John T said...
There is a misconception that Gleason grade always starts low and progress into a higher grade so G8s once started as G6s. This is not true as each tumor has its own individual DNA which regulates its grade and growth rate and this rarely changes. the vast majority of upgrades are due to entirely different tumors that have also formed.
I'm not agreeing or disagreeing -- I remain skeptical until there's more evidence. We know that the genes that are currently activated do
change all the time. It is the function of microRNAs to turn on and off different parts of the DNA -- and there is ongoing research about
their use in cancer therapy. Various kinases, that regulate cell growth and replication, are varyingly inhibited and activated over time and in response to the cell's environment. Cancer cells have a high ability to mutate in response to environmental stress.Sowalsky et al.
examined only 4 TMPRSS:ERG fusion positive tumors. Not all PC tumors display such fusion. They stayed on the fence on whether the G4s emerged sequentially or in parallel from a common ancestor. "These findings establish that a subset
of G3 tumors progress to G4 or
emerge from a common precursor."
Likewise, VanderWeele et al.
only examined four subjects. While there was some overlap in the DNA sequencing, they came down on the side of parallel development from a common ancestor, "These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores."
If there is a common ancestor, what is it? We know that there seem to be prostate cancer stem cells in very low concentrations in some tumors. Is it these that give rise to G3s, G4s and G5s? If so, why one and not the others? What is the process that drives this evolution, and how can we detect and interfere with it? Similarly, are G3s sometimes amped into G4s and G5s by aberrant microRNAs or the tumor microenvironment and what drives such a process? I think there are lots of unknowns about
the natural history of PC, and it may be different in different people.
In the meantime, I agree that true
G3s are safe until they're not, just as PDA's prom queen remains a virgin until she's not. And just as we might chaperone the prom queen, the G3s bear chaperoning with Active Surveillance.
Post Edited (Tall Allen) : 8/2/2013 2:47:19 PM (GMT-6)