sciencemag.org/content/347/6217/78.abstract So errybody is talking about that new fancy cancer study, attributing cancer incidence to bad luck. Just a warning, this is a longer one. Im not really going to talk too much about how that conclusion is just flat out wrong with regards to the finding in the actual paper. Yes, even in their own analysis, the most common cancers did end up having the strongest environmental component -- by a lot. That was a glaring mismatch between the press release/abstract and the actual paper, but that wont sell, because theres no controversy. There was something fishier going on though. In their methodology, they failed to describe how they searched the literature on the biological mechanism of stem-cell differentiation for the 31 types of cells/cancers they analyzed. So I went digging in their supplementary materials, and oh boy, this is where the meat of the paper really is (you really need to see for yourself, as its about 21 pages and 150 references deep with some very convoluted calculations that are simply taken at face value). This section makes me appreciate one thing about the paper -- a ton of work went into writing this. Its so much work that Im convinced the two authors either spent a decade on writing this paper, or were forced into doing a mediocre literature review without giving much thought to biological plausibility and the numbers they were using (guess which one Im leaning towards? :D). First of all, it was not a systematic review, and only vaguely discussed how they searched for the values they used (like we searched such and such database). No keywords or search terms were given. As they admit, their search strategy became increasingly more vague and difficult for rare cancers. They went in with the assumption that stem-cell differentiation was the primary mechanism of tissue homeostasis, regardless of how debatable or flat out wrong that assumption may be. However, using a very subtle scapegoat deep in the supplementary section (which I assure you, almost no one will read), they state that stem cell differentiation simply refers to any cell population (regular or stem cell alike) that is the primary source of maintaining organ/cell count homeostasis. Okay, lets call my dog a cat while were at it, but I dont think that means shell piss in a litter box anytime soon. Surely this extremely popular paper wont delude a generation of researchers into making some ridiculously poor assumptions about the nature of cell replication (and therefore the nature of cancer genesis), because thats never happened before. Anyways, I picked one of their strongest associations that supported their stem-cell-turnover bad luck hypothesis, pancreatic islet carcinoma, and decided to do my own literature search on it (as well as read through the studies they referenced). As it turns out, the assumption that islet cells are derived from stem cells is extremely debatable and nuanced. There is a large body of evidence showing that, under normal conditions, islet cells simply replicate via self-replication, and dont use any stem cells or specialized progenitor cells. Now this is kind of a huge problem, because the way they calculated the lifetime amount of cell replication was entirely dependent on progenitor cells, and didnt even consider that normal islet cells just self-replicate. If they were to include normal cell self-replication, this would dramatically skew their results, turning pancreatic islet carcinoma from the most susceptible to random DNA mutations, to an outlier that wouldnt even fit with their trend (since in their calculations they used a replication rate of 1-2 times per year in islet progenitor cells only, while other evidence shows the entire population of B-cells is replaced every month, or about 12 times per year). I also think its really interesting, and telling, that the turnover rate of islet cells actually decreases with aging (indicating, in line with some theories on aging, that diminished rates of cell turnover are synonymous with the process of aging and cancer development). Whats really interesting though, is that separate studies showed islet cells may be able use specialized progenitor cells for organ homeostasis -- but only after severe injury that significantly diminishes total organ cell count and invariably increasing the rate of total cell replication (during recovery). So lets think about that part for a second. If total cell replication over a lifetime is a determinant for cancer, and total cell replication over a lifetime is determined by non-random factors like injury and stress, then injury and stress are inescapably tied to total cell replication over a lifetime -- how can someone honestly go ahead and say cancer is from random mutations that are simply due to bad luck? Its impossible to differentiate injury and stress from the total amount of cell replication over a lifetime, so its impossible to bring randomness and luck into it as central causal mechanisms. Its common knowledge that when implanting cancerous cell lines into healthy normal living animals, the animals are typically resistant to developing cancer unless they are injured prior (i.e. surgical wounds, burns, etc.), and the cancerous cells are injected into the injured area as soon as possible (and then they typically develop tumors on the injured area, not in other places, even if the cancerous cells are administered intravenously). The longer you wait post-injury, the less likely the animal is to development cancer. A large history of similar findings (in experimental animal models, and observations of cancer development in human surgical wounds) indicates that cancer may need an ideal environment in order to proliferate (and environment has an explicitly different meaning than random and bad luck). That environment happens to be one where the immune system is pre-occupied with a fresh injury, healing, and increasing the rate of cell proliferation/replication/stem-cell differentiation, and not in a healthy living state (where the immune system can divert its attention to maintenance needs, like detecting and halting irregular cell growth). Some of the references used for this rant (just take the cyber.usask.ca out of the links): sciencemag.org.cyber.usask.ca/content/suppl/2014/12/31/347.6217.78.DC1/Tomasetti_SM.pdf ncbi.nlm.nih.gov/pubmed/19052237 ncbi.nlm.nih.gov/pmc/articles/PMC2678421/ sciencemag.org.cyber.usask.ca/content/347/6217/78/F2.expansion.html sciencemag.org.cyber.usask.ca/content/347/6217/78/F1.large.jpg scholar.google.ca.cyber.usask.ca/scholar?q=post-injury+cell+replication+carcinoma&btnG=&hl=en&as_sdt=0%2C5 scholar.google.ca.cyber.usask.ca/scholar?q=related:ftGUzljIG58J:scholar.google/&hl=en&as_sdt=0,5 ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.0030028 link.springer.cyber.usask.ca/article/10.1007/BF02552962 onlinelibrary.wiley.cyber.usask.ca/doi/10.1002/bjs.1800830815/abstract onlinelibrary.wiley.cyber.usask.ca/doi/10.1002/jso.2930560311/abstract onlinelibrary.wiley.cyber.usask.ca/doi/10.1002/1097-0142(19891115)64:10%3C2035::AID-CNCR2820641012%3E3.0.CO;2-L/abstract jci.org.cyber.usask.ca/articles/view/22098 sciencedirect.cyber.usask.ca/science/article/pii/S153458070700158X pnas.org.cyber.usask.ca/content/104/11/4718.short jnci.oxfordjournals.org.cyber.usask.ca/content/80/10/772.short nature.cyber.usask.ca/nature/journal/v429/n6987/full/nature02520.html press.endocrine.org.cyber.usask.ca/doi/abs/10.1210/jc.2010-0932 diabetes.diabetesjournals.org.cyber.usask.ca/content/50/suppl_1/S20.short
Posted on: Fri, 02 Jan 2015 20:12:05 +0000
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