Evaluation of the functional role(s) of TIMP-3 in prostate cancer progression.

Prostate cancer is the second highest cause of cancer death in men and its transformation to
an untreatable state depends on the loss of the cells' requirement for androgen.
Metalloproteinases such as matrix metalloproteinases (MMPs), a disintegrin and
metalloproteinases (ADAMs) and a disintegrin and metalloproteinase with thrombospondin
motifs (ADAMTSs) are implicated in prostate cancer. Tissue inhibitor ofmetalloproteinase
(TIMP) is a family of 4 inhibitors whose major functions are to regulate the activity of
metalloproteinases. TIMP-3 inhibits ADAMTSs, MMPs and ADAMs, and independently
inhibits angiogenesis.
The aims of this research were to investigate the expression and modulation of TIMP-3 in
prostate stromal and cancer cells in order to better understand its role(s) in prostate cancer.
The effects of androgen, growth factors and cytokines on TIMP-3 expression in prostate
stromal and cancer cells were analysed. Co-culture analyses were employed to investigate
the effect of cell-cell contact on TIMP-3 expression. RNAi experiments were carried out to
study the effects of TIMP-3 inhibition on biological functions. Tissue micro array analyses
were carried out in order to investigate correlation of TIMP-3 expression with prostate
cancer malignancy.
TIMP-3 expression was higher in prostate stromal cells than cancer cells. Co-culture
analyses showed up-regulation of TIMP-3 in stromal cells and down-regulation in cancer
cells. Immuno-staining in prostate tissues demonstrated higher TIMP-3 staining normal and
benign tissues compared to malignant tissue. The modulation of TIMP-3 expression
observed by androgen was cancer-cell-specific and by growth factors/cytokines was
stromal-cell-specific. RNAi-mediated down-regulation of TIMP-3 in cancer-associated
stromal cells resulted in increased migration and invasion. ECM lysates from transfected
stromal cells demonstrated reduced MMP-2 inhibition.
Overall, these results show the interplay of the stromal and tumour compartments in
modifying the activity of prostate tumour, and suggest that TIMP-3 is important in
modulating the migration and invasive potential.