First post in 2008 and also the first since I moved to Dundee.
These days I am trying to familiarise myself with prostate cancer and the effect of TGF-Beta on tumour progression. Some relevant information:
The prostate is a gland of the mammalian reproductive system that stores and produces an alkaline fluid (that makes 10-30% of the seminal fluid). Due to this acidity there is a lot of self renewal in the prostate. The following figure from wikipedia illustrates the different parts of a human prostate:
The most important parts of prostate are the peripheral zone (biggest and responsible for 70% of the prostate cancers), the central zone (25% of tumours), the transition zone and the anterior fibro-muscular zone that contains stroma and is responsible for about 5% of the cancers.
Prostate cancer normally starts in the peripheral zone and might be confined to the gland or spread to the surrounding tissue (stroma).
Probably the most relevant cells to study tumour initation and progression are the epithelial cells and the stromal cells. Epithelial cells are normally found in the surfaces of the structures of the body. Based on the results of the biopsy it is possible to estimate the Gleason score with grades 1 to 5. A GS of grade 1 meaning a less aggressive tumour and 5 being a very aggressive tumour. The twomost common patterns in the sample are graded this way and the two values combined into 1 in the range 2 to 10. This GS is a powerful predictor of a patient prognosis. A patient whose biopsy has a GS of value 6 or less has a 90% of chances of surviving more than 5 years whereas another one with a GS of 7 would have 50% or less.
Now…tumour cells are not the whole story here, the microenvironment, or a bit more specifically, the stroma, does play a role. The stroma is made of connective cells in a tissue such as fibroblasts, smooth muscle cells and from extracellular matrix (produced by the fibroblasts) and several types of growth factors such as TGF-Beta.
TGF-Beta is normally expressed at low levels in the base membrane (surrounding the prostate glands) and promote homeostasis by acting on hundreds of genes through SMAD-class proteins. The way that they help homeostasis is by:
- Epithelial inhibition.
- Recruiting mobile stroma.
- Myofibroblast induction (cells in between a fibroblast and a smooth muscle cell in differentiation).
TGF-Beta also seems to play a role in tumour progression and increased TGF-Beta expression is found in prostate cancers. Some questions still not answered and that could be addressed with a theoretical model are
- how would loss of TGF-Beta sensitivity affect tumour progression
- how would an increase in TGF-Beta expression affect tumour progression?
- what is the influence of this reactive stroma?