Development and diseases of the prostate

Lead Research Organisation: MRC Human Reproductive Sciences Unit

Abstract

This work is aimed at finding genes which control the growth of the prostate that are also involved in the growth of prostate cancer. It is important to do this so that we can learn more about the prostate and develop new tools for combating prostate cancer. The prostate is made up of different types of cells which fall into two main categories; epithelial cells and stromal cells. It is known that stromal cells control the growth of epithelial cells both under normal conditions and in prostate diseases such as prostate cancer. We do not know how this happens or which genes are involved, but if we did it might provide us with new diagnostic tools or targets for therapy in the long term.||We have looked at various genes to see if they are involved in the growth of the prostate and our work has shown that genes which control the formation of the prostate during embryonic life are also involved in prostate cancer growth. In addition, we are using new techniques to find other genes involved in the growth of the prostate and its transformation to prostate cancer.

Technical Summary

Prostate cancer is a substantial health burden which is set to increase as the population ages. However, we have a poor understanding of disease aetiology and few options for curative treatment.||This programme is focused upon stromal/epithelial interactions in the prostate to determine how the growth of this organ is controlled under normal conditions and in disease. It is clear that the stroma plays a key role in mediating the growth-regulatory effects of testosterone in developing and adult prostate. Furthermore, the stroma also plays a role in prostate carcinogenesis and can produce molecules that control neoplastic growth. Embryonic mesenchyme is able to inhibit tumour growth while adult tumour stroma can stimulate growth. However, we do not know the molecular mediators of these effects.||We have identified and characterised molecules and mechanisms that are involved in prostatic stromal/epithelial interactions, and demonstrated their function in prostate growth. Our studies have primarily used developmental systems to identify and test regulatory pathways, since these systems are actively growing and are highly tractable. In addition, several developmental pathways are known to be involved in disease and our work aims to examine the involvement of these in normal and neoplastic prostate growth. The pathways which we have characterised in the prostate include fibroblast growth factor 10 and sonic hedgehog signalling, as well as tissue compartments such as smooth muscle. Each of these appears to be relevant to prostate cancer.||We next propose to examine these pathways further, as well as completing and expanding a genomics project to identify new molecules involved in the control of prostate growth. We have characterised the gene expression profile of an important group of cells in the mesenchymal/stromal tissue compartment using the serial analysis of gene expression (SAGE) technique. We confirmed that SAGE was sufficiently sensitive and robust to identify low-abundance transcripts involved in regulating prostatic growth.||We have identified several new pathways not previously known to play a role in prostate growth, and which function both in developmental growth and cancer. Additionally, we have identified a few molecules of unknown function which we are presently characterising. We will extend our gene profiling analysis to include human prostate cancer associated fibroblasts, which are known to stimulate tumorigenesis, and propose to use this data to identify further pathways involved in prostate cancer. This approach may identify new diagnostic/prognostic markers or new targets for novel therapies in the long term.

Publications

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Dickinson RE (2010) Involvement of the SLIT/ROBO pathway in follicle development in the fetal ovary. in Reproduction (Cambridge, England)

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Donjacour AA (2003) FGF-10 plays an essential role in the growth of the fetal prostate. in Developmental biology

 
Description Annual Research Award
Amount £148,000 (GBP)
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2008 
End 07/2011
 
Description Collaboration with Dr Tony Riddick 
Organisation Western General Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We have characterised and manipulated the cancer-associated fibroblasts provided by Dr Riddick.
Collaborator Contribution Dr Riddick has provided clinical material and expertise, and is a co-applicant on a Grant.
Impact A successful grant application on which Dr Riddick is co-PI. Co-authorship on a submitted manuscript. Also a co-author on papers.
Start Year 2007
 
Description Collaboration with John Parnavelas and Bill Andrews 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We examined the effects of the gene knock out upon prostate development and anatomy
Collaborator Contribution Provided tissue from knock-out mice
Impact We have submitted a manuscript for publication, with co-authorship.
Start Year 2007
 
Description Collaboration with Prof Simon Hayward 
Organisation Vanderbilt University
Country United States 
Sector Academic/University 
PI Contribution We have provided locally isolated cancer-associated fibroblasts, as well as fibroblasts modified to express developmental pathways to alter their pro-tumorigenic signalling.
Collaborator Contribution Access to additional cancer-associated fibroblast samples, and access to kidney capsule grafting in mice to test the activity of our cancer-associated fibroblasts.
Impact Publication PubMed ID 17922897 Also contribution to a manuscript currently submitted
 
Description ECRR meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presentation on programme of Unit research to directors and senior staff of Scottish Research Institutes.

Discussion of research.
Year(s) Of Engagement Activity 2006
 
Description Lectures for prostate cancer support group (Edinburgh and W.Lothian) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact A lecture on general scientific research, as well as specific research into prostate cancer to a prostate cancer support group. The talk was 1hour, and was follwed by another hour of discussion. There were about 50 attendees.

I have continued to attend the support group, and help provide answers to lay questions about research in general as well as in regard to specific questions about prostate cancer research.
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Royal Society MP-Scientist pairing scheme 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact Royal Society MP-Scientist pairing scheme. This involved spending a week in Westminster learning about how science is represented in government and to try an increase the representation of science contribution. Discussion with civil service personnel and MPs.

Better links with MPs and among 'politically engaged' scientists.
Year(s) Of Engagement Activity 2006
 
Description School visit - Edinburgh Tynecastle 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact A 10 minute talk about science, why it matters, what the MRC does, why it is fun, and career paths in science. Also a 40 minute Q+A with pupils.

To encourage student participation in science, to introduce and describe the work of the MRC, and to build links with local secondary school teachers.
Year(s) Of Engagement Activity 2008,2010