Adenovirus‐mediated expression of TIMP‐1 and TIMP‐2 in bone inhibits osteolytic degradation by human prostate cancer
- 26 October 2007
- journal article
- Published by Wiley in International Journal of Cancer
- Vol. 122 (1), 209-218
- https://doi.org/10.1002/ijc.23053
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes that play critical roles in the pathogenesis of human cancers. Clinical trials using synthetic small molecule MMP inhibitors have been carried out but with little success. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that block the extracellular matrix‐degrading activity of MMPs. Here, we investigated the possibilities of genetically modifying human bones with TIMPs to create a high‐TIMP bone microenvironment, which is hostile to metastatic prostate cancer cells using adenovirus‐mediated gene transfer technology and SCID‐hu end‐organ colonization mouse model. Two strategies were used to achieve bone‐specific TIMP expression: (i) ex vivo bone adenoviral infection followed by in vivo bone implantation; and (ii) ex vivo BMS cell infection followed by injection into in vivo implanted human fetal bones. PC‐3 prostate cancer cells were injected into human fetal bones 4 weeks after implantation in SCID mice. In vitro, adenovirus‐mediated expression of TIMP‐1 or TIMP‐2 in bone fragments inhibited MMP‐2 activity, bone turnover and prostate cancer cell‐induced proteolytic degradation as determined by gelatin zymography, calcium measurement and DQ protein quenched fluorescence assay, respectively. In vivo, immunohistochemistry confirmed TIMP‐2 expression in AdTIMP‐2‐infected bone implants 4 weeks after implantation in SCID mice. Mice receiving AdTIMP‐treated bone fragments showed significantly reduced PC‐3‐induced osteolysis, osteoclast recruitment and bone turnover in the implanted bones. We propose that adenoviral gene transfer of TIMP‐1 and TIMP‐2 can prevent the proteolytic activity of prostate cancer cells in bone and that enhancing anti‐proteolytic defense mechanisms in target organs represents a promising form of prostate cancer gene therapy.This publication has 49 references indexed in Scilit:
- Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism‐based selective gelatinase inhibitorInternational Journal of Cancer, 2006
- Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progressionCancer and Metastasis Reviews, 2006
- Matrix metalloproteinases and tumor metastasisCancer and Metastasis Reviews, 2006
- Prostate cancer metastases to bone: Pathophysiology, pain management, and the promise of targeted therapyEuropean Journal of Cancer, 2005
- Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel–Lindau renal cell carcinomaOncogene, 2004
- Adenovirus‐mediated overexpression of tissue inhibitor of metalloproteinases‐1 in the liver: efficient protection against T‐cell lymphoma and colon carcinoma metastasisThe Journal of Gene Medicine, 2004
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002
- Synthetic inhibitor of matrix metalloproteases decreases tumor growth and metastases in a syngeneic model of rat prostate cancerin vivoInternational Journal of Cancer, 2000
- The Migration of Purified Osteoclasts Through Collagen Is Inhibited by Matrix Metalloproteinase InhibitorsJournal of Bone and Mineral Research, 1998
- Tissue inhibitor of metalloproteinases-2 inhibits the activation of 72 kDa progelatinase by fibroblast membranesBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1991