stem cell model, primarily from the fact that in certain cancers, tumorigenic cells can be distinguished from non-tumorigenic cells. This characterizes cancer stem cells: if there are two populations of tumor cells, this suggests a hierarchy in the tumor cells where some cells are able to both differentiate and self-renew. The differences between the stem cells and the differentiated cells would have to be epigenetic since it is unlikely that only some cells have the genetic ability to proliferate. This ability to distinguish between them does come with a caveat: sometimes there are non-neoplastic cells in tumors that may be seen as ‘non-tumorigenic’ or debris from the sample may be classified as a real non-tumorigenic cell.
Further, the epigenetic changes need to be confirmed since just the presence of both tumorigenic and non-tumorigenic cells does not confirm a stem cell hierarchy: genetic and environmental factors can also explain that and be consistent with a clonal evolution model. At this point there was no evidence that the difference was epigenetic rather than genetic. Although CSCs may be important in some cancers, the clonal evolution process is important in all cancers.
The cancer stem cell model deals with the tumorigenic potential of cells, not their fate. We can use data to figure out what cell populations may lead to cancer, but whether they do depends on the individual and that would be hard to study. Therapies are driven by the consideration of tumorigenic potential since it would be dangerous to ignore any potentially tumorigenic cells. However what cells are fated to become tumorigenic is context dependent.
Despite the evidence for cancer stem cells, there remain some problems. The evidence for CSCs from immunocompromised mice that grew tumors from transplanted human cells may underestimate the frequency of human cancer cells with tumorigenic potential. Fewer human cells are required to start a tumor in immunocompromised mice than they would in humans. Further, tumor heterogeneity after transplantation was quantified using only a few cell surface markers and not with any genetic tests. Some markers like CD133 do not distinguish between tumorigenic and non-tumorigenic cells in certain cancers which means markers alone are not a reliable assay for therapy efficacy. The degree to which these mouse models recapitulate the human environment is also unclear and incompatibilities between mice and human receptors and ligands may confound results.
It is also important to define cancer stem cells. Although conflated with tumor cells of origin which are normal cells that turn cancerous, the cancer stem cell model does not address the cell of origin. They should also not be confused with the origin of a clonal population because that is a different model for cancer.