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Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer.
- Source :
-
The Prostate [Prostate] 2015 Dec; Vol. 75 (16), pp. 1831-43. Date of Electronic Publication: 2015 Sep 01. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (© 2015 Wiley Periodicals, Inc.)
- Subjects :
- Animals
Disease Models, Animal
Disease Progression
Inflammation genetics
Inflammation metabolism
Inflammation pathology
Male
Matrix Metalloproteinase 2 genetics
Matrix Metalloproteinase 2 metabolism
Matrix Metalloproteinase 9 genetics
Matrix Metalloproteinase 9 metabolism
Mice
Mice, Knockout
Neoplasm Invasiveness pathology
PTEN Phosphohydrolase genetics
PTEN Phosphohydrolase metabolism
Prostate metabolism
Prostatic Neoplasms genetics
Prostatic Neoplasms pathology
Tissue Inhibitor of Metalloproteinase-3 genetics
Neoplasm Invasiveness genetics
Prostate pathology
Prostatic Neoplasms metabolism
Tissue Inhibitor of Metalloproteinase-3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0045
- Volume :
- 75
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Prostate
- Publication Type :
- Academic Journal
- Accession number :
- 26332574
- Full Text :
- https://doi.org/10.1002/pros.23056