It occurs to me that I haven’t done much straight science blogging lately. Yes, debunking pseudoscience and quackery is fun, useful, and has the potential to educate people about how science is misused, but this is ScienceBlogs. Since arriving here four weeks ago, I haven’t fulfilled my quota of science blogging, and it’s time to remedy that.
Fortunately, while perusing a recent issue of Cancer Research, I found just the ticket, something that would let me discuss science and still stay related to one of the main themes of this blog, alternative medicine.
The paper? A Gene Expression Signature that Can Predict Green Tea Exposure and Chemopreventive Efficacy of Lung Cancer in Mice, out of Washington University, Japan, and the Chemoprevention Branch at the National Cancer Institute. Here’s the abstract:
Green tea has been shown to be a potent chemopreventive agent against lung tumorigenesis in animal models. Previously, we found that treatment of A/J mice with either green tea (0.6% in water) or a defined green tea catechin extract (polyphenon E; 2.0 g/kg in diet) inhibited lung tumor tumorigenesis. Here, we described expression profiling of lung tissues derived from these studies to determine the gene expression signature that can predict the exposure and efficacy of green tea in mice. We first profiled global gene expressions in normal lungs versus lung tumors to determine genes which might be associated with the tumorigenic process (TUM genes). Gene expression in control tumors and green tea-treated tumors (either green tea or polyphenon E) were compared to determine those TUM genes whose expression levels in green tea-treated tumors returned to levels seen in normal lungs. We established a 17-gene expression profile specific for exposure to effective doses of either green tea or polyphenon E. This gene expression signature was altered both in normal lungs and lung adenomas when mice were exposed to green tea or polyphenon E. These experiments identified patterns of gene expressions that both offer clues for green tea’s potential mechanisms of action and provide a molecular signature specific for green tea exposure.
You can see why it caught my eye. I’m a sucker for an interesting gene expression profiling paper.
Basically, the investigators started by looking at mouse models of lung cancer induced by different chemical carcinogens and asking whether green tea or the major constituent of green tea thought to be responsible for its chemoprevention properties, polyphenon E, could prevent these tumors. This process is known as chemoprevention. Next, they looked at gene expression profiling of the tumors in order to determine whether a “signature” could be derived that would identify which tumors are more likely to respond to chemoprevention by green tea.
Gene expression profiling uses what’s known as oligonucleotide microarrays. These microarrays contain sequences for thousands of genes, and can be used to survey differences in gene expression over entire genomes. The result is an array with squares or dots ranging from red to green, each representing a single gene, with red generally meaning higher gene expression than in the control and green meaning lower expression. It’s a powerful tool. (Sadly, it’s also still a fairly expensive tool; otherwise I’d be doing a lot more gene expression profiling in my lab.) Basically, using this technique, it’s possible to measure changes in the level of the mRNAs for every gene in the genome. To analyze this data requires sophisticated computing algorithms, such as cluster analysis. More recently, software has been developed that allows one to identify intracellular signaling pathways that are turned on or off based on the pattern of genes that are turned on or off. One such tool is GeneMAPP, which is what the authors used to identify the pathways altered by exposure to green tea or polyphenon E.
The authors first compared gene expression profiles of lung cancer versus normal lung in order to identify genes that might be associated with the tumorigenic process. They found a large number of such genes (>2,000) that were differentially expressed. The changes noted, as in most cancers, were in cell signaling pathways related to transcription and cell cycle/proliferation. Also activated were pathways involved in inflammation, which is not surprising, given the relationship between chronic inflammation and tumorigenesis.
They then looked at the effect of green tea and polyphenon E on these tumors, they found that both significantly decreased the number of tumors caused by the carcinogenic chemicals. They further found that there was a subset of genes in the tumors in the animals receiving green tea that were reversed towards levels found in normal lungs, suggesting that they might be involved in the chemopreventative effect of green tea. For example, certain cell cycle genes that were turned on in cancer were turned off by green tea, and vice-versa. Ultimately they were able to narrow the data down to a 17 gene signature that could reliably identify both lung tumors and normal lung tissue that had been exposed to green tea.The usefulness of this result is that there are a number of clinical studies out there that are looking at green tea and green tea-derived compounds for their chemopreventative activities in a variety of cancers. it would be useful to have a gene expression profile that can be used to determine whether the tea or compounds was having a measurable biological effect.
One thing bugged me about this paper, however. Maybe I misinterpreted it, or maybe it’s just my background in clinical trials, where gene expression signature predictors mean signatures that predict response to treatment or prognosis, but to me the title implied that the authors were going to present data deriving a gene expression signature that could predict whether green tea would have an effect preventing lung tumors due to the chemical treatment. True, this would have been difficult to do rigorously, because it would have involved taking a multiple lung tissue samples from mice, first a pretreatment sample and then a sample after treatment with green tea in order to see if they showed changes in this 17 gene signature consistent with activity of green tea. Then the treatment with chemical carcinogens could begin, followed by green tea, to see if the presence of the 17 gene signature in response to treatment with green tea predicted which mice would demonstrate better chemoprevention with green tea. Logistically, this would have been a hell of an experiment to do. I know what they authors mean when they say that their gene expression signature predicts an effective dose of green tea. Basically, they mean that their expression profile can discriminate between untreated lung tissue and tissue of mice treated with an effective dose of green tea; i.e., predict which sample was treated and what sample was not without knowing which is which.
But this is mainly a nitpick about the title, which seemed to promise more than the paper actually delivered. (This should be a lesson to budding scientists to be careful about their titles.) Overall, it’s a rather cool study showing that, contrary to the claims of some alties, it is quite possible to apply state-of-the-art science to alternative medicine claims.
Hmm. That wasn’t a particularly insolent post, respectful or otherwise. Where are some creationists when you need them?