Cell cycle regulation and aggressive forms of prostate cancer
Posted Jan 02 2010 12:00am
A new paper by Wang et al. in a recent issue of Cancer Research has proposed details of a specific connection between control over the growth and division of prostate cancer cells and clinical occurrence of the more aggressive forms of prostate cancer.
In itself, this is not a surprising idea. After all, all cancers are a result of the growth of “rogue” cells that “should not” really be growing in the way that they do. However, what Wang and his colleagues are saying is it may be possible to identify much more precisely the specific cell regulation process that has “broken down” in men with aggressive prostate cancer.
The original abstract of the paper by Wang et al. is extremely “dense” and couched in “bioscience-speak,” so we will see if we can explain what they have shown in something closer to “real English.” Then we’ll try an analogy.
Using cells from 62 different patients with aggressive forms of prostate cancer (all Gleason score ≥ 8) and 63 patients with non-aggressive forms of the disease (all originally diagnosed with Gleason score ≤ 5), they were able to do the following:
Test >13,900 individual genes that code for the same number of different “messenger RNA” molecules (nucleic acids that helps to “manage” cell growth and division)
Test 273 different forms of microRNA (nucleic acids that control when groups of genes are “turned on ” and “turned off”)
Identify — with great accuracy – significant differences in and 7 of the microRNAs and 1,100 of the messenger RNAs
Identify a particular group of 20 “hub” genes (a so-called ”coexpression module”) that were very commonly “overexpressed” (they were “turned on” way more than they should have been) in the cells from patients with aggressive forms of prostate cancer
Now it was already known — from earlier research — that five of the seven differentially expressed microRNAs are involved in some way in control of the cell cycle, and that two of those five microRNAs specifically act on (“target”) three of the 20 hub genes. The way in which they act on the “targeted” genes is to reduce the level of expression of the three hub genes, which then leads to cell growth inhibition and apoptosis. So … that’s all clear for everyone, right?
Maybe not. So let’s try the analogy.
Image 13,900 floodlights at a ballpark. Each floodlight is a gene. It can be fully “turned on,” fully “turned off”, or controlled to work at some level in between by a dimmer. There is an individual “dimmer” (a piece of messenger RNA) for each floodlight (gene). Okay?
In theory, we can dim or brighten each floodlight individually, but in fact they are set to work together in groups known as “banks” of lights. The same is true for genes. The microRNA molecules are the master switches that can brighten or dim a whole bank of genes. For a specific bank of lights or genes to work properly, they all have to go on at the right level of ”brightness” at the same time. So for a night-time ball game in the summer, the lights all reliably come on together at (say) 7:00 pm and go out together when the game ends. Wang and his colleagues have been able to show that there is a similar, grouped, “switching” effect that may be controlling risk for aggressive prostate cancer.
Even in a man who gets prostate cancer, when the the right groups of genes (banks of “floodlights”) are appropriately and normally ”turned on” (think “brightened”) or “turned off” (think “dimmed”) together, then the cell growth system still gets “powered up” and “powered down” normally and the prostate cancer doesn’t grow particularly fast. However, if certain specific genes that control how long all the lights stay “turned on” when they should be “turned off” start to malfunction, then the cell growth system may stay “on” too long and continue to be ”powered up” (leading to faster growth of prostate cancer cells) when it shouldn’t be. It’s as though, in the ballpark, some of the banks of lights don’t go out when they should at the end of the game, but just stay on all night and all the next day too.
What the research team may have been able to suggest is precisely which biological “switches” must work together to “leave some banks of lights on” leading to rapid and aggessive growth of prostate cancer cells. Does that help?
There will be an enormous amount of work needed to demonstrate what this may imply for the clinical treatment of aggressive forms of prostate cancer — but it does seem to suggest that we have taken one more step toward understanding what causes the difference between indolent and aggessive forms of this disorder.