Testosterone, blood and the eye would seem to have little in common, yet there is a link and it involves prostate cancer. Tumours require neovascularization to grow and this depends on a balance between key regulators. In the prostate, androgens such as testosterone drive angiogenic inducers such as vascular endothelial growth factor (VEGF) to stimulate blood-vessel growth. Androgen withdrawal causes endothelial-cell apoptosis followed by epithelial-cell apoptosis, which continues even after levels of VEGF recover, so other factors must have a role. Now, Doll and colleagues have identified pigment epithelium-derived factor (PEDF) — known to inhibit angiogenesis in the eye — as a key inhibitor of stromal vasculature, as well as epithelial-cell growth in the prostate, and show that it is also regulated by androgens.

The authors generated Pedf-deficient mice ( Serpinf1 −/− ) to study the role of PEDF in normal growth and development. Deleting Serpinf1 caused excessive angiogenesis not only in the eye but also in two hormone-sensitive organs — the prostate and the pancreas. By 3 months old, the Serpinf1−/− mice had developed prostatic hyperplasia. So, does PEDF regulate growth and microvessel density in the human prostate too? Doll et al. examined PEDF expression in normal human prostate tissue and found strong staining in both epithelial and stromal cells; benign prostate hyperplasia tissue was also intensely stained, but PEDF staining was either minimal or absent in prostate tumours.

Doll and colleagues used prostate cell lines — normal epithelial cells (PrEC), stromal cells (PrSC) and cancer cells (including PC-3) — to study the function and regulation of PEDF more closely. All the cell lines secreted PEDF, although the angioinducive factors were dominant as media conditioned by these cell lines did stimulate endothelial-cell migration in an in vitro assay. Of the cancer cell lines studied, PC-3 cells secreted the most PEDF and the media from this cell line had the lowest angioinducive activity — this activity was substantially increased by addition of antibodies to PEDF.

So, the data indicate that PEDF secreted by prostate cells is anti-angiogenic, but what is the link with androgens? Treatment of PrSC cells with increasing amounts of dihydrotestosterone decreased PEDF secretion sequentially and castration of rats increased PEDF staining in prostate tissue. PEDF expression was minimal in human prostate biopsy specimens before androgen ablation therapy, but after therapy there was strong staining in tumour epithelial cells and focal staining in stromal cells. PEDF is therefore an important contributor to the anticancer effects of androgen ablation.