Stem Cell Theory Of Cancer

While natural heterogeneity of cancer specimens is well documented, and the ability to isolate hundreds to thousands of cells with techniques such as LCM have allowed microarray analysis of more pure populations, the recent re-introduction of the cancer stem cell theory (24,25) has presented an extreme example of the need to isolate rare populations of cells. Cancer stem cells appear to exist at a frequency on the order of 1 in 1000 cells (26). While obtaining completely pure populations of stem cells remains difficult, highly enriched populations of these cells can be isolated using flow cytometry separating on the basis of the presence of certain specific cell markers.

One hypothesis is that cancer stem cells are relatively immune to current therapeutic methodologies, due in large part to the fact that these cells divide only infrequently and are generally quiescent. As these cells also have the potential to cause the formation of a new cancer, therapeutics targeted to these specific cells would be of immense benefit. The fact that cancer stem cells occur in such low frequency dictates that what may arguably be the most important signature to identify within the tumor is completely lost in most microarray analyses.

While laser capture microdissection and other related techniques may allow for the generation of relatively homogenous cell populations, most such purification steps will largely eliminate any potential cancer stem cells, because these techniques necessitate the identification of differentiated cell types for isolation. As such, cancer stem cells would frequently be eliminated from analysis, and any cancer stem cells that may be accidentally included in the analysis would be in such low occurrence that their signature would most certainly be missed.

Assuming that the cancer stem cell theory is in fact correct, then we can see how it is possible that the reason we have not yet learned a great deal about cancer using microarrays is not due to the technology itself, but more due to its application and the sample that is being used to profile the cancer. As techniques are introduced that will allow the profiling of single cells, it may be possible to obtain specific gene expression signatures for these cancer stem cells. Drugs developed specifically to target these genes will revolutionize the means by which the disease is treated. Elimination of these tumor progenitors would not only help eradicate the initial disease, but would also essentially prevent recurrence as well. The problem, however, is that it is very difficult to profile individual cells, and techniques to do so have only recently been introduced.

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