Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer.
BACKGROUND
Altered expression and activity of proteases is implicated in inflammation and cancer progression. An important negative regulator of protease activity is TIMP3 (tissue inhibitor of metalloproteinase 3). TIMP3 expression is lacking in many cancers including advanced prostate cancer, and this may facilitate invasion and metastasis by allowing unrestrained protease activity.


METHODS
To investigate the role of TIMP3 in prostate cancer progression, we crossed TIMP3-deficient mice (Timp3(-/-)) to mice with prostate-specific deletion of the tumor suppressor Pten (Pten(-/-)), a well-established mouse model of prostate cancer. Tumor growth and progression were compared between Pten(-/-), Timp3(-/-) and control (Pten(-/-), Timp3(+/+)) mice at 16 weeks of age by histopathology and markers of proliferation, vascularity, and tumor invasion. Metalloproteinase activity within the tumors was assessed by gelatin zymography. Inflammatory infiltrates were assessed by immunohistochemistry for macrophages and lymphocytes whereas expression of cytokines and other inflammatory mediators was assessed by quantitative real time PCR and multiplex ELISA.


RESULTS
Increased tumor growth, proliferation index, increased microvascular density, and invasion was observed in Pten(-/-), Timp3(-/-) prostate tumors compared to Pten(-/-), Timp3(+/+) tumors. Tumor cell invasion in Pten(-/-), Timp3(-/-) mice was associated with increased expression of matrix metalloprotease (MMP)-9 and activation of MMP-2. There was markedly increased inflammatory cell infiltration into the TIMP3-deficient prostate tumors along with increased expression of monocyte chemoattractant protein-1, cyclooxygenase-2, TNF-α, and interleukin-1β; all of which are implicated in inflammation and cancer.


CONCLUSIONS
This study provides important insights into the role of altered protease activity in promoting prostate cancer invasion and implicates prostate inflammation as an important promoting factor in prostate cancer progression.
Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, Ontario, Canada.|Physiology & Experimental Medicine Research Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.|Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto 1 King's College Circle, Toronto, Ontario, Canada.|Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
Hibret A
HA
Adissu
Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, Ontario, Canada.|Physiology & Experimental Medicine Research Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.|Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto 1 King's College Circle, Toronto, Ontario, Canada.
Colin
C
McKerlie
Princess Margaret Cancer Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
Marco
M
Di Grappa
Princess Margaret Cancer Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
Paul
P
Waterhouse
Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, Ontario, Canada.
Qiang
Q
Xu
Princess Margaret Cancer Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
Hui
H
Fang
Princess Margaret Cancer Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
Rama
R
Khokha
Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
Geoffrey A
GA
Wood
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*
D019717:Tissue Inhibitor of Metalloproteinase-3; D051059:PTEN Phosphohydrolase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
cytokines; macrophages; metalloproteinases; tissue inhibitor of metalloproteinase 3