Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer. Issue 16 (1st September 2015)

• Record Type: Journal Article
• Authors: Adissu, Hibret A.; McKerlie, Colin; Di Grappa, Marco; Waterhouse, Paul; Xu, Qiang; Fang, Hui; Khokha, Rama; Wood, Geoffrey A.
• Is Part Of: Prostate. Volume 75:Issue 16(2015)
• Page Start: 1831
• Page End: 1843
• Publication Date: 2015-09-01
• Subjects: Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.23056
• Languages: English
• ISSNs: 0270-4137

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="pros23056-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>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.</p> </sec> <sec id="pros23056-sec-0002" sec-type="section"> <title>METHODS</title> <p>To investigate the role of TIMP3 in prostate cancer progression, we crossed TIMP3‐deficient mice (<italic>Timp3</italic><sup><italic>−/−</italic></sup>) to mice with prostate‐specific deletion of the tumor suppressor <italic>Pten</italic> (<italic>Pten</italic><sup><italic>−/−</italic></sup>), a well‐established mouse model of prostate cancer. Tumor growth and progression were compared between <italic>Pten</italic><sup><italic>−/−</italic></sup>, <italic>Timp3</italic><sup><italic>−/−</italic></sup> and control (<italic>Pten</italic><sup><italic>−/−</italic></sup>, <italic>Timp3</italic><sup><italic>+/+</italic></sup>) 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.</p> </sec> <sec id="pros23056-sec-0003" sec-type="section"> <title>RESULTS</title> <p>Increased tumor growth, proliferation index, increased microvascular density, and invasion was observed in <italic>Pten</italic><sup><italic>−/−</italic></sup>, <italic>Timp3</italic><sup><italic>−/−</italic></sup> prostate tumors compared to <italic>Pten</italic><sup><italic>−/−</italic></sup>, <italic>Timp3</italic><sup><italic>+/+</italic></sup> tumors. Tumor cell invasion in <italic>Pten</italic><sup><italic>−/−</italic></sup>, <italic>Timp3</italic><sup><italic>−/−</italic></sup> 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.</p> </sec> <sec id="pros23056-sec-0004" sec-type="section"> <title>CONCLUSIONS</title> <p>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. <italic>Prostate 75:1831–1843, 2015</italic>. © 2015 Wiley Periodicals, Inc.</p> </sec> </abstract>