Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer
Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer
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DOI：
10.1002/pros.23056
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发表时间：
2015-12-01
期刊：
影响因子：
2.8
通讯作者：
Wood, Geoffrey A.
中科院分区：
文献类型：
--
作者：
Adissu, Hibret A.;McKerlie, Colin;Wood, Geoffrey A.
背景：蛋白酶的表达和活性改变与炎症和癌症进展有关。蛋白酶活性的一个重要负调节因子是TIMP3（金属蛋白酶3的组织抑制剂）。TIMP3在包括晚期前列腺癌在内的许多癌症中缺乏表达，这可能通过允许不受限制的蛋白酶活性来促进侵袭和转移。方法为了研究TIMP3在前列腺癌进展中的作用，我们将TIMP3缺陷小鼠（TIMP3(-/-)）与前列腺特异性缺失肿瘤抑制因子Pten（Pten(-/-)）的小鼠（一种已建立的前列腺癌小鼠模型）杂交。比较16周龄时Pten（-/-）、Timp3（-/-）和对照组(Pten（-/-）、Timp3（+/+）小鼠的肿瘤生长和进展，通过组织病理学、增殖、血管分布和肿瘤侵袭等标志物进行比较。用明胶酶谱法测定肿瘤内金属蛋白酶活性。采用免疫组化法检测巨噬细胞和淋巴细胞的炎症浸润，采用实时荧光定量PCR和多重ELISA法检测细胞因子和其他炎症介质的表达。结果与Pten（-/-）、Timp3（+/+）前列腺肿瘤相比，Pten（-/-）、Timp3（-/-）前列腺肿瘤的肿瘤生长、增殖指数、微血管密度增加、侵袭性增强。Pten（-/-）、Timp3（-/-）小鼠肿瘤细胞侵袭与基质金属蛋白酶(MMP)-9表达升高和MMP-2活化相关。timp3缺失的前列腺肿瘤中炎症细胞浸润明显增加，单核细胞趋化蛋白-1、环氧化酶-2、TNF-和白细胞介素-1的表达增加；所有这些都与炎症和癌症有关。结论本研究对蛋白酶活性改变在促进前列腺癌侵袭中的作用提供了重要的见解，并提示前列腺炎症是前列腺癌进展的重要促进因素。《中华医学会杂志》，2015。(c) 2015 Wiley期刊公司
BACKGROUNDAltered 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.METHODSTo 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.RESULTSIncreased 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-, and interleukin-1; all of which are implicated in inflammation and cancer.CONCLUSIONSThis 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. Prostate 75:1831-1843, 2015. (c) 2015 Wiley Periodicals, Inc.