Role of tissue inhibitor of metalloproteinase-3 in prostatic inflammation and prostate cancer progression
Modulation of the extracellular microenvironment by matrix metalloproteases (MMPs) is important in a variety of physiological and pathological processes including inflammation and cancer. Tissue inhibitor of metalloproteinase 3 (TIMP3) is a broad spectrum inhibitor of MMPs and a negative regulator of inflammation, a process implicated in prostate cancer development, progression, and the emergence of hormone-independent disease. In this thesis we explored the role of TIMP3 in prostatic inflammation and prostate cancer progression using genetically engineered mice. Heightened prostatic inflammatory response was observed in 'Timp3-/-' mice following castration, indicating that TIMP3 loss may create a proinflammatory prostate environment conducive to malignant progression. This was tested in a prostate cancer model by crossing TIMP3-deficient mice with prostate-specific PTEN-deficient mice. TIMP3-deficiency promoted tumor growth and invasion, with increased MMP-2 activity, inflammation, and expression of proinflammatory factors implicated in cancer progression. In summary, this study demonstrated that TIMP3-deficiency promotes prostatic inflammation and prostate cancer progression; thus showing the potential of restoring/augmenting TIMP3 activity as a novel therapeutic approach for inflammation-associated neoplasia. Further, this model might be useful to study the pathogenesis of hormone-independent prostate cancer.