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Bad Luck and Stem Cells

Although mathematicians and statisticians have torn into how the research was done, few have questioned the basic premise behind the study and its findings.
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There has been a bit of furor in the media around a recent study about most cancer being "bad luck." Posts by others in the medical field call into question the research findings, how the media covered the story, and how the original press release became a catalyst for what the media reported -- sometimes incorrectly. For example, some articles misinterpreted the statement "two-thirds of the difference between the number of cancers that develop in different tissues," inaccurately portraying the conclusions as related to "two-thirds of all cancers."

Although mathematicians and statisticians have torn into how the research was done, few have questioned the basic premise behind the study and its findings. The paper, by Tomasetti and Vogelstein, looks at the relationship between stem cell divisions in various organs and cancer risk. It suggests that two-thirds of the difference between the number of cancers that develop in different tissue can be explained by the fact that some tissues have stem cells that divide more frequently than others -- and those that divide more frequently have, in essence, more opportunities for a mutation to develop during cell division.

This study is based on the idea cancer is only a genetic disease. However, as Stuart Baker points out in a recent commentary in the Journal of the National Cancer Institute, while this has been the standard way of thinking about cancer, it is actually a theory, known as Somatic Mutation Theory, about cancer development. There is another theory, called the Tissue Organization Field Theory (TOFT), that I also believe we need to consider, because it takes into account what I have come to think of as the other key player in cancer development: the microenvironment or neighborhood of cells that surround the tumor.

It takes two things for a tumor to develop: a mutated cell and a local neighborhood egging it on. A mutated cell that is not dividing, either because the neighborhood is keeping it calm or it doesn't need to, will not be as much a problem as one that is. I think this may be especially true for tumors that develop in the breast, because the female breast is constantly undergoing changes like development during adolescence, hormonal fluctuations during menstruation, or preparation to start (or stop) breastfeeding.

The breast is completely different from other organs, such as the lungs, liver, bowel, and pancreas that mature and then perform their functions. The breast and the uterus are the only organs I can think of that don't have jobs until after puberty, when once a month they get primed to go into action -- and then if there is no pregnancy, they regroup and start again. If you hold with the idea that all cancer comes from cell division and mutation, the normal menstrual cycle alone stimulates a lot of cell division and cell death. Unlike the uterus, though, the breast doesn't get to shed all those cells before it gets ready for the next month's cycle. Breastfeeding provides the only opportunity for many mutated cells to be killed and shed; after a woman finishes breastfeeding, the breast undergoes massive involution and then reconstitutes again. This is part of the reason why there are no good measurements of stem cell division for breast tissue -- as well as the reason why the researchers said they didn't include the breast in their "bad luck" analysis.

We know that the more years you menstruate, the higher your chances of getting breast cancer, which would go along with this theory about having more cells and presumably, stem cell divisions and opportunities to develop mutations. But then at menopause, the music stops and the breast happily retires and just sits there with no need for stem cell divisions at all, and that's when the neighborhood of cells that surround a mutated cell becomes an even more important factor.

When we think about cancer in general, and breast cancer in particular, we have to take into account the fact that the breast is a unique organ. It is pretty amazing to consider all the changes it goes through in a lifetime. I firmly believe we will not decipher the secrets of how and why breast cancer develops until we acknowledge this and put more effort into learning more about the basic anatomy and physiology of the breast!