The Academic Urology Unit
Research in Prostate Cancer
The group has a specific interest in investigating the molecular mechanisms that allow prostate tumour cells to leave the prostate, survive in the circulation and form secondary tumours (metastases) in the skeleton. This is a common feature of advanced, life-threatening disease in patients with prostate cancer. Current studies use an integrated in vitro and in vivo approach to study simultaneously tumour cells (the seed) and the bony micro-environment (the soil) and the signaling systems acting between them. The latter studies are focused on pathways involving members of the TGFbeta superfamily (TGFbetas 1-3 and BMPs) and modulators of the RANK (receptor activator of NFk B)/RANK ligand and of the Wnt signaling systems. This work is determining which cells make these factors in primary and metastatic tumours as well as exploring the mechanisms by which interactive signaling facilitates the survival and growth of tumour cells in bone. The primary aim of these studies is to identify novel approaches to inhibit the metastatic process that will lead new treatments for advanced prostate cancer.
The role of Proteases
We have shown previously the importance of proteases and their inhibitors in prostate cancer. Some MMP inhibitors can clinically decrease angiogenesis and inhibit the matrixin-related ADAMs and ADAMTS. ADAMTS-8 (METH-2) has more potent anti-angiogenic effects than thrombospondin-1 and endostatin. uPA is implicated in metastasis and tumour progression. Some MMPs are implicated in shedding from cells of receptors. For instance, IL-6R is shed from cells, the soluble receptor is an agonist for IL-6 action. MMP inhibitors such as BB94 inhibit shedding of IL-6R. Such synthetic ADAM inhibitors may affect prostate growth in bone, which is rich in IL-6. Using our models, we are determining the expression and role of these proteinases in prostate cancer progression and invasion.
Angiogenesis, macrophage trafficking and PSA specific gene targeting
High micro-vessel density is a feature of late stage prostate cancer and is associated with poor prognosis. Systemic anti-VEGF antibody delays primary and secondary tumours in animals. Macrophages concentrate in hypoxic areas in breast and prostate cancer. We have demonstrated that macrophages express HIF-1 and HIF-2 when exposed to hypoxia and can be transfected using replication deficient adenoviruses that are used to carry HRE-driven reporter or therapeutic gene products into hypoxic areas of human tumour spheroids in vitro. Macrophages may prove to be suitable vehicles for targeted gene therapy. We are determining macrophage migration in vivo and investigating HIF-1/HIF-2 expression in prostate cancer. We combine the mouse dorsal skinfold chamber model of angiogenesis with tumour spheroid technology to investigate whether macrophages play a crucial role in prostate tumour angiogenesis in vivo. The 50 kDa fragment of human fibrinogen (fibrinogen E fragment [Fgn E] is a potent anti angiogenic and is more powerful than equimolar doses recombinant human endostatin. We have now snnthesisied 24-amino aacid derivative of FgnE (alpha 1-24) that mimics its anti-angiogenic effects. We are assessing FgnE + alpha 1-24 on progression of prostate cancer and compare therapeutic efficacy of the direct anti-angiogenic agent injection versus and established macrophage-based gene delivery systems of these agents in vivo.
The emphasis in prostate cancer is on the ProtecT trial (Prostate testing for cancer and Treatment). The trial represents the largest investment to date by the British government in prostate cancer research. Its main aim is to test the effectiveness of treatment in early prostate cancer. The study consists of a case-finding programme in primary care by dedicated nurses, and a randomised trial of treatment comparing monitoring, surgery and radiotherapy and their effect on survival from the disease at 10 years. 130,000 men will be tested by the year 2006 in 9 regions of the UK, and approximately 3000 patients with prostate cancer will be diagnosed and studied. The study will be an invaluable resource of material and data to complement ongoing translational work.
Imaging of the prostate using 3-D transrectal ultrasound imaging is also an ongoing interest of the Unit, and is being evaluated carefully in parallel with other new technologies in the detection and staging of prostate cancer. A recent study of serum osteoprotegerin levels and markers of bone turnover revealed exciting results, and is being presented at international meetings this year, with a publication to follow shortly. This is made possible through good collaboration with the Metabolic Unit in Sheffield, headed by Prof Richard Eastell, and strong support from Roche Pharmaceutical Industry. We also have now full Ethics approval to develop our biorepository of serum, blood, tissue (fresh and archival) and DNA extraction and storage from patients with prostate cancer as well as controls, as part of our UK Prostate Cancer Collaborative network.