Stem cells, cancer and “bad luck”

Bilbao, Spain - January 16, 2015

Just a few weeks ago a paper by Tomasetti and Vogelstein describing a mathematical model that correlates cancer incidence with the number of stem cell divisions in a plethora of human tissues was published in Science. This parameter is related to the cell replication activity of a particular tissue, ie, the cell turnover rate in that tissue, as some tissues renew their cells more slowly than others (compare brain tissue to intestinal epithelium). For about 2/3 of the tumors explored, the overall cancer incidence was much more strongly correlated with the number of stem cell divisions than with genotoxic or environmental insults, thus pointing to “bad luck” the occurrence of a tumor in most patients, for those tumors that fell within those 2/3 described. For example, in the case of skin tumors, basocellular carcinoma is 3 times more frequent than melanoma, although the target cell of origin for both cell types apparently are exposed to the same intensity of UV light. This is justified by the greater number of stem cell divisions in the basal compartment of the skin.

This report superficially seems obvious, prima facie: the more divisions cells in a tissue carry on, the higher the chance to suffer a spontaneous mutation that may eventually lead to oncogenic transformation. This is equivalent to link car speed with traffic wrecks, as we all understand that the faster you drive, the more likely it is to have an accident. However, this is the first time that this has been mathematically modeled using real incidence data and stem cell division experimental data (although from the literature), and it still shows what we all have in mind, that the more active a tissue is (in terms of cell replacement), the more likely it will develop a tumor. The big four tumors: breast, prostate, lung and colon, are derived from tissues that undergo continuous cell renewal supported by an active stem cell compartment.

Mutations have multifactorial origin (UV light as mentioned, random errors during DNA replication, chemical insults from the environment, multiple forms of cell stress, etc..), thus occur randomly in any cell, but only if a cell divides (replicates its DNA) it may fix the mutation and transmit it to its progeny. Keep in mind that in order for a cell to become a malignant tumor many changes need to be present concomitantly, so it is rather unlikely than a cell becomes transformed.

By no means this report points to the stem cell as the only culprit of cancer development, however, the more a stem cell compartment needs to expand to maintain tissue homeostasis, the greater the chance to suffer a potential oncogenic mutation. Let me dig a little on tissue homeostasis.

Tissues are organized in a cell hierarchy, from a primitive mostly quiescent stem cell that self-renews and has the potential to generate all the cell types in the tissue, to dividing progenitors (transit amplifying cells) that progressively give rise to committed differentiated cells and loose the ability to self-renew. Only cells that can self-renew (so at least one of the daughter cells remains with the same lineage potential) are the cells that “stay” for the life of the tissue. Cell lineage can be envisioned as a continuous from a primitive tissue stem cell to actively dividing self-renewing progenitors that progressively give rise to non-replicating differentiated cells. Therefore, the bigger the stem cell and associated progenitor compartment is (which equals to higher tissue renewal), the more likely it is that a potential oncogenic mutation is fixed in an early stage cell and thus will be present in its entire progeny.

Tumors are cell associations organized in a cell hierarchy that somewhat functionally resembles the normal hierarchical organization of a tissue, from a cell of origin (so called cancer stem cell or a tumor initiating cell) in the apex, to cells that no longer retain the ability to give rise to more tumor cells. The similarity with the normal tissue is: tumors are heterogeneous in cell composition with a few cells that can maintain the growth of the tumor (the cancer stem cells) and the bulk of the tumor mass.

So, what are cancer stem cells? Are they transformed stem cells? Are they potentially malignant cells that acquire stem cell features? There are over 220 different types of tumors, many of them variations arising in the same tissue, what is the origin of this heterogeneity?

These and other questions will be discussed in the next posts; so do not miss the upcoming updates!

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