Review of Vogelstein “Bad Luck” Cancer & Stem Cell Paper in Science

There are so many big questions about cancer. They resonate with me very strongly as a cancer researcher and a cancer survivor myself (more on my cancer story here).

  • What really causes cancer?
  • Why does it feel sometimes like we are struggling so much in the “War on Cancer”?
  • What is the role of stem cells in cancer and are there “cancer stem cells“?
  • What can we do to better prevent cancer or treat cancer once it happens?

A new Science paper by Cristian Tomasetti and Bert Vogelstein from Hopkins seeks to provide some possible answers to these kind of fundamental cancer questions.

The paper, entitled “Variation in cancer risk among tissues can be explained by the number of stem cell divisions”, argues that the more that the normal stem cells of a given tissue proliferate over one’s lifetime, the more common it is to find cancers sprouting up in that same tissue.

This relationship was reported as significant with essentially an 80% correlation. You can see the relative correlation for specific types of cancer as well below in Figure 1 from the paper.

They postulate that the relationship between stem cell proliferation and cancer is linked together mechanistically by mutations that randomly arise in stem cells each time that they divide.

cancer stem cells

The paper is summed up in the journal in one sentence: “Errors arising by chance during normal stem cell division explain more cancers than do hereditary or environmental factors.” It’s a very attractive notion, but how solid is it? I’m still thinking it through.

The authors argue that a substantial proportion of human cancer are simply due to bad luck. What this means, if you accept that notion, is that for those of us who get cancer much of the time there would have been nothing that we could have done differently to prevent it and further that the genes we got from our parents may not have played major roles. It’s an intriguing, provocative paper that makes some bold assertions, but there are some issues that leave some of the key issues remaining as theories.

The most difficult issue is how to consistently and accurately calculate the number of lifetime stem cell divisions in a series of diverse tissues. This is extremely difficult and it’s not difficult to imagine such calculations being off by one or more orders of magnitude. Going through their supplemental data frankly I still am not sure how convincingly this was achieved. It’s not a simple matter by any stretch of the imagination.

Another factor is that not all cancers are going to originate with stem cells. Some tumors arise from progenitor cells or from differentiated cells that de-differentiate.

Further, many organs have more than one type of stem or precursor-like population. How does one handle that in modeling?

It is also possible that epigenetics play a substantial role in the argued for proliferation-associated cancers. For example, with every stem cell division there may be an increased risk not only of mutations, but also of epigenetic changes (in some forms called epi-mutations) that over time transform the normal stem cells into cancer cells.

I found this paper very thought provoking, but it’s just a start in a way. Let’s see what others find when they attempt similar calculations.

Update

Other folks’ take on the papers are more skeptical:

Bob O’Hara & GrrlScientist

Aaron Meyer